Estrogenic endocrine disruptors: Molecular mechanisms of action

Environment International 83 (2015) 11–40

Contents lists available at ScienceDirect

Environment International journal homepage: www.elsevier.com/locate/envint

Review

Estrogenic endocrine disruptors: Molecular mechanisms of action Ryoiti Kiyama a,⁎, Yuko Wada-Kiyama b a b

Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan Department of Physiology, Nippon Medical School, Bunkyo-ku, Tokyo 113-8602, Japan

a r t i c l e

i n f o

Article history: Received 16 December 2014 Received in revised form 26 May 2015 Accepted 27 May 2015 Available online 11 June 2015 Keywords: Endocrine disruptor Estrogen action Molecular mechanism Techonology Signal transduction Toxicity pathway

a b s t r a c t A comprehensive summary of more than 450 estrogenic chemicals including estrogenic endocrine disruptors is provided here to understand the complex and profound impact of estrogen action. First, estrogenic chemicals are categorized by structure as well as their applications, usage and effects. Second, estrogenic signaling is examined by the molecular mechanism based on the receptors, signaling pathways, crosstalk/bypassing and autocrine/ paracrine/homeostatic networks involved in the signaling. Third, evaluation of estrogen action is discussed by focusing on the technologies and protocols of the assays for assessing estrogenicity. Understanding the molecular mechanisms of estrogen action is important to assess the action of endocrine disruptors and will be used for risk management based on pathway-based toxicity testing. © 2015 Elsevier Ltd. All rights reserved.

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . Estrogenic chemicals . . . . . . . . . . . . . . . . . . . 2.1. Structure-based categorization of estrogenic chemicals 2.1.1. Phenolic estrogens . . . . . . . . . . . . 2.1.2. Non-phenolic estrogens . . . . . . . . . . 2.1.3. Chemical basis for estrogen action . . . . . 2.2. Function-based categorization of estrogenic chemicals 2.2.1. Food additives/dietary supplements . . . . 2.2.2. Pesticides . . . . . . . . . . . . . . . . 2.2.3. Pharmacological estrogens . . . . . . . . . 2.2.4. Plasticizers . . . . . . . . . . . . . . . . 2.2.5. Pollutants . . . . . . . . . . . . . . . . Molecular mechanisms of estrogenic signaling . . . . . . . 3.1. Receptors . . . . . . . . . . . . . . . . . . . . 3.1.1. Nuclear receptors . . . . . . . . . . . . . 3.1.2. Membrane receptors . . . . . . . . . . . 3.1.3. Other membrane receptors . . . . . . . . 3.2. Cell functions and signaling pathways . . . . . . . . 3.2.1. Apoptosis . . . . . . . . . . . . . . . . 3.2.2. Carcinogenesis . . . . . . . . . . . . . . 3.2.3. Cell growth and proliferation . . . . . . . . 3.2.4. Differentiation/development . . . . . . . . 3.2.5. Inflammation . . . . . . . . . . . . . . . 3.3. Signaling networks . . . . . . . . . . . . . . . . 3.3.1. Crosstalk/bypassing . . . . . . . . . . . . 3.3.2. Autocrine/paracrine signaling . . . . . . . 3.3.3. Homeostatic networks . . . . . . . . . . .

⁎ Corresponding author. E-mail address: [email protected] (R. Kiyama).

http://dx.doi.org/10.1016/j.envint.2015.05.012 0160-4120/© 2015 Elsevier Ltd. All rights reserved.

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R. Kiyama, Y. Wada-Kiyama / Environment International 83 (2015) 11–40

4.

Evaluation of estrogen action . . . . . . 4.1. Assays for detecting estrogen action 4.1.1. Ligand-binding assay . . 4.1.2. Reporter-gene assay . . . 4.1.3. Yeast two-hybrid assay . 4.1.4. Transcription assay . . . 4.1.5. Protein assay . . . . . . 4.1.6. Cell assay . . . . . . . . 4.1.7. Animal test . . . . . . . 4.1.8. Signaling pathway analysis 4.2. Pathway-based risk assessment . . 5. Conclusion and future prospects . . . . . Acknowledgments . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . .

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Estrogen is a female hormone that plays a role in menstrual and estrous reproductive cycles. The role of estrogen is thus complex and includes involvement in the physiology of reproductive organs and tissues (e.g., breast, ovary and endometrium), lipid metabolism, protein synthesis, behavior (e.g., lordosis behavior) and diseases (e.g., cancer and neurodegenerative/cardiovascular diseases) (Deroo and Korach, 2006; Gillies and McArthur, 2010). While three major estrogens, estrone, estradiol and estriol, are known, there are a number of estrogenic chemicals of natural and industrial origins, as mostly characterized by comparing them with the major estrogens. Furthermore, estrogenic chemicals are those that are not only directly responsible for activating or inhibiting estrogen action, but also those indirectly modulating its action; thus, a variety of chemicals should be considered to understand its action. Estrogenic chemicals are thus considered as a type of important chemicals acting as an endocrine disruptor, which is defined as “an exogenous agent that interferes with the production, release, transport, metabolism, binding, action or elimination of natural

Extracellular Network

Non-genomic Pathway

Estrogen

Estrogen

Hormone/ GF/Cytokine

Membrane ER

Other Receptor

Autocrine/Paracrine Signaling

Crosstalk Bypassing Signaling Signaling Protein Proteins

Signaling Protein

Signaling-pathway Analysis (S)

Yeast Twohybrid Assay (Y) Pol II Co-regulator

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27 28 28 28 29 29 29 29 30 30 30 31 31 31

The mechanism of estrogenic signaling at the cellular level is summarized in Fig. 1 (see also Kiyama and Zhu, 2014; Kiyama et al., 2014). Estrogenic signal networks can be categorized into intracellular and extracellular types. The genomic pathway, which involves transcription of target genes, and the non-genomic pathway, which rapidly transduces signals mediated by membrane-bound estrogen receptors (ERs) and/

Genomic Pathway

Nuclear ER

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2. Estrogenic chemicals

Intracellular Network

Estrogen

. . . . . . . . . . . . . .

hormones in the body responsible for the maintenance of homeostasis and the regulation of developmental processes” (Kavlock et al., 1996). During our research for characterization of estrogenic chemicals, we found that quite a number of chemicals have been reported to be estrogenic. They were analyzed by a number of different assays and evaluated by different criteria to judge that they are estrogenic. Furthermore, their mechanisms of action seem to be quite complicated. As we failed to find a comprehensive list of estrogenic chemicals in literatures, we examined potentially estrogenic chemicals one by one to find why they were reported to be estrogenic.

1. Introduction

Ligand-binding Assay (L)

. . . . . . . . . . . . . .

Transcription

ERE

Target Gene

Reporter-gene Assay (R)

Transcription Assay (T)

Protein Protein Assay (P)

Function Cell Assay (C) Animal Test (A)

Fig. 1. Signaling pathways, crosstalk and autocrine/paracrine/homeostatic signaling networks of estrogenic chemicals.

R. Kiyama, Y. Wada-Kiyama / Environment International 83 (2015) 11–40

or other receptors through crosstalk and/or bypassing, belong to the former, while the pathways of autocrine and/or paracrine signaling, which involve other hormones, growth factors and cytokines, belong to the latter. The genomic pathway, or the classical pathway, is initiated by the binding of chemicals (or ligands) with the nuclear ERs, ERα and ERβ, and the ligand-bound ERs act as transcription factors to up-regulate or down-regulate the transcription of target genes or estrogen-responsive genes, in transcription machinery containing RNA polymerase II and co-regulators of transcription, such as RIP-140, p300/CBP and SRC-1 (Parker, 1998; Moggs and Orphanides, 2001). On the other hand, estrogen binds to the membrane or cytoplasmic receptors and stimulates signaling proteins through the non-genomic pathway, which occurs rapidly, sometimes just minutes after stimulation, and involves a number of signaling pathways. This type of signaling starts by the binding of ligands to membrane/cytoplasmic ERs, and several ERs, including G-protein-coupled estrogen receptor 1 (GPER), have been identified. However, several new receptors and variants of known receptors were identified, such as ER-X and ER-α36 (see Section 3), increasing the complexity of estrogenic signaling. Estrogenrelated receptors also mediate estrogenic signaling. Meanwhile, recent studies have revealed that intracellular networks cooperate with various types of autocrine and/or paracrine signaling, and thus cells in different tissues or locations are also involved in the extracellular networks (see Section 3). One of the reasons why a number of new signaling pathways were identified recently is the availability of a variety of new technologies to detect estrogenic chemicals (Fig. 1); they revealed the novel characteristics of chemicals, such as biphasic and metabolic effects detected by cell proliferation assay, the activity of selective estrogen-receptor modulators (SERMs) detected by cell assay and new estrogen-responsive genes detected by DNA microarray assay (see Section 4). Thus, estrogenic chemicals include chemicals or their metabolites that have not only estrogenic effects but also anti-estrogenic ones, and they transduce signals to estrogen signaling through crosstalk, bypassing and extracellular networks.

2.1. Structure-based categorization of estrogenic chemicals To understand the action of estrogenic chemicals at the molecular level, especially at the cell signaling level, we categorized estrogenic chemicals based on several characteristics. First, the estrogenic chemicals categorized by structure are summarized in Table 1. A number of estrogenic chemicals are phenolics, and phenolic estrogens include simple phenols, phenolic acids/phenolic aldehydes, acetophenones, tyrosine derivatives, phenylacetic acids, hydroxycinnamic acids, phenylpropenes, coumarins/isocoumarins/ chromones, naphthoquinones, bisphenols, benzophenones, stilbenes/stilbenoids, anthraquinones, chalcones/chalconoids, flavones/flavonoids, lignans/neolignans, diarylheptanoids, flavolans and hydroxylated polycyclic aromatic hydrocarbons (PAHs). On the other hand, chemicals without a phenolic ring can also show estrogenic activity, which include anilines, carboranes, indoles, metalloestrogens, perfluorinated compounds, phthalates, PAHs and terpenes/terpenoids (monoterpenes, sesquiterpenes, diterpenes, triterpenes, tetraterpenes, sterols, steroids, saponins and meroterpenes). While estrogenic or anti-estrogenic activity can be detected by various methods (see Section 4), they have limitations in their sensitivity (e.g., concentration-dependent activity), distinguishing agonists/ antagonists and specificity (e.g., cell/tissue types and signaling pathways). Thus, the same estrogenic chemicals can show contradictory results (listed in Tables 1 and 2), such as differences in estrogenic and anti-estrogenic, agonistic and antagonistic, and ligand/pathwaydependent and -independent responses, differences in increased and decreased gene expression or enzymatic activity, as well as differences

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in assay systems, which were reported for the chemicals summarized below. The list of chemicals showing contradictory results in estrogenicity. Phlorizin (Wang et al., 2010), quercetin/naringenin (Marino et al., 2012), naringin (Guo et al., 2011), epigallocatechin 3-gallate (Kuruto-Niwa et al., 2000), glabridin (Tamir et al., 2000), enterodiol/enterolactone (Feng et al., 2008), 3-methylcholanthrene (Swedenborg et al., 2008), abietic acid/botulin/β-sitosterol (Mellanen et al., 1996), methoxychlor (Lemaire et al., 2006), bifenthrin/permethrin (Brander et al., 2012), raloxifene (Lee et al., 2011), tamoxifen (Jiang et al., 1995; Obrero et al., 2002), PCBs (Zhang et al., 2014a) and BDE 47 (Karpeta et al., 2014).

Biphasic activity, where estrogenic activity was observed at low concentrations and anti-estrogenic activity at high concentrations, has been reported for phytoestrogens (Wang, 2002). Enterolactone, a lignin, stimulates DNA synthesis in MCF-7 cells at 10–50 μM, but inhibits it at higher concentrations. Enterolactone was shown to be a selective ER activator through its interaction with ER (Penttinen et al., 2007). SERMs are the chemicals that show differential (agonist or antagonist) effects on different tissues or cells, where the effects are based on the modulation of receptor functions by differential interactions between the receptor and the ligand, which would be beneficial for the treatment of hormone-responsive cancer and osteoporosis (Maximov et al., 2013). Such effects are likely to occur at downstream pathways, such as in the case of raloxifene (Lee et al., 2011) and tamoxifen (Jiang et al., 1995; Obrero et al., 2002), where ER-dependent and -independent modulations of signaling were observed. 2.1.1. Phenolic estrogens Phenolic estrogens are categorized by the number of skeletal carbons (Table 1; Vermerris and Nicholson, 2008). While phenol itself is not estrogenic, simple modifications, such as chlorination (pentachlorophenol), nitration (nitrophenol) and alkylation (nonylphenol), confer estrogenicity on the derivatives. The derivatives of phenolic acid and phenolic aldehyde, such as gallic acid, parabens, benzaldehydes, syringic acid and ellagic acid, show estrogenicity. More complex phenolics and their derivatives, including phenylethanoids (acteoside and martynoside), tyrosine derivatives (thyroid hormone), phenylacetic acid, naphthoquinones, bisphenols, benzophenones and phenylpropanoids, also show estrogenicity. Phenylpropanoids are a group of chemicals synthesized by plants from phenylalanine, and include hydroxycinnamic acids (caffeic acid and ferulic acid), phenylpropenes (anethole and eugenol), coumarins and related chemicals (auraptene, bergapten, daphnetin, esculetin, icariin and icaritin), stilbenes/stilbenoids, anthraquinones, chalcones/chalconoids and flavones/flavonoids (anthoxanthins, flavanones, flavanonols, flavans, anthocyanidines, isoflavones, isoflavanes, isoflavenes, coumestans, pterocarpans and flavonolignans). PAHs are known to show estrogenicity, which is partly explained by the presence of hydroxylated phenolic rings (3,9-benz[a]anthracene diols and cinanthrenol A; Table 2) or by the introduction of a hydroxyl group after hydroxylation or metabolization within a cell. 2.1.2. Non-phenolic estrogens A number of non-phenolics have been identified as estrogenic chemicals, which include anilines, carboranes (boron estrogens), indoles, metalloestrogens, perfluorinated compounds, phthalates, PAHs and terpenes/terpenoids (Table 1). Anilines are aromatic amines and used as precursors to polyurethane, synthetic dyes and other industrial chemicals. Because of similarities in their structure and biological activity, anilines were expected to show estrogenicity (Hamblen et al., 2003). Carboranes are a group of chemicals composed of boron, carbon and hydrogen atoms in polyhedral forms, and have advantages for designing new ER agonists/antagonists and SERMs due to their unique threedimensional structure and superior synthetic flexibility (Armstrong and Valliant, 2007). Indoles consist of a benzene ring fused to a pyrrole ring. Some indoles show estrogenicity without having a phenolic hydroxyl

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R. Kiyama, Y. Wada-Kiyama / Environment International 83 (2015) 11–40

Table 1 Estrogenic chemicals categorized by structure. Estrogenic chemical Phenolicb Simple phenol (C6) Alkylphenols (C6–C4–C6–C12) 3,4-Dichlorophenol, 4-tert-octylphenol, pentachlorophenol (agonist) 4-Nitrophenol (estrogenic) 4-Nitrophenol, 3-methyl-4-nitrophenol, 4-Nitro-3-phenylphenol (estrogenic) p-n-Nonylphenol, p-n-octylphenol Phenolic acid/phenolic aldehyde (C6–C1) Octyl gallate Parabens (methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutylparabens) 3-Phenoxybenzaldehyde (estrogenic) Syringic acid, ellagic acid Acetophenone (C6–C2) 2,2-Dimethoxy-2-phenyl-acetophenone (estrogenic) Phenylethane/phenylethanoid (C6–C2) Acteoside, martynoside (estrogenic) Tyrosine derivative (C6–C2) Thyroid hormone Phenylacetic acid (C6–C2) Phenylacetate (anti-estrogenic) Hydroxycinnamic acid (C6–C3) Caffeic acid phenethyl ester Caffeic acid phenethyl ester (SERM) Ferulic acid (estrogenic) Rhodoeosein (p-coumaric acid) (estrogenic) Phenylpropene (C6–C3) Anethole (estrogenic), eugenol (anti-estrogenic) Eugenol (antagonist) Coumarin/isocoumarin/chromone (C6–C3) 4-Aryl-coumarin dimer (estrogenic) Auraptene (anti-estrogenic) Bergapten (anti-estrogenic) Daphnetin, esculetin (anti-estrogenic) Icariin Icariin Icariin, icaritin (estrogenic) Isocoumarins (estrogenic) SP500263 (a synthetic SERM) Umbelliferone Naphthoquinone (C6–C4) Alkannin (shikonin) Juglone Juglone, lawsone, menadione, 1,4-naphthaquinone, plumbagin (antagonist) Menadione (vitamin K3) (anti-estrogenic) Menatetrenone (vitamin K2) Plumbagin Plumbagin Bisphenol (C6–C1–C6) Bisphenol A Bisphenols (A, B, F) (estrogenic) Bisphenol A, 4,4′-dihydroxybiphenyl, 4-hydroxybiphenyl, tetrabromobisphenol A, tetrachlorobisphenol A (estrogenic) Chlorinated bisphenol As (estrogenic) Benzophenone (C6–C1–C6) 2,4-Dihydroxybenzophenone, 2,2′,4,4′-tetrahydroxybenzophenone (agonist/antagonist) Stilbene/stilbenoid (C6–C2–C6) Piceatannol (estrogenic/anti-estrogenic) Piceid, pterostilbene, resveratrol Pinosylvin, isorhapontigenin, isorhapontin (estrogenic) Resveratrol Resveratrol Resveratrol Resveratrol Vitisin B (a resveratrol tetramer) Anthraquinone (C6–C2–C6) Aloe-emodin, emodin (anti-estrogenic) Anthraquinone, benzanthrone (estrogenic)

Signaling pathway

Reference (assaya)

ER ER

Tollefsen and Nilsen, 2008 (L) Li et al., 2010b (R)

ER ER

Li et al., 2006 (A) Taneda et al., 2004 (R)

ER/NF-κB/NO/inflammation

Yoshitake et al., 2008 (S)

ERα/PI3K/Akt/Alzheimer's disease ERα/PR/pituitary cancer

Zhang et al., 2013 (S) Vo et al., 2011 (S)

ER ER/NO/endothelial cells

McCarthy et al., 2006 (R) Simoncini et al., 2011 (S)

ER

Wada et al., 2004 (R)

ER

Papoutsi et al., 2006 (R)

TR/Integrin receptor/ERα/proliferation (crosstalk)

Meng et al., 2011 (S)

ER/CDKN1A/breast cancer

Liu et al., 2007 (S)

ERβ ERα, ERβ/ERK/Akt/apoptosis HER2/ERα/ERK/Akt/Cyclin D1/proliferation ERβ

Jung et al., 2010 (A, C, L, P, R) Tolba et al., 2013 (S) Chang et al., 2006 (S) Brennan et al., 2013 (R)

ER ER

Howes et al., 2002 (C) Anita et al., 2012 (L)

ER ER TGF-β/SMAD4/ERα/proliferation ER/proliferation ER/ERK/JNK/osteoblasts TGF-β/Smad/ERK/GPER/nephropathy GPER/EGFR/MAPK/proliferation ERβ ER/Osteoclastogenesis ER

Nishimura et al., 2000 (C, L) de Medina et al., 2010 (L, R, T) Panno et al., 2012 (S) Jiménez-Orozco et al., 2011 (A, C, P, T) Song et al., 2013 (S) Li et al., 2013a (S) Ma et al., 2014 (S) De Angelis et al., 2005 (L, R) Kung Sutherland et al., 2003 (S) Kirkiacharian et al., 2004 (L)

ERα/Nrf2/NQO1/DNA damage ER/Pin1/ERK/LC-3/autophagy ER

Yao et al., 2010 (S) Namgoong et al., 2010 (S) Thasni et al., 2013 (C, L, T)

ER ERα/vitamin K/leukemia ERα(46 kDa)/BRCA1/apoptosis NF-κB/Bcl-2/apoptosis

Jung et al., 2004 (L, R, Y) Nishiguchi et al., 1999 (S) Thasni et al., 2008 (S) Ahmad et al., 2008 (S)

GPER/ERK/c-Fos/transcription ER ERα

Dong et al., 2011 (S) Hashimoto et al., 2001 (C, L, Y) Olsen et al., 2003 (C, L, P)

ER

Hu et al., 2002 (L, Y)

ER

Ohta et al., 2012 (A)

ER/MAPK/ERK/Akt/PR/proliferation ERβ/oxidative stress ER ERα, ERβ/MAPK/atheroprotection ER/NO/cGMP/differentiation GPER/cAMP/PKC/K channels ERα/SIRT1/cAMP/inflammation ER/PDGF/cell adhesion

Vo et al., 2010 (S) Robb and Stuart, 2014 (S) Mellanen et al., 1996 (A, C) Klinge et al., 2005 (S) Song et al., 2006 (S) Dong et al., 2013b (S) Nwachukwu et al., 2014 (S) Ong et al., 2011 (S)

ERα/proliferation ERα

Huang et al., 2013 (S) Machala et al., 2001 (R)

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Table 1 (continued) Estrogenic chemical Anthraquinone (C6–C2–C6) 2,6-Dihydroxyanthraquinone (estrogenic) Emodin 2-Hydroxyanthraquinone (estrogenic) Mitoxantrone (estrogenic) Chalcone/chalconoid (C6–C3–C6) Candidachalcone Chalcone (anti-estrogenic) 2-Hydroxychalcone, 4-hydroxychalcone, 4′-hydroxychalcone (estrogenic) Isoliquiritigenin (estrogenic/anti-estrogenic) Licochalcone A (estrogenic) Nothofagin, (isovitexin; a flavone) (estrogenic) Phloretin (estrogenic) Phloretin Phlorizin (estrogenic/anti-estrogenic) Flavone/flavonoid (C6–C3–C6) Anthoxanthin (flavone and flavonol) Apigenin (anti-estrogenic) Apigenin Apigenin, luteolin Baicalein Baicalein, daidzein Baicalein, quercetin (anti-estrogenic) Fisetin, galangin, luteolin (estrogenic) Isorhamnetin, kaempferol, quercetin (estrogenic) Kaempferide (anti-estrogenic) Kaempferol (estrogenic) Luteolin (anti-estrogenic) Myricetin (estrogenic) β-Naphthoflavone Oroxylin-A Quercetin Quercetin, naringenin (differential effects) Quercetin, naringenin (anti-estrogenic) Wogonin Flavanone Chrysin (estrogenic) Hesperetin Liquiritigenin (agonist) Naringenin Naringenin (anti-estrogenic) Naringin (estrogenic) Naringenin Naringenin (agonist) Naringenin (anti-estrogenic) Naringenin, naringin (estrogenic/anti-estrogenic) Sakuranetin Flavanonol Astilbin, engeletin (estrogenic) Taxifolin (agonist) Flavan Epicatechin, epicatechin 3-gallate, epigallocatechin, epigallocatechin 3-gallate (estrogenic/anti-estrogenic) Epicatechin 3-gallate, epigallocatechin 3-gallate (estrogenic) Epigallocatechin 3-gallate Epigallocatechin 3-gallate (anti-estrogenic) Epigallocatechin 3-gallate (anti-estrogenic) Epigallocatechin 3-gallate (estrogenic) Epigallocatechin 3-gallate Epigallocatechin 3-gallate Anthocyanidin Cyanidin-3-glycoside (anti-estrogenic) Delphinidin Malvidin Isoflavone Biochanin A (estrogenic) Cajanin (estrogenic) Calycosin (anti-estrogenic) Calycosin, formononetin (anti-estrogenic) Daidzein Daidzein, genistein Daidzein, genistein, (apigenin, coumestrol) (agonist) Formononetin (agonist) Formononetin

Signaling pathway

Reference (assaya)

ER ERα/PI3K/Akt/JNK/Alzheimer's disease ER ERα

Matsuda et al., 2001 (C) Liu et al., 2010a (S) Kurihara et al., 2005 (Y) Oda et al., 2013 (T)

ER ERα/MAPK/JNK/MCF-7 cells ER

Hegazy et al., 2011 (L) Collins-Burow et al., 2012 (S) Kohno et al., 2005 (R)

ERα/cell growth ER ER ER Non-genomic ER/LXR/fatty liver ER

Maggiolini et al., 2002 (S) Rafi et al., 2000 (C) Shimamura et al., 2006 (P) Ise et al., 2005 (T) Han et al., 2014 (S) Wang et al., 2010 (C, Y)

ERβ ER/TNF-α/NO/Akt/vascular diseases ER ER/NF-ĸB/NO/TNF-α/inflammation ER/neuroprotection ER/IRS-1/ROS/ERK/JNK/proliferation ER ER ER ERα ERα/IGF-1/PI3K/Akt/proliferation ERα AhR/PI3K/Akt/MAPK/ERK/ERα/carcinogenesis ER/TNF-α/IL-1β/IL-6/NO/inflammation ERβ/cyclin D1/caspase-3/apoptosis ER Non-genomic ERα/ERK/proliferation ER/PARP/Bax/apoptosis

Mak et al., 2006 (C, R, T) Palmieri et al., 2014 (S) Innocenti et al., 2007 (R) Fan et al., 2013 (S) Choi et al., 2013 (S) Lin et al., 2007 (S) Resende et al., 2013 (C, R) Oh and Chung, 2004 (C, L, T) Collins-Burow et al., 2000 (L) Guo et al., 2012 (R, T) Wang et al., 2012 (S) Maggiolini et al., 2005 (L, P, R, T) Wang et al., 2014 (S) Wang et al., 2013c (S) Bulzomi et al., 2012b (S) Marino et al., 2012 (review) Virgili et al., 2004 (S) Chung et al., 2008 (S)

ERα TrkA receptor/MAPK/PKA/PKC/ERα/neuroprotection ERβ ERα,ERβ/MAPK/caspase-3/apoptosis mERα/ERK/PI3K/MAPK/proliferation ERα ERα/MAPK/Akt/caspase-3/apoptosis ER ERα/MAPK/proliferation ER ERβ

Berthier et al., 2007 (C, T) Hwang et al., 2012 (S) Mersereau et al., 2008 (L, R, T) Totta et al., 2004 (S) Galluzzo et al., 2008 (S) Pang et al., 2010 (C, P, R, T) Bulzomi et al., 2012a (S) Kim and Park, 2013 (C, R, T) La Rosa et al., 2014 (S) Guo et al., 2011 (A, C, L, Y) Tohno et al., 2010 (L)

ER ER

Wungsintaweekul et al., 2011 (C) Plísková et al., 2005 (R)

ER

Kuruto-Niwa et al., 2000 (R)

ER FOXO3a/ERα/invasion ER ER ERα ERα/ERK/Akt/Alzheimer's disease ER/MAPK/Akt/caspase-3/apoptosis

Goodin et al., 2002 (A, L, R) Belguise et al., 2007 (S) Farabegoli et al., 2007 (C, T) Laschke et al., 2008 (C, P) Li et al., 2010a (C, P, T) Fernandez et al., 2010 (S) Park et al., 2012 (S)

ER ERα/ Src/ERK/NO/vasodilation ER/NO/endothelial cells

Fernandes et al., 2010 (C, T) Chalopin et al., 2010 (S) Simoncini et al., 2011 (S)

ERα ER ERβ/IGF-1R/MAPK/PI3K/Akt/cell growth ERβ/IGF-1R/proliferation ERβ,GPER/neuroprotection ERα/TNF-α/NO/inflammation ER ER ER/Ras/MAPK/Bax/Bcl-2/apoptosis

Chan et al., 2007 (C, P, R, T) Umehara et al., 2008 (C, R) Chen et al., 2014a (S) Chen et al., 2013 (S) Kajta et al., 2013 (S) Nakaya et al., 2005 (S) Harris et al., 2005 (R) Ji et al., 2006 (C, R) Chen and Sun, 2012 (S) (continued on next page)

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Table 1 (continued) Estrogenic chemical Isoflavone Genistein, (quercetin) (estrogenic) Genistein Genistein Genistein (anti-estrogenic) Genistein (estrogenic) Glycitein (estrogenic) Irigenin, tectorigenin Irisolidone, tectorigenin (estrogenic) Puerarin Puerarin (estrogenic) Isoflavane Equol (estrogenic) Equol Equol, phenoxodiol Glabridin (estrogenic/anti-estrogenic) Isoflavene Glabrene, glabridin (estrogenic) Coumestan Coumestrol (anti-estrogenic) Coumestrol Psoralidin (agonist) Pterocarpan Glycinol (estrogenic) Glyceollins (antagonist) Medicarpin (estrogenic) Flavonolignan Silibinin (estrogenic) Lignan/neolignan ((C6-C3)2) Arctigenin Enterodiol, enterolactone (estrogenic/anti-estrogenic) Hydroxymatairesinol (estrogenic) Secoisolariciresinol (anti-estrogenic) Sesamin, sesamolin, sesamol (estrogenic) Diarylheptanoid (C6–C7–C6) Curcumin (estrogenic) Curcumin (anti-estrogenic) Flavolan (condensed tannin) ((C6-C3–C6)n) Propelargonidins (estrogenic) Estrogenic hydrocarbon without a phenolic ring Aniline Alkylanilines (4-amino-benzophenone, 4-aminobiphenyl, butyl-4-aminobenzoate) (estrogenic) Carborane (boron estrogen) Carboranes (agonist) 9,10-Dimethyl-m-carborane (SERM) Estrone 3-carboranylmethyl ether Indole 3,3′-Diindolylmethane Indole-3-carbinol (agonist) Indole-3-carbinol (anti-estrogenic) Indole-3-carbinol (anti-estrogenic) Melatonin (anti-estrogenic) Melatonin 2-Phenylindoles (anti-estrogenic) 2-Phenyl-isoindole-1,3-dione Serotonin Metalloestrogen Arsenic (anti-estrogenic) Arsenic trioxide (anti-estrogenic) Antimony chloride, barium chloride, bis(tri-n-butyltin), cadmium chloride, chromium chloride, lithium hydroxide (estrogenic) Cadmium Cadmium, calcium, chromium, cobalt, copper, lead, mercury, nickel, tin Cadmium, copper, zinc (estrogenic) Chromium, cobalt, copper, lead, mercury, nickel, tin, vanadate Selenium (anti-estrogenic) Perfluorinated compound Fluorotelomer alcohols (estrogenic) Fluorotelomer alcohols (6:2 FTOH, 8:2 FTOH, NFDH) (estrogenic)

Signaling pathway

Reference (assaya)

GPER/ERK/c-Fos/cell growth ERα, ERβ GPER/IL-1β/MAPK/inflammation ERα/IGF-1R/IRS-1/Akt/carcinogenesis ERα/MAPK/NF-κB/AP-1/differentiation ER ER/CDKN1B/apoptosis ER ER/PI3K/Akt/CaMKII/AMPK/NO/cardioprotection ER/ERK/PI3K/Akt/proliferation

Maggiolini et al., 2004 (S) Sotoca et al., 2011 (P, T) Luo et al., 2012 (S) Hwang et al., 2013 (S) Liao et al., 2014 (S) Song et al., 1999 (A, L) Morrissey et al., 2004 (S) Shin et al., 2006 (C, P, T) Hwang et al., 2011 (S) Wang et al., 2013a (S)

ERα/ERK/proliferation GPER/EGFR/ERK/Akt/NO/cardioprotection ER/RhoA/Rho kinase/vasorelaxation ER

Liu et al., 2010b (S) Rowlands et al., 2011 (S) Tilley et al., 2012 (S) Tamir et al., 2000 (A, C, L)

ER

Somjen et al., 2004a (A, C)

ER ERα, ERβ ER

Ndebele et al., 2010 (C, P) Chandsawangbhuwana and Baker, 2014 (L) Liu et al., 2014 (C, L, P, R, T)

ER ER ERβ/differentiation

Boué et al., 2009 (L, R, T) Burow et al., 2001 (C, L) Bhargavan et al., 2012 (S)

ERβ

Nejati-Koshki et al., 2012 (C, P, T)

ERα ER ER ER/EGFR/BCL2/cell growth ER

Jin et al., 2013 (L) Feng et al., 2008 (L) Cosentino et al., 2007 (C, T) Saggar et al., 2010 (S) Pianjing et al., 2011 (C, R, T)

ER Erβ/proliferation

Bachmeier et al., 2010 (P, T) Piccolella et al., 2014 (S)

ER

Chang et al., 2003 (C)

ER

Hamblen et al., 2003 (R)

ERα ER ER

Endo et al., 2001 (L, R) Ohta et al., 2014 (C, L) Sweet, 1981 (A, L)

AhR/ERα/endocrine disruption ER ER/proliferation ERα/IGF-1R/IRS-1/proliferation (crosstalk) MT1(GPCR)/ERα/proliferation (crosstalk) MT2/ER/cAMP/scoliosis ER ERβ Serotonin 1A receptor/GPER/depressive disorder

Liu et al., 2006 (S) Riby et al., 2000 (C, L, R, T) Ashok et al., 2001 (S) Marconett et al., 2012 (S) Kiefer et al., 2005 (S) Letellier et al., 2008 (S) Biberger and von Angerer, 1996 (A, L, R) Ullrich et al., 2007 (L) Li et al., 2013c (S)

ERα/VEGF/Cyclin D1/CDK4/reproduction ERα ER

Chatterjee and Chatterji, 2010 (S) Chow et al., 2004 (C, L, P, R, T) Choe et al., 2003 (C, R)

ER/ERK/cancer risk ER

Ali et al., 2012 (S) Byrne et al., 2013 (review)

ER ERα

Denier et al., 2009 (R) Martin et al., 2003 (C, L, R)

ERα

Lee et al., 2005 (C, L, P, R, T)

ER ER

Maras et al., 2006 (C, T) Ishibashi et al., 2007 (Y)

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Table 1 (continued) Estrogenic chemical Perfluorinated compound Perfluorooctanesulfonic acid Perfluorobutanesulfonic acid, perfluorooctanesulfonic acid (estrogenic) Perfluorooctanoate, perfluorohexane sulfonate, perfluorooctane sulfonate (estrogenic) Perfluorooctyl iodide Phthalate Bis(2-ethylhexyl) phthalate, butyl benzyl phthalate, diisononyl phthalate, di(n-butyl) phthalate (estrogenic) n-Butyl benzyl phthalate (estrogenic) Butyl benzyl phthalate, dibutyl phthalate, di(2-ethylhexyl) phthalate (estrogenic) Butyl benzyl phthalate (estrogenic) Butyl benzyl phthalate, dibutyl phthalate, diethyl phthalate, diisobutyl phthalate, diisiononyl phthalate (estrogenic) Butyl benzyl phthalate, dibutyl phthalate, diethyl phthalate, diisopropyl phthalate (estrogenic) Butyl benzyl phthalate, di(n-butyl) phthalate, di-hexyl phthalate (estrogenic) Di(n-butyl) phthalate (crosstalk) Polycyclic aromatic hydrocarbon (PAH) 3-Alkyl naphthalenes Anthracene, benz[a]anthracene, chrysene, benzo[b]fluoranthene, benzo[a]pyrene (estrogenic) Benz[a]acridine, benz[a]anthracene-7,12-dione (estrogenic) Cinanthrenol A Benz[a]anthracene, benzo[a]pyrene, fluoranthene (estrogenic) 3,9-Benz[a]anthracene diols Benzo[a]pyrene (estrogenic) 7,12-Dimethylbenz(a)anthracene 6-Hydroxy-chrysene, 2,3-benzofluorene, benzo[a]pyrene (anti-estrogenic) 2-Hydroxyfluorene, 2-hydroxyphenanthrene, n-propyl-p-hydroxybenzoate (estrogenic) 3-Methylcholanthrene (anti-estrogenic) 3-Methylcholanthrene (estrogenic/anti-estrogenic) Phenanthrenes (antagonist) Terpene/terpenoid Monoterpene Citral, geraniol, nerol (estrogenic) 3-(4-Methylbenzylidene) camphor Sesquiterpene Farnesol (estrogenic) Parthenolide Diterpene Retinoic acid Retinoic acid (anti-estrogenic) Triterpene Celastrol (anti-estrogenic) 27-Deoxyactein Tetraterpene β-Carotene, lycopene, phytoene, phytofluene (anti-estrogenic) Sterol Abietic acid, betulin, β-sitosterol (estrogenic/non-estrogenic) Cholesterol 25-Hydroxycholesterol 27-Hydroxycholesterol (SERM) Stigmasterol (estrogenic) Steroid Aldosterone (a mineralocorticoid) Progesterone (estrogenic) Progestin (estrogenic) Progestin (estrogenic) Testosterone Testosterone Testosterone Saponin Ginsenoside Rb1 Ginsenoside Rg1 Ginsenoside Rg1 (estrogenic) Ginsenoside Rg1

Signaling pathway

Reference (assaya)

ER/AhR/PPAR/endocrine disruption ER

Fang et al., 2012 (S) Lou et al., 2013 (A, T)

ER ER

Kjeldsen and Bonefeld-Jørgensen, 2013 (R) Wang et al., 2013d (A, T)

ER

Chen et al., 2014c (A)

ER ER ER ER

Hashimoto et al., 2000 (Y) Ghisari and Bonefeld-Jorgensen, 2009 (C, R) Picard et al., 2001 (C, L) Harris et al., 1997 (C, R)

ER

Parveen et al., 2008 (T)

ER

Zacharewski et al., 1998 (A, C, L, R)

ER/TGF-β/prostate cancer

Lee et al., 2014 (S)

ER ER

Fang et al., 2008 (L) Gozgit et al., 2004 (L, R, T)

ER ER ER

Machala et al., 2001 (R) Machida et al., 2014 (L) Kummer et al., 2008 (A)

ER ER/ERK/Akt/COX-2/proliferation ER ER

Anstead and Kym, 1995 (L) Tsai et al., 2004 (S) Garcia-Segura et al., 1992 (A) Tran et al., 1996 (R)

ER

Kamiya et al., 2005 (Y)

AhR/ER/endocrine disruption AhR/ER/endocrine disruption ER

Chaloupka et al., 1992 (S) Swedenborg et al., 2008 (S) Schmidt et al., 2003 (L, R)

ER ER

Howes et al., 2002 (R) Klann et al., 2005 (A, L)

Farnesoid X receptor/ER/proliferation NF-κB/ERα/inflammation

Journe et al., 2008 (S) Mahmoodzadeh et al., 2009 (S)

RAR/mER/MAPK/differentiation RARα/LSD1/PKA/ERα/proliferation

Kauss et al., 2008 (S) Ombra et al., 2013 (S)

ERα/Cyclin D1/PR/c-Myb/proliferation ERβ

Jang et al., 2011 (S) Onorato and Henion, 2001 (L)

ER

Hirsch et al., 2007 (C, P, R)

ER

Mellanen et al., 1996 (A, C)

LXRβ/ERα/PI3K/Akt/NO/metabolism ERα/HIF-1α/apoptosis ER/osteoporosis ER

Ishikawa et al., 2013 (S) Lappano et al., 2011 (S) DuSell et al., 2010 (S) Boldrin et al., 2013 (R)

GPER/Ca2+/bradycardia PR/ER/Src/ERK/PI3K/Akt/proliferation RP/ER/Src/Ras/ERK/proliferation (crosstalk) PR/ERβ/ERK/Akt/proliferation (crosstalk) ER-α36/ERK/Akt/carcinogenesis AR/ER/Alzheimer's disease AR/ER

Brailoiu et al., 2013 (S) Ballaré et al., 2006 (S) Migliaccio et al., 1998 (S) Vallejo et al., 2005 (S) Lin et al., 2009 (S) Rosario et al., 2010 (S) Vasconsuelo et al., 2011 (review)

ER/ERK/Akt/apoptosis ER/IGF-1R/neuroprotection ER ERα/MAPK/ERK/PI3K/Akt/Alzheimer's disease

Hashimoto et al., 2012 (S) Gao et al., 2009 (S) Chen et al., 2012 (A) Shi et al., 2012 (S) (continued on next page)

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Table 1 (continued) Estrogenic chemical Saponin Ginsenoside Rg1 (estrogenic) Ginsenoside Rg3 Ginsenoside Rh2 (estrogenic) Ginsenoside Re Gypenoside XVII Protopanaxadiol, protopanaxatriol Soysaponin I (estrogenic) Withaferin A Meroterpene Bakuchiol (estrogenic)

Signaling pathway

Reference (assaya)

ER ER/PI3K/Akt/AMPK/NO/cardioprotection ER ER/NO/K channel/vasodilation ER/PI3K/Akt/Nrf2/ARE/autophagy ERβ/GR/NO/cardioprotection ER ERα/MAPK/p53/apoptosis

Gao et al., 2014 (P, R, T) Hien et al., 2010 (S) Kovalchuk et al., 2006 (Y) Nakaya et al., 2007 (S) Meng et al., 2014 (S) Leung et al., 2009 (S) Ali et al., 2009 (R) Zhang et al., 2011 (S)

ER

Lim et al., 2011 (C, L, R)

Estrogenic chemicals categorized by structure are shown along with their effects, such as estrogenic and anti-estrogenic. a Abbreviations for assays are: animal test (A), cell-proliferation assay (C), ligand-binding assay (L), proten assay (e.g., Western blotting and immunoassay) (P), reporter-gene assay (R), signaling pathway analysis (S), transcription assay (e.g., RT-PCR and DNA microarray assay) (T) and yeast two-hybrid assay (Y). b Phenolics are categorized by the number of skeletal carbons according to Vermerris and Nicholson (2008). AhR: arylhydrocarbon receptor; AMPK: AMP-activated protein kinase; CaMKII: Ca2+/calmodulin-dependent protein kinase; EGFR: epidermal growth factor receptor; ER: estrogen receptor; ERK: extracellular signal-regulated kinase; FOXO: Forkhead box O; GPCR: G-protein-coupled receptor; GPER: G-protein-coupled estrogen receptor 1; GR: glucocorticoid receptor; HIF-1α: hypoxia-inducible factor 1; IGF-1R: insulin-like growth factor 1 receptor; IL: interleukin; IRS-1: insulin receptor substrate-1; JNK: c-Jun N-terminal kinase; LXR: liver X receptor; MAPK: mitogen-activated protein kinase; mER: membrane estrogen receptor; MT: melatonin receptor; NO: nitrogen oxide; PARP: poly(ADP-ribose) polymerase; PDGF: platelet-derived growth factor; PI3K: phosphoinositide 3-kinase; PKA: protein kinase A; PPAR: peroxisome proliferator-activated receptor; PR: progesterone receptor; RARα: retinoic acid receptor α; SERM: selective estrogen receptor modulator; TGF-β: transforming growth factor β; TNF-α: tumor necrosis factor α; TrkA receptor: neurotrophic tyrosine kinase receptor type 1.

group (Table 1). Metalloestrogens are inorganic metal ions that bind to and activate ERs, and are classified into groups of metal/metalloid anions and bivalent cationic metals (Byrne et al., 2013). Estrogenic activity has been reported for arsenic, antimony, barium, cadmium, calcium, chromium, cobalt, copper, lead, lithium, mercury, nickel, selenium, tin, vanadate and zinc (Table 1). Perfluorinated compounds, such as fluorotelomer alcohols and perfluorohexane/perfluorooctane sulfonates, are fluorocarbon-based oligomers, synthesized by telomerization. Volatile fluorotelomer alcohols form perfluorinated carboxylic acids, such as perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA), by biodegradation, which persist in the environment and are found in the blood of humans and wildlife. They have been shown to be estrogenic. Phthalate esters are esters of phthalic acid and alcohols, and widely used as plasticizers. Various phthalate esters, such as bis(2-ethylhexyl) phthalate, butyl benzyl phthalate, dibutyl phthalate, diethyl phthalate, diisobutyl phthalate, diisononyl phthalate and di(n-butyl) phthalate, were found to show estrogenicity by various technologies (Table 1). Finally, terpenes/terpenoids are a group of chemicals having isoprene units, (C5H8)n, and their derivatives, such as mono-, sesqui-, di-, triand tetra-terpenes, as well as a diverse group of meroterpenes/sterols/ steroids/saponins. Some of them are estrogenic (Table 1). 2.1.3. Chemical basis for estrogen action The structural basis of estrogenicity has been examined by comparing the activity of chemicals before and after substituting chemical groups. Anstead & Kym examined benz[a]anthracene and its analogs by molecular modeling, and found that a polycyclic planar ring system mimicking the steroid AB-ring is an important feature for the binding affinity for ERs and carcinogenicity (Anstead and Kym, 1995). Routledge & Sumpter examined the estrogenicity of alkylphenols with different structural features (differences in size, branching and position) by a yeast reporter gene assay, and found that alkylphenols substituted at the 4-position with 6- to 8-carbon-containing, tertiary alkyl groups exhibited higher activities (Routledge and Sumpter, 1997). By examining 120 aromatic chemicals, Schultz et al. found the importance of the hydroxyl groups at positions 3 (C3–OH; A-ring) and 17 (C17–OH; D-ring) of 17β-estradiol and hydrophobicity of its B- and C-rings (Schultz et al., 2002). Hamblen et al. further examined the importance of C3–OH by substituting it (4-substituted phenols) with the amino group (4-substituted anilines) and found that 4-substituted anilines showed activities at least 105 times lower than that of 17β-estradiol (Hamblen et al., 2003). C3–OH, which is present in 17β-estradiol, 17α-estradiol and 17α-ethinylestradiol but absent in mestranol and quinestrol, is suggested to confer anti-apoptotic behavior (Mann et al.,

2007) and to be important for the development of SERMs (Baker, 2013), while B-ring, which is saturated in the above compounds but unsaturated in equilin and equilenin, is associated with the affinity for ERs and the differential actions between ERα and ERβ (Bhavnani et al., 2008; Bhavnani and Stanczyk, 2014). 2.2. Function-based categorization of estrogenic chemicals Estrogenic chemicals can be categorized by applications, usage and effects (Table 2): They are related to various types of food additives/ dietary supplements, pesticides (antimicrobials/essential oils, biocides, disinfectants/sanitizers, fungicides, herbicides, insecticides, miticides, repellents, rodenticides and pheromones), pharmacological estrogens (mycoestrogens, nonsteroidals, pharmaceuticals, pure ER antagonists, SERMs and steroidals), plasticizers (phthalate/trimellitate/salicylate esters and organophosphates) and pollutants (heavy metals or metalloestrogens, persistent organic pollutants or POPs, pesticide residues, pharmaceutical pollutants and PAHs). Note that these categories are arbitrary, so many estrogenic chemicals may belong to more than one category. 2.2.1. Food additives/dietary supplements The categories of food additives and dietary supplements contain a number of chemicals with structural diversity (Table 2). The categories of active components, antioxidants/preservatives, color additives, cosmetics, emulsifiers/thickeners, flavor enhancers and vitamins consist of phenolics and chemicals having a phenolic ring (e.g., coumestrol, gallate, hydroxyanisole and tetrahydrocannabinol), unsaturated hydrocarbons (e.g., carotenes, linoleic acid and lycopene), azo compounds (e.g., tartrazine and sunset yellow), polysaccharides/sugar derivatives (e.g., carrageenan, cyclodextrins and guanylate), saponins (ginsenosides and notoginsenosides), and vitamins and their metabolites (e.g., niacin and tocopherols). The chemicals in these categories have roles in various biological effects: osteoporosis (caffeine; Zhou et al., 2009), apoptosis (geniposide; Li et al., 2014b), cardioprotection (nectandrin B; Hien et al., 2011), neuroprotection (notoginsenoside R1; Meng et al., 2014), vascular relaxation (notoginsenoside Ft1; Shen et al., 2014), cell proliferation (vitamin D; Gilad et al., 2005) and inflammation (niacin; Santolla et al., 2014). 2.2.2. Pesticides Pesticides are substances intended for preventing, destroying, repelling or mitigating any pest, and include avicides, bactericides, disinfectants (antimicrobials), fungicides, herbicides, insecticides, miticides, molluscicides, nematicides, predacides, piscicides, repellents,

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Table 2 Estrogenic chemicals categorized by applications, usage and effects. Estrogenic chemical Food additive/dietary supplement Active component Aurantio-obtusin, 6-hydroxymusizin (estrogenic); rubrofusarin, torachrysone, toralactone (anti-estrogenic) Caffeine (anti-estrogenic) Coumestrol, isoliquiritigenin, liquiritigenin (estrogenic) Geniposide Ginsenosides (see saponin in Table 1) γ-Linolenic acid (antagonist) Nectandrin B Notoginsenoside R1 Notoginsenoside Ft1 Antioxidant/preservative Butylated hydroxyanisole, propyl gallate (estrogenic) Semicarbazide (anti-estrogenic) Color additive β-Carotene, lycopene (anti-estrogenic) Lycopene Tartrazine, sunset yellow Cosmetic Talc Emulsifier/thickener Carrageenan (anti-estrogenic) β-Cyclodextrin Flavor enhancer Guanylate Δ9-Tetrahydrocannabinol (anti-estrogenic) Vitamin Niacin (vitamin B3) Retinoic acid (anti-estrogenic) Tocopherols (anti-estrogenic) Vitamin C (anti-estrogenic) Vitamin D Vitamin D Vitamin D analog (JK 1624 F2-2) Pesticide Antifouling agent Tributyltin Antimicrobial/essential oil Anethole, citral, geraniol, nerol (estrogenic) Eugenol (antagonist) 4-Hydroxyphenyl sulfonamides (anti-estrogenic) Biocide Hydroxytyrosol, oleuropein (anti-estrogenic) Disinfectants/sanitizer Chloroxylenol (dettol) (estrogenic) Hexachlorophene (anti-estrogenic) Nitrophenols (estrogenic) 4-Phenylphenol (agonist) Fungicide Biphenyl, chlordecone, diclofop-methyl, dieldrin, dodemorph, endosulfan, lindane, methyl parathion, PCBs, triadimefon (estrogenic) Boric acid (estrogenic) Brefeldin A Chlordecone (kepone), dicofol, fenarimol, methoxychlor, myclobutanil, nitrofen, pyridate (estrogenic) Conazoles (anti-estrogenic) Cypermethrin, malathion, propiconazole, prothioconazole, terbuthylazine (estrogenic) Dichlorophenyls (estrogenic) Diazinon, prothiofos, pyriproxyfen, thiabendazole, tolclofos-methyl (estrogenic) Dieldrin (estrogenic) Dieldrin, endosulfan, fenarimol, methiocarb, prochloraz (agonist) Diphenylamines (estrogenic) Fenarimol (estrogenic) Fenhexamid, fludioxonil (agonist) Flutolanil, isoprothiolane (estrogenic) Hexachlorobenzene (estrogenic) Mercuric chloride (estrogenic) PBDEs

Signaling pathway

Reference (assaya)

ER

El-Halawany et al., 2007 (C, L, Y)

ER/cAMP/PKA/osteoporosis ER mER/PI3K/MAPK/apoptosis

Zhou et al., 2009 (S) Hong et al., 2011 (R) Li et al., 2014b (S)

ER AMPK/ERα/PI3K/Akt/NO/cardioprotection ER/PI3K/Akt/Nrf2/ARE/neuroprotection GR/ER/ERK/Akt/NO/vascular relaxation

Menendez et al., 2004 (R) Hien et al., 2011 (S) Meng et al., 2014 (S) Shen et al., 2014 (S)

ER ER

ter Veld et al., 2006 (R) Maranghi et al., 2010 (C, R)

ER ER/RAR (crosstalk) ER

Prakash et al., 2001 (C, T) Chalabi et al., 2004 (C, T) Axon et al., 2012 (P, R, T)

ER

Frazier-Jessen et al., 1996 (A)

ER E2 (complex formed)

Misiewicz et al., 1996 (A) Oishi et al., 2008 (P, Y)

E2/ER/NO/cGMP/cell permeability ERα

Gorodeski, 2000 (S) Takeda, 2014 (review)

GPER/EGFR/ERK/inflammation ER E2/ER/PPARγ/Akt/breast cancer (crosstalk) ER ER/ERK/c-Jun/VDR/proliferation E2/ERα/PPARγ/VDR (crosstalk) ER

Santolla et al., 2014 (S) Boettger-Tong and Stancel, 1995 (A, T) Lee et al., 2009 (S) Mense et al., 2009 (A) Gilad et al., 2005 (S) Alimirah et al., 2012 (S) Somjen et al., 2004b (L)

ERα/MAPK/ERK/proliferation

Sharan et al., 2013 (S)

ER ER ER/NF-κB/inflammation

Howes et al., 2002 (L, R) Anita et al., 2012 (L) Sabatucci et al., 2006 (S)

ER/ERK/proliferation

Sirianni et al., 2010 (S)

ER ER ER ER

Houtman et al., 2004 (R) Jung et al., 2004 (L, R, Y) Furuta et al., 2004 (A, R) Li et al., 2010b (R)

ER

Petit et al., 1997 (L, R)

ER ER/ERK/Akt/P70S6K/cardioprotection ER

Wang et al., 2008b (A, C, L) Dong et al., 2013a (S) Okubo et al., 2004 (C)

ER ER

Kjærstad et al., 2010 (C) Kjeldsen et al., 2013 (R)

ER ER

von Angerer et al., 1980 (A) Manabe et al., 2006 (C, T)

ERα, ERβ, GPER/ERK/Akt/proliferation ER

Briz et al., 2011 (S) Andersen et al., 2002 (C, R)

ER ER ER ER ERα/IGF-1/proliferation ER ER

Ohta et al., 2008 (C, L) Andersen et al., 2006 (A, T) Medjakovic et al., 2014 (L) Oh et al., 2007 (C, P, T) García et al., 2010 (S) Zhang et al., 2008 (A, C, L) Li et al., 2013b (L) (continued on next page)

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Table 2 (continued) Estrogenic chemical Fungicide PCB3 (4-chlorobiphenyl) (estrogenic) Procymidone (estrogenic) Herbicide Atrazine (antagonist) Triclopyr (estrogenic) Glyphosate (estrogenic) Sulfonylureas Triazine (antagonist) Insecticide Aldicarb, bendiocarb, carbaryl, methomyl, oxamyl, propoxur (antagonist) Aldrin, quinalphos (estrogenic) Benomyl, chlordane, chlordecone, o,p′-DDT, dieldrin, endosulfan, endrin, fenarimol, fenbuconazole, fenvalerate, methoxychlor, trans-nonachlor, toxaphene, vinclozolin (estrogenic); aldrin, carbaryl, chlordecone, dieldrin, endosulfan, endrin, methoxychlor (anti-estrogenic) β-BHC, δ-BHC (agonist) Bifenthrin, permethrin (agonist/antagonist) Chlorpyrifos (estrogenic/anti-estrogenic) Chlorpyrifos, dieldrin, endosulfan, fenarimol, pirimicarb, prochloraz, tolchlofos-methyl (anti-estrogenic) Cyhalothrin, deltamethrin, fenvalerate, permethirn (estrogenic); cyfluthrin, etofenprox, permethrin (anti-estrogenic) Cypermethrin, fenvalerate, permethrin (estrogenic) Diazinon, prothiofos, pyriproxyfen, thiabendazole, tolclofos-methyl (estrogenic) Diazinon, prothiofos, pyriproxyfen, thiabendazole, tolclofos-methyl (estrogenic) Fenthion sulfoxide (estrogenic) Fenvalerate, sumithrin (estrogenic) Methoxychlor (estrogenic) Methoxychlor (estrogenic) Methoxychlor (estrogenic) Methoxychlor, triclosan Monocrotophos (estrogenic) Ryanodine Tetramethrin (anti-estrogenic) Miticide Dicofol (agonist) Repellent Cypermethrin, deltamethrin, fenvalerate, permethrin (estrogenic) Permethrin (estrogenic) Rodenticide Vitamin D Vitamin D (calcitriol) (anti-estrogenic) Pheromone Androstenol Pharmacological estrogen Mycoestrogen Zearalenone Zearalenone (estrogenic) Zeranol (α-zearalanol) (estrogenic) Zeranol (α-zearalanol) (estrogenic) Nonsteroidal Diarylpropionitrile Diarylpropionitrile Diethylstilbestrol Pharmaceutical Acetaminophen (estrogenic) Acetaminophen (anti-estrogenic) Acetaminophen (anti-estrogenic) Acetylsalicylic acid (aspirin) Amphipathic benzenes Bezafibrate, fenofibrate, gemfibrozil (estrogenic) Ephedrine (anti-estrogenic) Fluoxetine (estrogenic) Ibuprofen (anti-estrogenic) Isoproterenol Isoproterenol Oxybenzone (estrogenic) Tocotrienol (vitamin E)

Signaling pathway

Reference (assaya)

ERβ ER/MAPK/ROS/proliferation

Ptak et al., 2008 (P) Radice et al., 2006 (S)

ER ER ER mER/K channels/insulin secretion ERβ

Eldridge et al., 2008 (review) Xie et al., 2005 (P) Thongprakaisang et al., 2013 (C, P, R) Nadal et al., 1998 (S) Henke et al., 2002 (L, R)

ER

Klotz et al., 1997 (L, R)

ER ER

Chatterjee et al., 1992 (A, P, T) Lemaire et al., 2006 (C, R)

ERβ ER ERα ER

Kojima et al., 2004 (R) Brander et al., 2012 (A, P, R) Ventura et al., 2012 (C, P) Grünfeld and Bonefeld-Jorgensen, 2004 (C, T)

ER

Du et al., 2010 (C, R)

ER ER

Sun et al., 2014 (R) Kojima et al., 2005 (R)

ERα

Manabe et al., 2006 (C, T)

ER ER ER (ERα/ERβ-independent) ER/ERK/proliferation ERα ER/Cyclin D1/Ras/Bax/apoptosis ER Ryanodine receptor/ER/PKCε/PKA/Ca2+/ sweat gland ER

Yamada et al., 2010 (Y) Go et al., 1999 (C, T) Ghosh et al., 1999 (T) Park et al., 2009 (S) Lee et al., 2012 (C, T) Kim et al., 2014 (S) Tian et al., 2009 (A, P, T) Muchekehu and Harvey, 2008 (S)

ER

Hoekstra et al., 2006 (R)

ER

Chen et al., 2002 (C, L, T)

ER

Tange et al., 2014 (R)

ERβ/caveolin-1/ERK/VDR VDR/ER/proliferation

Gilad and Schwartz, 2007 (S) Swami et al., 2013 (S)

CAR/ER/GRIP-1/differentiation

Min et al., 2002 (S)

ER/Wnt/anti-reproduction ERα ERα ER

Wagner and Lehmann, 2006 (S) Li et al., 2012 (P, R, T) Liu et al., 2002 (T) Takemura et al., 2007 (A, L)

ERβ/cAMP/PKA/vasorelaxation ERβ/PI3K/Akt/vasorepression GPER/PKA/ERK/CREB/testis

Valero et al., 2011 (S) Wu et al., 2012 (S) Zhang et al., 2014b (S)

ER (indirect) ER ER ER ERα ERα ER ER ER β-Adrenoreceptor/ER/NO/cAMP/vasorelaxation β-Adrenoreceptor/ER/cardioprotection ER ERβ

Harnagea-Theophilus et al., 1999 (A, L) Dowdy et al., 2003 (C, P, R) Schwartz-Mittelman et al., 2005 (R, Y) van Aswegen et al., 1992 (L) Gunther et al., 2008 (R) Isidori et al., 2009 (C, R) Arbo et al., 2009 (A) Müller et al., 2012 (A, R) Sibonga et al., 1998 (A) Chan et al., 2002 (S) Walters and Sharma, 2003 (S) Coronado et al., 2008 (A, P) Comitato et al., 2009 (L, P, T)

Kim et al., 2005 (A, T)

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Table 2 (continued) Estrogenic chemical Pure ER antagonist 1,1-Dichloro-2,2,3-triarylcyclopropanes (agonist) Fulvestrant (ICI 182,780) (anti-estrogenic) Fulvestrant (ICI 182,780) (anti-estrogenic) Fulvestrant (ICI 182,780) Fulvestrant (ICI 182,780) Selective estrogen receptor modulator (SERM) Arzoxifene, bazedoxifene, droloxifene, EM-800, HMR-3339, idoxifene, lasofoxifene, levormeloxifene, ormeloxifene, ospemifene, pipendoxifene, raloxifene, tamoxifen, toremifene Clomifene, tamoxifen Femarelle Melatonin Raloxifene Raloxifene Raloxifene Raloxifene, tamoxifen Tamoxifen Tamoxifen Tamoxifen (anti-estrogenic) Tamoxifen Steroidal 17β-Dihydroequilenin, 17β-dihydroequilin, equilenin, Δ8,17β-E2 Equilin (estrogenic) Equilin, equilenin Equilin, equilenin Estetrol (E4) (SERM) 17α-E2 17α-E2 17β-E2 Estradiolquinone (estrogenic) Estrone (E1), estradiol (E2), estriol (E3) 17α-Ethinylestradiol, 17β-E2 valerate (estrogenic) Mestranol, quinestrol Moxestrol Plasticizer Dicarboxylic ester (see phthalate in Table 1) Organophosphate Tricresyl phosphate, triphenyl phosphate (agonist) Salicylate ester Benzyl salicylate Tricarboxylic ester (trimellitate) Tris(2-ethylhexyl) trimellitate (estrogenic) Pollutant Heavy metal (see metalloestrogen in Table 1) Persistent organic pollutant (POP) Aroclor 1221, PCB180 (estrogenic) Aroclor 1254 o,p′-DDD, p,p′-DDD, alachlor (estrogenic) DDE p,p′-DDE, o,p′-DDT, β-HCH (estrogenic) o,p′-DDT (estrogenic) Dioxins β-HCH Hexabromocyclododecane (HBCD) (estrogenic) Hydroxylated PBDEs (agonist) Hydroxylated PCBs (agonist) 6-Methyl-1,3,8-trichlorodibenzofuran, 3,3′,4,4′-tetrachlorobiphenyl (SERM) Monohydroxylated PCBs (estrogenic) PBDEs (estrogenic) PCB104, HO-PCB104 (estrogenic); PCB155 (anti-estrogenic) PCB118 (estrogenic) PCB126 (estrogenic) PCBs (agonist/antagonist) 3,3′,4,4′,5-Pentachlorobiphenyl (agonist) Polychlorinated dibenzofurans (anti-estrogenic) TCDD (anti-estrogenic) Tetrabromodiphenyl ether (BDE 47) (estrogenic) Tetrabromodiphenyl ether (BDE 47) (estrogenic/anti-estrogenic)

Signaling pathway

Reference (assaya)

ERα ERα/Wnt/β-catenin/carcinogenesis ER/HER/c-Src/proliferation GPER/TGF-β1/Smad/migration GPER/ERK/calpain/cell adhesion

Cheng et al., 2004 (L, R) Cao et al., 2014 (S) Kirkegaard et al., 2014 (S) Li et al., 2014a (S) Chen et al., 2014b (S)

ER

Shelly et al., 2008 (review)

ER ER ER ROS/MAPK/CREB/HO-1/inflammation (ER-independent) ER/TNF-α/ERK/caspase-3/apoptosis GPER/Akt/Bcl-2/neuroprotection mER/ERK/NF-κB/cell protection Cell growth (ER-independent) ER/apoptosis (ER-dependent/independent) ERα/IGF-1R/EGFR/MAPK/proliferation ERα/Wnt3A/β-catenin/differentiation

Han et al., 2002 (C, P) Somjen et al., 2007 (A, P) Cos et al., 2008 (review) Lee et al., 2011 (S) Hattori et al., 2012 (S) Bourque et al., 2014 (S) Stice et al., 2012 (S) Jiang et al., 1995 (C, P, T) Obrero et al., 2002 (S) Santen et al., 2009 (S) Gao et al., 2013 (S)

ERβ

Bhavnani et al., 2008 (L, P, R)

ER/NMDA receptor/cell growth ER/NO/cardioprotection ERβ/antioxidant/apoptosis ER/Actin/migration ER-X/MAPK/ERK/PI3K/Akt/brain mER/Rho/ROCK/cofilin/neuroprotection mER/Natriuretic peptide receptor A/cGMP/Ca2+/hepatocytes ER/LTD4 receptor/differentiation mER/ERK/Ca2+/proliferation ER/MAPK/cell growth ER/ROS/apoptosis SXR/CAR/ERα/metabolism

Brinton et al., 1997 (S) Novensa et al., 2010 (S) Bhavnani and Stanczyk, 2014 (S) Giretti et al., 2014 (S) Toran-Allerand et al., 2005 (S) Hirahara et al., 2013 (S) Stratton et al., 2010 (S) Dietsch et al., 1996 (S) Watson et al., 2008 (S) Prifti et al., 2003 (S) Mann et al., 2007 (S) Min, 2010 (S)

ER

Kojima et al., 2013 (R)

ER

Hashimoto et al., 2003 (C)

ER

ter Veld et al., 2006 (R)

ER ERα/cyclin D1/Bcl-2/caspase-3/apoptosis ER mER/ERK/reproduction ER/Src/ERK/proliferation ER AhR/ERα/endocrine disruption ER ER ER ER AhR/ERα/endocrine disruption

Uslu et al., 2013 (A) Qu et al., 2014 (S) Klotz et al., 1996 (L, R) Bulayeva and Watson, 2004 (S) Silva et al., 2010 (S) Uchida et al., 2010 (A, T) Ahmed et al., 2009 (S) Steinmetz et al., 1996 (L, R) Dorosh et al., 2011 (C, T) Meerts et al., 2001 (R) Connor et al., 1997 (A, C, P, R) Liu et al., 2006 (S)

ERα ERα ER

Arulmozhiraja et al., 2005 (Y) Mercado-Feliciano and Bigsby, 2008 (L, R) Fielden et al., 1997 (A, C, L, R)

ER ER ER ER ER ER ER ER

Garritano et al., 2006 (R) Mortensen and Arukwe, 2008 (P) Zhang et al., 2014 a (C, R, Y) Abdelrahim et al., 2006 (P, R, T) Krishnan and Safe, 1993 (P) Tian et al., 1998 (T) Dang et al., 2007 (A, P, T) Karpeta et al., 2014 (P, T)

(continued on next page)

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Table 2 (continued) Estrogenic chemical

Signaling pathway

Reference (assaya)

Pesticide residue (see pesticide shown above) Pharmaceutical pollutant (see pharmacological estrogen shown above) Polycyclic aromatic hydrocarbon (see Table 1) Estrogenic chemicals categorized by applications, usages and effects are shown along with their effects, such as estrogenic and anti-estrogenic. Characterization of estrogenicity, such as estrogenic/anti-estrogenic and agonist/antagonist, is based on the description in each reference. Only a representative category for each chemical is shown. a Abbreviations for assays are: animal test (A), cell-proliferation assay (C), ligand-binding assay (L), proten assay (e.g., Western blotting and immunoassay) (P), reporter-gene assay (R), signaling pathway analysis (S), transcription assay (e.g., RT-PCR and DNA microarray assay) (T) and yeast two-hybrid assay (Y). AhR: arylhydrocarbon receptor; BHC: benzene hexachloride; CAR: constitutive androstane receptor; DDD: dichlorodiphenyldichloroethane; DDE: dichlorodiphenyldichloroethylene; DDT: dichlorodiphenyltrichloroethane; E2: estradiol; ER: estrogen receptor; ERK: extracellular signal-regulated kinase; GPER: G-protein-coupled estrogen receptor 1; HCH: hexachlorocyclohexane; IGF-1R: insulin-like growth factor 1 receptor; IRS-1: insulin receptor substrate-1; MAPK: mitogen-activated protein kinase; mER: membrane estrogen receptor; NO: nitrogen oxide; PBDE: polybrominated diphenyl ether; PCB: polychlorinated biphenyl; PI3K: phosphoinositide 3-kinase; PKA: protein kinase A; PKC: protein kinase C; PPAR: peroxisome proliferator-activated receptor; RAR: retinoic acid receptor; ROS: reactive oxygen species; SERM: selective estrogen receptor modulator; SXR: steroid and xenobiotic receptor; TCDD: 2,3,7,8-tetrachlorodibenzo-p-dioxin; TGF-β: transforming growth factor β; TNF-α: tumor necrosis factor α; VDR: vitamin D receptor; VEGF: vascular endothelial growth factor.

rodenticides, defoliants, desiccants and growth regulators (Randall et al., 2013). The pesticides within a particular class may share a common mode of action due to their structural similarity, and several chemical groups, such as carbamates, organochlorides, organometallic compounds, organophosphates, pyrethroids and sulfonylureas, have been used. Many of them show estrogenic activity (Table 2), such as those summarized below. The list of pesticides showing estrogenic activity. Aldicarb, bendiocarb, carbaryl, methiocarb, methomyl, oxamyl, pirimicarb and propoxur (carbamates); aldorin, atrazine, chlordane, chlordecon, chloroxylenol, DDT, dichlorophenyls, dicofol, dieldrin, endosulfan, endrin, fenarimol, fenvalerate, hexachlorobenzene, hexachlorocyclohexanes, hexachlorophene, methoxychlor, nitrofen, procymidone, propiconazole, terbuthylazine, toxaphene, triadimefon, triclopyr, triclosan and vinclozolin (organochlorides); tributyltin (an organometallic compound); chlorpyrifos, diazinon, fenthion, malathion, parathion and quinalphos (organophosphates); eugenol, nitrophenol and 4-phenylphenol (phenolics); bifenthrin, cyfluthrin, cyhalothrin, cypermethrin, deltamethrin, etofenprox, permethrin, sumithrin and tetramethrin (pyrethroids); and sulfonylureas.

Estrogenic pesticides bind to ERs and affect the downstream signaling pathways, such as the ER/ERK pathway for cell proliferation (tributyltin, hydroxytyrosol, oleuropein, diedrin, procymidone and methoxychlor), the ER/ERK/Akt/P70S6K pathway for cardioprotection (brefeldin A), the ER/IGF-1 pathway for cell proliferation (hexachlorobenzene), the membrane ER/K channel pathway for insulin secretion (sulfonylurea), the ER/cyclin D1/Ras/Bax pathway for apoptosis (methoxychlor) and the ryanodine receptor/ER/PKCε/PKA/Ca2+ pathway in the sweat gland (ryanodine). Note that the same chemical may act as an estrogenic or an anti-estrogenic depending on the assay used (e.g., bifenthrin, chlorpyrifos and permethrin) or the receptors involved (such as methoxychlor) (see Table 2). 2.2.3. Pharmacological estrogens Pharmacological estrogens can be categorized into the groups of mycoestrogens, nonsteroidals, pharmaceuticals, pure ER antagonists, SERMs and steroidals (Pazaiti et al., 2012). Mycoestrogens are estrogens produced by fungi, and include zearalenone, which is widely contaminated in agricultural products as a mycotoxin. Zearalenone and its derivatives interact with ERα and ERβ in a manner similar to estrogen and thus have been used as anabolic agents for animals and also proposed for hormonal replacement therapy in postmenopausal women or as oral contraceptives (Pazaiti et al., 2012). A number of pharmaceuticals, such as those used for the replacement or addition of estrogen (diethylstilbestrol, pure ER agonists, SERMs and steroids) or for other purposes (acetaminophen, aspirin, bezafibrate, ephedrine, fenofibrate, gemfibrozil and tocotrienol), are estrogenic (Table 2). Note that a number of chemicals other than those listed in Table 2 have been reported to be SERMs, which include those categorized as synthetic estrogens and phytoestrogens, such as bisphenol A, methoxychlor, naringenin, nonylphenol, octylphenol and resveratrol, based on the differences in

gene activation in different cells (Ruh et al., 1995; Gould et al., 1998; Gaido et al., 1999; Yoon et al., 2001; Safe et al., 2001). 2.2.4. Plasticizers Plasticizers are used to increase the plasticity or fluidity of mainly plastics, and some dicarboxylic and tricarboxylic esters, such as phthalate and trimellitate esters, salicylate esters, such as benzyl salicylate (a tissue conditioner), and organophosphates, such as tricresyl phosphate and triphenyl phosphate, used as plasticizers, show estrogenicity (Table 2). Phthalates and trimellitates are di- or tri-carboxylic acid derivatives of benzene, respectively, and they do not have a phenolic hydroxyl group. Estrogenicity is increased when the mass of participating alcohols in esters becomes large (Parveen et al., 2008). Meanwhile, organophosphates are phosphoric acid esters of alcohols and used widely for solvents, pesticides and plasticizers, but they may cause adverse neuropsychiatric and neurological effects, such as on the neurobehavioral development of fetuses and children, by inhibiting acetylcholinesterase in nerve cells (Chen, 2012). Tricresyl phosphate and triphenyl phosphate are esters of cresol or phenol, respectively, and while there is no phenolic ring, they interact with the ER and show anti-proliferative effects through the NF-κB pathway (Sabatucci et al., 2006). 2.2.5. Pollutants Pollutants can be tentatively categorized into heavy metals and organic compounds, although any compounds found in the environment can be considered as pollutants. The organic pollutants include POPs (Wang and Needham, 2007), pesticide residues, pharmaceutical pollutants and PAHs, such as the chemicals derived from industrial products, including pesticides, pharmaceuticals, plastics and volatile organic compounds (e.g., those in paint and coatings), and their derivatives, and most of the categories include estrogenic chemicals (Table 2). Estrogenic chemicals of industrial origins are those listed in the categories of pesticides, pharmacological estrogens and plasticizers (see above), while those of other industrial origins or their byproducts are DDT, dioxins/dioxin-like compounds (Aroclors, PCBs and TCDD), hexachlorocyclohexanes (HCHs) and PBDEs/PCDEs. 3. Molecular mechanisms of estrogenic signaling The mechanism of estrogenic signaling can be divided into pathways and networks (Fig. 1). The pathways that direct the signal to specific functional outcomes, such as apoptosis, carcinogenesis, cell growth/proliferation, differentiation/development and inflammation, are mostly initiated by the binding of estrogen or estrogenic chemicals to ERs. ERs can be classified into the groups of nuclear and membrane receptors, which transduce signals through various pathways (Table 3). Specific signaling pathways, such as PI3K, MAPK/ERK and NF-κB signaling (Ribeiro and Freiman, 2014), can be found in the pathways for different outcomes as functional modules, where specific signaling pathways and functional outcomes can be selected by selecting specific effectors.

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Table 3 Estrogen-signaling pathways categorized by receptors and the ways of signaling. Receptor signaling pathway Nuclear receptor Estrogen receptor α (ERα) (see Tables 1 and 2) 4,4′,4″-(4-Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT)/ERα Estrogen receptor β (ERβ) (see Tables 1 and 2) 2,3-Bis (4-hydroxyphenyl)-propionitrile (DPN)/ERβ Estrogen-related receptor (ERR) Apigenin, kaempferol (antagonist)/ERRγ Biochanin A, daidzein, genistein (agonist)/ERRα; chlordane, toxaphene (antagonist)/ ERRα; diethylstilbestrol (antagonist)/ERRα, ERRβ, ERRγ Chlordane, toxaphene (antagonist)/ERRα Kaempferol (antagonist)/ERRα, ERRγ Resveratrol/ERα/ERRα/respiratory chain Membrane/cytosolic receptor G-protein-coupled estrogen receptor (GPER) (see Tables 1 and 2) E2/GPER/Serotonin 1A receptor/mood disorders E2/GPER/serotonin 1A receptor/desensitization E2/GPER/serotonin 1A receptor/hippocampus Genistein, bisphenol A, kepone, nonylphenol, zearalenone/GPER ER-X 17α-E2/ER-X 17α-E2/ER-X/MAPK/differentiation 17α-E2/ER-X/MAPK/ERK/PI3K/Akt/brain 17α-E2, 17β-E2/ER-X/Ca2+ channel/contraction ER-α36 E2/ER-α36/breast cancer E2/ER-α36/MAPK/ERK/HER2/stem cells E2/ER-α36/MAPK/ERK/breast cancer E2/ER-α36/c-Src/proliferation Testosterone/ER-α36/ERK/Akt/carcinogenesis Other DDE/mER/ERK/reproduction 17α-E2/mER/Rho/ROCK/cofilin/neuroprotection 17α-E2, 17β-E2/new ER/MAPK/ERK/fibroblasts 17β-E2/mER/natriuretic peptide receptor A/cGMP/Ca2+/hepatocytes Estrone (E1), estradiol (E2), estriol (E3)/mER/ERK/Ca2+/proliferation Geniposide/mER/PI3K/MAPK/apoptosis mER/hypothalamus mER/signalosome (IGFR, EGFR, Ras, c-Src, etc.)/second messengers Naringenin/mERα/ERK/PI3K/MAPK/proliferation Raloxifene, tamoxifen/mER/ERK/NF-κB/cell protection Retinoic acid/RAR/mER/MAPK/differentiation Sulfonylurea/mER/K channels/insulin secretion Other receptor/signaling (crosstalk) AhR Biochanin A, formononetin/AhR/ER/cancer prevention 3-Methylcholanthrene/AhR/ER/endocrine disruption β-Naphthoflavone/AhR/ERα/hepatocytes (bypassing) β-Naphthoflavone/AhR/PI3K/Akt/MAPK/ERK/ERα/carcinogenesis TCDD/AhR/E2/ER/proteasome-mediated degradation TCDD/AhR/E2/ER/transcription AR/PR EGF/EGFR/AR/ER/Src/DNA synthesis Genistein/AR/ER/transcription Piceatannol/ER/MAPK/ERK/Akt/PR/proliferation Progesterone/PR/ER/Src/ERK/PI3K/Akt/proliferation Progesterone, E2/PR/ER Progesterone, E2/PR/ER Progestin/PR/ERβ/ERK/Akt/proliferation IGF-1R Calycosin, formononetin/ERβ/IGF-1R/proliferation E2/ERα/IRS-1/IGF-1R/PI3K/Akt/carcinogenesis Genistein/ERα/IGF-1R/IRS-1/Akt/proliferation Ginsenoside Rg1/ER/IGF-1R/neuroprotection Indole-3-carbinol/ERα/IGF-1R/IRS-1/proliferation Resveratrol/ERα/IGF-1R/IRS-1/Akt/cyclin D1/endocrine disruption Other Androstenol/CAR/ER/GRIP-1/differentiation Bergapten/TGF-β/SMAD4/ERα/proliferation Cholesterol/LXRβ/ERα/PI3K/Akt/NO/metabolism Epigallocatechin gallate + curcumin/EGFR/VEGFR-1/ERα/cell growth Ethanol/adenosine receptor/ERα/proliferation (ligand-independent) Hesperetin/TrkA receptor/MAPK/PKA/PKC/ERα/neuroprotection Isoproterenol/β-adrenoreceptor/ER/NO/cAMP/vasorelaxation

Reference

Stauffer et al., 2000 Meyers et al., 2001 Huang et al., 2010 Ariazi and Jordan, 2006

Yang and Chen, 1999 Wang et al., 2013e Lopes Costa et al., 2014

Xu et al., 2009 McAllister et al., 2012 Akama et al., 2013 Thomas and Dong, 2006 Soltysik and Czekaj, 2013 (review) Toran-Allerand et al., 2002 Toran-Allerand et al., 2005 Ullrich et al., 2008 Rao et al., 2011 (review) Kang et al., 2011 Zhang et al., 2014c Wang et al., 2013b Lin et al., 2009 Bulayeva and Watson, 2004 Hirahara et al., 2013 Nethrapalli et al., 2005 Stratton et al., 2010 Watson et al., 2008 Li et al., 2014b Micevych and Kelly, 2012 (review) Soltysik and Czekaj, 2013 (review) Galluzzo et al., 2008 Stice et al., 2012 Kauss et al., 2008 Nadal et al., 1998

Medjakovic and Jungbauer, 2008 Chaloupka et al., 1992 Gräns et al., 2010 Wang et al., 2014 Wormke et al., 2003 Krishnan et al., 1995 Migliaccio et al., 2006 Takahashi et al., 2006 Vo et al., 2010 Ballaré et al., 2006 Katzenellenbogen, 2000 (review) Thakkar and Mehta, 2011 (review) Vallejo et al., 2005 Chen et al., 2013 Tian et al., 2012 Hwang et al., 2013 Gao et al., 2009 Marconett et al., 2012 Kang et al., 2013 Min et al., 2002 Panno et al., 2012 Ishikawa et al., 2013 Somers-Edgar et al., 2008 Etique et al., 2009 Hwang et al., 2012 Chan et al., 2002 (continued on next page)

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Table 3 (continued) Receptor signaling pathway Other (continued) Melatonin/α1/β-adrenoceptor/ER/cAMP/pinealocytes Methyl-amoorain + DMBA/ER/Wnt/β-catenin/carcinogenesis Protopanaxadiol, protopanaxatriol/ERβ/GR/NO/cardioprotection Resveratrol/ER/TGF-β2/Smad/lung epithelial cells Ryanodine/ryanodine receptor/ER/PKCε/PKA/Ca2+/sweat gland Tamoxifen/EGFR/HER2/MAPK/Akt/ER/proliferation Thyroid hormone/TR/ERα/proteolysis Thyroid hormone/TR/integrin receptor/ERα/proliferation Autocrine/paracrine signaling Autocrine signaling E2/ER/Akt/IGF-1R/InsR/breast cancer E2/ER/ERBB4/PR/cell growth E2/ER/IGF/IGF-1R/breast cancer E2/ER/IGF-1R/MAPK/cyclin D1, cyclin E/cell growth E2/ER/MAPK/PDGF/PDGFR/proliferation E2/ER/PDGF/PDGFR/ERK/proliferation Exemestane/ER/amphiregulin/EGFR/MAPK/proliferation Wnt/EGFR/ERK/ER/proliferation (crosstalk) Paracrine signaling Adiponectin/APNR/ERβ/differentiation E2/ER/Factor X/coagulation factor VII/Thrombin/development E2/ER/FGF/FGFR/Tbx3/carcinogenesis E2/ER/TGF-β1/TGF-βR/Smad2/thyroid E2/ER/Wnt/β-catenin/AXIN2/proliferation E2/ERα/JNK/cardioprotection MCP-1/CCRs/PI3K/Akt/mTOR/ERα/proliferation (ligand-independent) Autocrine/paracrine signaling Androgen/AR/E2/ERα, ERβ/spermatogenesis E2/ER/ANF/ANF receptor/cGMP/anti-hypertrophy E2/ER/IGF-1/IGF-1R/osteoblasts E2/ER/NF-κB/cytokines/cytokine receptors/inflammation, etc. E2/ER/STAT3/IL-6/IL6R/apoptosis E2/ERα/CXCL12/CXCR4/MAPK/proliferation E2/ERβ/CXCL12/CXCR4/MAPK/proliferation 17α-E2/ER-X/MAPK/ERK/PI3K/Akt/brain

Reference Hernández-Díaz et al., 2001 Mandal et al., 2013 Leung et al., 2009 Suenaga et al., 2008 Muchekehu and Harvey, 2008 Osborne et al., 2005 (review) Alarid et al., 2003 Meng et al., 2011

Fox et al., 2013 Zhu et al., 2006 Hamelers et al., 2003 Kashima et al., 2009 Barbarisi et al., 2001 Finlay et al., 2003 Wang et al., 2008a Schlange et al., 2007 Rahal and Simmen, 2011 Jazin et al., 1990 Fillmore et al., 2010 Gantus et al., 2011 Ono et al., 2013 Mahmoodzadeh et al., 2014 Riverso et al., 2014 Pearl et al., 2011 Babiker et al., 2004 Kassem et al., 1998 Härkönen and Väänänen, 2006 (review) Wang et al., 2001 Hall and Korach, 2003 Sauvé et al., 2009 Toran-Allerand et al., 2005

Estrogen-signaling pathways are categorized by the types of receptors and the ways of signaling. AhR: arylhydrocarbon receptor; ANF: atrial natriuretic factor; APNR: adiponectin receptor; AR: androgen receptor; CAR: constitutive androstane receptor; CCRs: CC chemokine receptors; DDE: dichlorodiphenyldichloroethylene; DMBA: 7,12-dimethylbenz(a)anthracene; E2: estradiol; ER: estrogen receptor; ERK: extracellular signal-regulated kinase; ERR: estrogen-related receptor; FOXO: Forkhead box O; GPER: G-protein-coupled estrogen receptor 1; GR: glucocorticoid receptor; IGF: insulin-like growth factor; IGF-1R: IGF-1 receptor; IL-1: interleukin 1; IL6R: interleukin 6 receptor; InsR: insulin receptor; IRS-1: insulin receptor substrate-1; JNK: c-Jun N-terminal kinase; LXR: liver X receptor; MAPK: mitogen-activated protein kinase; mER: membrane estrogen receptor; mTOR: mammalian target of rapamycin; NO: nitrogen oxide; PDGF: platelet-derived growth factor; PDGFR: PDGF receptor; TrkA receptor: neurotrophic tyrosine kinase receptor type 1; PI3K: phosphoinositide 3-kinase; PKA: protein kinase A; PKC: protein kinase C; PR: progesterone receptor; RAR: retinoic acid receptor; SERM: selective estrogen receptor modulator; TCDD: 2,3,7,8-tetrachlorodibenzo-p-dioxin; TGF-β: transforming growth factor β; TGFBRs: TGF-β receptors; TR: thyroid hormone receptor; VDR; vitamin D receptor; VEGF: vascular endothelial growth factor; VEGFR-1:VEGF receptor 1.

Signaling pathways can influence each other not only through signaling pathways by crosstalk (exchanging signals between different receptors and/or pathways) and/or bypassing (signaling uni-directionally from one pathway to another) at the intracellular level, but also through the secretion of hormones or growth factors to transduce signals to different cells or tissues, which may result in completely different types of functional outcome. Feedback regulation of such signaling networks through crosstalk/bypassing and autocrine/paracrine networks would make signaling more complex, which may also contribute to pathways other than estrogen signaling and eventually result in forming a homeostatic network. 3.1. Receptors Estrogenic chemicals first bind to ERs to initiate cell signaling. There are three major ERs, in which ERα and ERβ are nuclear ERs and the Gprotein-coupled estrogen receptor 1 (GPER) is a membrane ER. In addition, recent studies have revealed the presence of other ERs, such as the estrogen-related receptors (ERRs), variants of ERα or ERβ (ER-X and ER-α36) and uncharacterized ERs. These receptors share some common features, although there are differences in structure, signaling pathways, cell specificity and functional outcomes. 3.1.1. Nuclear receptors There are two major nuclear ERs, ERα and ERβ, which are encoded by different genes, ESR1 located at 6q25.1 and ESR2 located at

14q23.2–q23.3 on human chromosomes, respectively. These receptors have similar molecular sizes (595 amino acids for ERα and 530 amino acids for ERβ) and share a common structural architecture composed of three functional domains: the A/B domain at the N-terminal is involved in transcriptional activation of estrogen-responsive genes (AF1); the C domain contains a two-zinc-finger structure responsible for receptor dimerization and DNA binding; and the E/F domain at the Cterminal mediates ligand binding, receptor dimerization, nuclear translocation and transactivation of target gene expression (AF-2) in association with co-regulators (Nilsson et al., 2001). While no ligand binds to the A/B domain and thus AF-1 is ligand-independent, ligands bind to the E/F domain and thus AF-2 is affected by ligands. Furthermore, ESR1 and ESR2 are known to show splice variants, which add variation in terms of cell/tissue-specific expression, ligand-binding specificity, cell localization and cell functions (Taylor et al., 2010). Transactivation of target genes is mediated by the binding of ERs with estrogen-responsive genes with specific sequence motifs, such as GGTCACAGTGACC (KleinHitpass et al., 1986), often with the help of other transcription factors, such as Sp1 and AP1 (Safe, 2001). The estrogenic chemicals that transduce signals through ERα and/or ERβ are summarized in Tables 1 and 2. While they usually cannot distinguish between ERα and ERβ, some show a preference or exclusivity for one of these (Escande et al., 2006). The difference in transactivation activity of various compounds between ERα and ERβ was investigated, where some phytoestrogens showed significant preferences in the binding affinity (Kuiper et al., 1998). Such differences in estrogenic

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action between ERα and ERβ have been investigated by using selective antagonists against each receptor, such as 4,4ʹ,4″-(4-propyl-[1H]pyrazole-1,3,5-triyl)trisphenol (PPT) for ERα (Stauffer et al., 2000) and 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN) for ERβ (Meyers et al., 2001) (Table 3). Recently, another nuclear receptor family, estrogen-related receptor (ERRs), was found to be partly involved in estrogen signaling. ERRs (ERRα, ERRβ and ERRγ) act as ligand-dependent transcription factors, although no natural ligand has been identified. ERRs regulate the genes that are distinct from ER-regulated genes and are associated with physiological functions, such as negative regulation of osteoblast differentiation (Gallet and Vanacker, 2010). Estrogenic signaling mediated by ERRs has been reported for biochanin A, daidzein, genistein and resveratrol (estrogenic), as well as apigenin, chlordane, diethylstilbestrol, kaempferol and toxaphene (Table 3). Crosstalk between ER and ERRs was reported for resveratrol-induced functional modulation of the respiratory chain (Lopes Costa et al., 2014). 3.1.2. Membrane receptors The presence of membrane ERs (mERs) was evidenced by rapid, thus non-genomic, mechanisms of estrogen signaling, which were observed as rapid alterations in the levels of cAMP, cGMP and Ca2+, and in the activity of enzymes (Soltysik and Czekaj, 2013). There are several mERs, which are classified by their structure: canonical ERα and ERβ translocated to the membrane after modification, variants of ERα and ERβ (e.g., ER-X and ER-α36), GPER and less characterized mERs. Canonical ERα and ERβ bind to caveolin-1 after being palmitoylated, which are translocated to the membrane and anchored there as a dimer (Soltysik and Czekaj, 2013). They mediate rapid signaling for hypothalamic function (Micevych and Kelly, 2012). ER-X is a 62–63 kDa membrane protein likely to be derived from ERα as a splicing variant (Soltysik and Czekaj, 2013). ER-X is activated with 17α-E2, and associated with the function of the brain and the uterus through MAPK and ERK signaling (Table 3). ER-X could be involved in the E2-induced inhibition of Ca2+ influx and contraction in murine cardiomyocytes derived from ERα/ERβ-knockout mice (Ullrich et al., 2008). ER-α36 is a splice variant of ERα lacking both AF-1 and AF-2 but retaining the DNA-binding domain and the partial ligand-binding domain, and is predominantly localized at the membrane. ER-α36 inhibits wild-type ERα (ER-α66) and ERβ in a dominant-negative manner and thus contributes to the resistance of breast cancer to endocrine therapy (Rao et al., 2011). ER-α36 mediates estrogenic signaling through the MAPK/ERK pathway in breast cancer cells and c-Src-mediated signaling in gastric cancer cells (Table 3). ER-α36 is involved in testosteroneinitiated carcinogenesis by transducing estrogenic signals after testosterone is converted to estrogen (Lin et al., 2009). GPER, previously known as G-protein-coupled receptor 30 (GPR30), is a G-protein-coupled receptor (GPCR) encoded by the GPER gene located at chromosome 7p22.3 with high expression in the hypothalamus, pituitary gland, adrenal medulla, renal pelvis and ovary (Hazell et al., 2009; Soltysik and Czekaj, 2013). GPER is a 7-membrane-spanning protein with high affinity for E2 and other chemicals such as aldosterone; thus, the binding of estrogen to GPER induces rapid nongenomic signaling. Other than the cell membrane, GPER has been reported to be located at the endoplasmic reticulum, Golgi apparatus and even in the nucleus (Soltysik and Czekaj, 2013). GPER can be activated directly by the binding of ligands other than estrogen, such as bisphenol A, daidzein, dieldrin, diethylstilbestrol, equol, fulvestrant, genistein, icariin, icaritin, kepone, niacin, nonylphenol, quercetin, raloxifene, resveratrol and zearalenone as agonists to the receptor (Table 3). Kajta et al. used two tetrahydro-3H-cyclopenta[c]quinoline analogs, G15, a selective GPER antagonist, and G1, a selective GPER agonist, to study the neuroprotective effect of daidzein (Kajta et al., 2013). GPER is involved in the signaling pathways mediated by other receptors, such as serotonin/serotonin 1A receptor (Li et al., 2013c), and crosstalk

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with other signaling pathways, such as GPER/TGF-β1 crosstalk in fulvestrant-induced cell migration (Li et al., 2014a) or icariin-induced expression of type IV collagen (Li et al., 2013a), GPER/IL-1β crosstalk in genistein-induced inflammatory response (Luo et al., 2012), and GPER/EGFR crosstalk in equol-induced NO synthesis (Rowlands et al., 2011), icariin- or icaritin-induced cell proliferation (Ma et al., 2014) or niacin-induced inflammatory response (Santolla et al., 2014). GPER is known to inhibit serotonin 1A receptor selectively (Xu et al., 2009; McAllister et al., 2012; Akama et al., 2013) and to accelerate the efficacy of its inhibitor fluoxetine (Li et al., 2013c) in neuronal cells, so it is a target to treat mood disorders. 3.1.3. Other membrane receptors Several groups of researchers found that cell signaling is initiated by unidentified or unspecified membrane receptors (Soltysik and Czekaj, 2013). Some of them are likely to be variants of ERα or ERβ, while the others are likely to be factors other than ERα, ERβ, ER-X or GPER (Nethrapalli et al., 2005). Endogenous estrogens (E1, E2 and E3) and estrogenic chemicals, such as DDE, 17α-E2, geniposide, naringenin (anti-estrogenic), raloxifene, retinoic acid, sulfonylurea and tamoxifen, bind to mER and transduce signals through pathways, such as ERK, NF-κB and PI3K/MAPK signaling, to contribute to apoptosis, cell proliferation, differentiation and other cell functions (Table 3). Crosstalk was implicated between mER and other receptors, such as natriuretic peptide receptor (Stratton et al., 2010), RAR (Kauss et al., 2008), and IGFR and EGFR in signalosomes (Soltysik and Czekaj, 2013) or K channels (Nadal et al., 1998). 3.2. Cell functions and signaling pathways There are a number of signaling pathways linked to estrogen and estrogenic chemicals (a comprehensive list is shown in Kiyama et al., 2014), which are associated with specific cell functions, such as chromatin/epigenesis, apoptosis, autophagy, cellular metabolism, translational control, cell cycle/DNA damage/cytoskeletal formation, immunology/ inflammation response, neurological diseases and development/ differentiation. Here, we discuss further the role of estrogenic chemicals in some cell functions: apoptosis, carcinogenesis, cell growth and proliferation, differentiation/development and inflammation. 3.2.1. Apoptosis Estrogen is known to stimulate growth and inhibit apoptosis (see Section 3.2.3). However, recent progress has revealed that estrogen can induce apoptosis through several pathways, such as Fas/FasL, mitochondrial, NF-κB and PI3K/Akt pathways (Lewis-Wambi and Jordan, 2009). Fas/FasL plays a key role in the extrinsic pathway, a type of signaling of external origin, while the mitochondrial pathway is induced by various stresses and involves p53, Bax and other pro-apoptotic proteins. Estrogenic chemicals are also related to either the inhibition or the induction of apoptosis (Tables 1 and 2): Aroclor 1254, caffeic acid phenethyl ester, epigallocatechin 3-gallate, formononetin, 25hydroxycholesterol, irigenin, mestranol, naringenin, plumbagin, quercetin, quinestrol, tamoxifen, tectorigenin, withaferin A and wogonin (pro-apoptotic); and equilenin, equilin, geniposide, ginsenoside Rb1, methoxychlor, raloxifene and triclosan (anti-apoptotic). Furthermore, estrogenic chemicals transduce signals through specific signaling pathways: Aroclor 1254 (ERα/cyclin D1/Bcl-2/caspase-3), epigallocatechin 3-gallate (ER/MAPK/Akt/caspase-3), formononetin (ER/Ras/MAPK/ Bax/Bcl-2), naringenin (ERα, ERβ/MAPK/caspase-3), plumbagin (ER/ NF-κB), quercetin (ERβ/caspase-3), withaferin A (ERα/MAPK/p53) and wogonin (ER/PARP/Bax) (pro-apoptotic); and E2 (ER/STAT3/IL-6/ IL6R), geniposide (mER/PI3K/MAPK), ginsenoside Rb1 (ER/ERK/Akt), methoxychlor and triclosan (ER/cyclin D1/Ras/Bax) and raloxifene (ER/TNF-α/ERK/caspase-3) (anti-apoptotic).

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3.2.2. Carcinogenesis Estrogen plays significant roles in the development of breast and other cancers, and blockade of estrogen action with antagonists reduces the risk (Villa, 2008; Yue et al., 2013). The estrogenic chemicals (including those that modulate estrogenic signaling) that are associated with carcinogenesis or cancer functions are as follows: cadmium, di(n-butyl) phthalate, parabens and testosterone (positive effects); and genistein, β-naphthoflavone, phenylacetate and tocopherols (negative effects) (Tables 1 and 2). The signaling pathways involved in estrogen-related carcinogenesis or cancer functions are: cadmium (ER/ERK), di(n-butyl) phthalate (ER/TGF-β), E2 (ER/Akt/IGF-1R/InsR, ER/IGF/IGF-1R, ERα/IRS1/IGF-1R/PI3K/Akt and ER-α36/MAPK/ERK), methyl-amoorain + DMBA (ER/Wnt/β-catenin), testosterone (ER-α36/ERK/Akt) and tocopherols (E2/ER/PPARγ/Akt). Crosstalk of signaling in breast cancer has been reported for the signaling pathways between estrogen and AhR (β-naphthoflavone: Wang et al., 2014), IGF-1 (genistein; Hwang et al., 2013), TGF-β (Band and Laiho, 2011), PR (parabens; Vo et al., 2011) or PPARγ (di(n-butyl) phthalate; Lee et al., 2009) (Table 3). The cancer-related signaling induced by estrogen or estrogenic chemicals can be modulated by other chemicals, such as testosterone (Lin et al., 2009), tocopherols (Lee et al., 2009) and TGF-β (Lee et al., 2014).

3.2.3. Cell growth and proliferation Cell growth and differentiation are key steps for the differentiation and development of cells, tissues and organs and thus include a number of cellular events, such as cell division, cell adhesion, cell movement, cell survival and cellular response to a variety of stimuli and stresses. Estrogen promotes the growth and proliferation of various types of cell for various cellular events, and thus, cell growth and proliferation have been examined for various estrogenic chemicals and the signaling pathways related to them (Tables 2 and 3). Estrogenic chemicals associated with cell growth and differentiation are summarized below. The list of estrogenic chemicals associated with cell growth and differentiation. Benzo[a]pyrene, bisphenol A, p,p'-DDE, o,p'-DDT, dieldrin, equilin, equol, estrone (E1), estradiol (E2), estriol (E3), 17α-ethinylestradiol, 17β-E2 valerate, ferulic acid, genistein, β-HCH, hexachlorobenzene, icariin, icaritin, methoxychlor, puerarin, procymidone, quercetin and tributyltin (estrogenic); and aloe-emodin, baicalein, bergapten, calycosin, emodin, formononetin, celastrol, curcumin, daphnetin, esculetin, epigallocatechin gallate + curcumin, fulvestrant, hydroxytyrosol, indole-3-carbinol, luteolin, naringenin, oleuropein, quercetin, secoisolariciresinol and tamoxifen (anti-estrogenic).

Isoliquiritigenin and piceatannol show dose-dependent estrogenic and anti-estrogenic effects (Maggiolini et al., 2002; Vo et al., 2010). The major signaling pathways identified for estrogenic chemicals are ER/Akt (benzo[a]pyrene, bisphenol A, dieldrin, ferulic acid, luteolin and puerarin), ER/ERK (baicalein, benzo[a]pyrene, p,p'-DDE, o,p'-DDT, dieldrin, E1, E2, E3, equol, ferulic acid, β-HCH, hydroxytyrosol, methoxychlor, naringenin, oleuropein, puerarin, quercetin and tributyltin), ER/ MAPK (17α-ethinylestradiol, 17β-E2 valerate, naringenin, piceatannol, procymidone and tributyltin) and GPER/ERK (dieldrin, genistein and quercetin). There are cases where signals induced by estrogenic chemicals affect other signaling pathways: bisphenol A, calycosin, formononetin, hexachlorobenzene, indole-3-carbinol, luteolin and tamoxifen for IGF-1 signaling; equilin for NMDA signaling; icariin, icaritin and secoisolariciresinol for EGF signaling; celastrol and piceatannol for progesterone signaling; epigallocatechin gallate + curcumin for VEGF signaling; and fulvestrant for Wnt/β-catenin signaling. Furthermore, estrogenic signaling can be modulated by chemicals in other signaling pathways by crosstalk, such as bergapten in TGF-βR/ERα (Panno et al., 2012), farnesol in farnesoid × receptor/ER signaling (Journe et al., 2008), melatonin in MT1/ERα signaling (Kiefer et al., 2005), progesterone and progestin in PR/ER signaling (Migliaccio et al., 1998; Vallejo et al., 2005; Ballaré et al., 2006), retinoic acid in RARα/ERα signaling (Ombra et al., 2013), 3,5,3′-triiodothyronine in integrin receptor/ERα

signaling (Meng et al., 2011) and vitamin D in VDR/ER signaling (Gilad et al., 2005; Swami et al., 2013), while the signals induced by estrogen affect other signaling pathways through autocrine/paracrine networks involving the secretion of hormones and growth factors, such as ER/CXCL12/CXCR4 (Hall and Korach, 2003; Sauvé et al., 2009), ER/ EGFR (Osborne et al., 2005), ER/ERBB4 (Zhu et al., 2006), ER/IGF-1R (Kashima et al., 2009), ER/PDGFR (Barbarisi et al., 2001; Finlay et al., 2003) and Wnt/β-catenin signaling (Ono et al., 2013). There are cases of ligand-independent activation of ER, where combinations of signal inducers and receptors, such as ethanol/adenosine receptor (Etique et al., 2009) and MCP-1/CCRs (Riverso et al., 2014), affect ERα signaling in the absence of its ligands for the induction of cell proliferation. On the other hand, exemestane, an aromatase inhibitor, modulates estrogen synthesis and affects ER and EGFR synergistically by autocrine signaling for cell proliferation (Wang et al., 2008a). Note that silent estrogens, a type of estrogenic chemicals without explicit cell proliferation activity, were observed for some chemicals including brefeldin A, revealed by DNA microarray assay (Dong et al., 2013a; Kiyama and Zhu, 2014). The presence of such a type of estrogenic chemicals suggests that signaling pathways related to estrogen action, such as cell growth, can be separated or differentially manifested not only by SERMs but also by different types of chemicals, and such a new type of chemicals could be explored to modulate estrogen action at the cell signaling level. 3.2.4. Differentiation/development Estrogen plays critical roles in the sexual differentiation and development of the brain, breast, prostate and other tissues and organs (Ohtani-Kaneko, 2006; McPherson et al., 2008; Simões and Vivanco, 2011). Estrogenic chemicals associated with cell differentiation and development are adiponectin, estradiolquinone, genistein, medicarpin, resveratrol and tamoxifen (estrogenic or synergistic), and androstenol and retinoic acid (anti-estrogenic or inhibitory), and the associated signaling pathways are ER/NO/cGMP (resveratrol), ERα/MAPK/NF-κB/ AP-1 (genistein), ERα/Wnt3A/β-catenin (tamoxifen) and mER/MAPK (retinoic acid) (Tables 2 and 3). Crosstalk was observed for the ER signaling with CAR (androstenol; Min et al., 2002), LTD4 receptor (estradiolquinone; Dietsch et al., 1996) and APNR (adiponectin; Rahal and Simmen, 2011). 3.2.5. Inflammation Estrogen has anti-inflammatory and vasoprotective effects when it is administered, and several signaling pathways, such as the TNF-α/ NF-κB/JNK pathway, have been suggested to mediate its effects (Xing et al., 2009). Estrogenic chemicals affect the inflammatory response positively (daidzein and genistein) or negatively (baicalein, genistein, 4-hydroxyphenyl sulfonamides, niacin, p-n-nonylphenol, p-noctylphenol, oroxylin-A and resveratrol), or modulate the signaling induced by estrogen (parthenolide, an NF-κB inhibitor) (Tables 1 and 2). The signaling pathways involved are ER/NF-κB (4-hydroxyphenyl sulfonamides), ER/NF-κB/NO (p-n-nonylphenol and p-n-octylphenol), ER/NF-ĸB/NO/TNF-α (baicalein), ER/TNF-α/IL-1β/IL-6/NO (oroxylinA), ERα/TNF-α/NO (daidzein and genistein), GPER/EGFR/ERK (niacin) and GPER/IL-1β/MAPK (genistein). The anti-inflammatory effects of an SERM, raloxifene, are ER-independent (Lee et al., 2011), suggesting the presence of a new anti-inflammatory target. Resveratrol shows pathway-selective ER signaling, where it activates the inflammatory pathway but not the cell proliferation pathway, presumably by altering the way of recruiting the coregulators associated with ERα (Nwachukwu et al., 2014). 3.3. Signaling networks Estrogen receptors or estrogenic signaling can crosstalk with other receptors or signaling, either (1) by modulating estrogenic signaling (mostly induced with E2) by signals induced with other chemicals or

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(2) by the interaction between different receptors or pathways. The former case may include crosstalk through the genomic pathway, such as between ERα and AhR (Safe and Wormke, 2003). The latter case may include (2–1) direct interaction between different receptors or pathways, (2–2) one-way crosstalk, or bypassing, where signaling is unidirectional because one of the pathways involved is abortive due to the lack of appropriate effectors or signal mediators, and (2–3) paracrine and autocrine signaling, where other hormones or growth factors are involved in the signaling. Note that, in some cases, ligands are not significant or required to transduce signaling from one signaling pathway to another, where activation/inhibition of signaling is done by direct interactions between receptors, or the first signaling results in the production or the activation of the second receptor. 3.3.1. Crosstalk/bypassing Crosstalk of ER or estrogenic signaling pathways with other receptors or receptor-mediated signaling pathways has been reported for receptors, such as AhR, EGFR, HER2 and IGF-1R, and signaling pathways, such as MAPK/ERK, c-Src, PI3K/Akt, NF-κB and NOTCH (Safe and Wormke, 2003; Ribeiro and Freiman, 2014). These pathways mostly promote the growth of cancer cells, so understanding them is essential for cancer treatment. Furthermore, signals induced by the binding of ligands (as agonists), such as biochanin A, formononetin, 3methylcholanthrene, β-naphthoflavone and TCDD, to AhR are mediated by crosstalk between ER and AhR to contribute to various cell functions through pathways such as PI3K/AKT and MAPK/ERK signaling, or through transcription or proteasome-mediated degradation of ERα (Table 3). Biochanin A and formononetin are estrogenic chemicals, but could act as AhR agonists and thus be anti-estrogenic through the crosstalk (Medjakovic and Jungbauer, 2008). AhR signaling is bypassed by ER signaling (or crosstalk between ER and AhR is uni-directional) because inhibitory effects were observed only for β-naphthoflavone, which inhibits ER signaling, but not for 17α-ethinylestradiol, which inhibits AhR signaling (Gräns et al., 2010). Crosstalk has been reported between ER and PR for ER ligands (genistein and piceatannol) or PR ligands (progesterone and progestin) (Table 3), or between ER and AR in a ligand-independent manner (Migliaccio et al., 2006). While ERβ and PR form a complex and crosstalk with each other (Vallejo et al., 2005), crosstalk between ER and growth factors could down-regulate PR expression (Thakkar and Mehta, 2011). Crosstalk between ER and IGF-1R induced with estrogen or estrogenic/anti-estrogenic chemicals, such as calycosin, formononetin, genistein, ginsenoside Rg1, indole-3-carbinol and resveratrol, involves pathways, such as IRS-1 and PI3K/Akt signaling, and cell functions, such as cell proliferation and neuroprotection (Table 3). Crosstalk between ER and other receptors, such as α1/βadrenoceptor, CAR, GR, HER2, integrin receptor, LXRβ, natriuretic peptide receptor, PPARγ, RAR, ryanodine receptor, TGF-βR, TR and VEGFR-1, was also reported along with estrogen or estrogenic chemicals (lycopene, resveratrol, tamoxifen and tocopherols), or ligands for receptors, such as androstenol/CAR, cholesterol/LXRβ, epigallocatechin gallate/EGFR, ethanol/adenosine receptor, hesperetin/TrkA receptor, isoproterenol/β-adrenoreceptor, protopanaxadiol and protopanaxatriol/ GR, ryanodine/ryanodine receptor, thyroid hormone/TR and vitamin D/VDR and Wnt/Fz (Table 3). 3.3.2. Autocrine/paracrine signaling Since cells communicate with other cells in the neighborhood or in distant locations (by paracrine or endocrine signaling) or with themselves (by autocrine signaling) through hormones, growth factors, cytokines, ions and other mediators, it is important to examine such communications to understand the action of estrogen under physiological conditions. The signals induced by estrogen or estrogenic chemicals modulate signaling pathways for other hormones and growth factors, which are secreted and transported, and finally affect the same cell or other cells.

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Autocrine/paracrine signaling was reported for receptors, such as ANF receptor, APNR, AR, CCRs, CXCR4, EGFR (ERBB4), FGFR, IGF-1R/ InsR, IL6R, PDGFR and TGF-βR, where the hormones and growth factors released are ANF, adiponectin, androgen, MCP-1, CXCL12 (SDF-1), EGF (amphiregulin), FGF, IGF-1/insulin, IL-6, PDGF and TGF-β1, respectively. The signaling pathways involved are ERK, JNK, MAPK, NF-κB, PI3K/Akt/ mTOR and Wnt/β-catenin signaling, which are related to cell growth and proliferation in breast and other cancer cells, and differentiation and other functions (Table 3). In paracrine signaling, hormones and growth factors are secreted from a cell type and transported to another cell type. For example, adiponectin secreted from adipocytes is transported to epithelial cells, and binding of adiponectin to its receptor and synergistic activation of ERβ with genistein facilitate epithelial cell differentiation (Rahal and Simmen, 2011). MCP-1 secreted from normal epithelial cells binds to its receptor on breast cancer cells and activates their cell division with the help of activation of ERα through PI3K/Akt/mTOR signaling (Riverso et al., 2014). Estrogen-induced activation of a procoagulant/coagulation factor further activates prothrombin to form thrombin, which is a paracrine factor that acts to develop the uterus (Jazin et al., 1990). Wnt proteins secreted from mature myometrial cells in response to estrogen and progesterone induce myometrial stem cells to develop leiomyomas in the uterus (Ono et al., 2013). Estrogen-induced secretion of growth factors and hormones from cardiomyocytes to other cells induces neovascularization and attenuates fibrosis (Mahmoodzadeh et al., 2014). The role of 17α-E2 as an autocrine/paracrine factor was implicated in brain functions and therapeutic use in association with its preferred receptor ER-X (Toran-Allerand et al., 2005). Finally, since estrogen itself is an important member of the autocrine/paracrine factors, the modulation of estrogen signaling is crucial to develop SERMs for the prevention and treatment of postmenopausal degenerative and neoplastic diseases (Härkönen and Väänänen, 2006). 3.3.3. Homeostatic networks Extracellular networks adopt a homeostatic nature when they have a system of feedback regulation in autocrine/paracrine signaling. While such networks play important physiological and developmental roles, such as that in estrogen regulation of estrous cyclicity (Yeo and Herbison, 2014), ovulation (Wintermantel et al., 2006) and spermatogenesis (Chimento et al., 2014), too much positive or negative feedback regulation would cause the development and progression of cancer and other diseases. For example, positive feedback activation in an autocrine loop between CXCR4/CXCL12 and ERα/ERβ signaling pathways promotes the ER-dependent development of breast cancer (Sauvé et al., 2009; Boudot et al., 2011). The feedback regulation involving estrogen can be categorized by the role of ER: (1) modulation of signaling proteins or transcription factors for growth factor and other signaling-related genes to increase/decrease the activity of signal mediators (e.g., Sauvé et al., 2009), (2) transcriptional modulation of ER genes to increase/decrease (mostly increase) the amount, and thus the sensitivity, of ERs (e.g., Wintermantel et al., 2006) and (3) modulation (mostly increasing) of estrogen synthesis by regulating aromatase activity (e.g., Wang et al., 2008a). Examples of feedback regulation have been reported for estrogen, although other estrogenic chemicals could also be involved, and such regulation of estrogen signaling could be used as targets for developing tumor-targeting drugs (Renoir et al., 2013). 4. Evaluation of estrogen action Estrogen action is evaluated first by the structural and functional characteristics of chemicals (Tables 1 and 2), whose functional outcomes are interpreted partly by the signaling pathways that they induce (see Section 3). When these collections of information are used to predict the effect of estrogenic chemicals, we need to understand the details of the technologies, especially their

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advantages/disadvantages and the limitations of the methods used for the evaluation. Comparison of in vitro assays including their advantages and limitations was already discussed (Mueller, 2004; Kiyama and Zhu, 2014). Here, we summarize the methods used for the evaluation of estrogen action. 4.1. Assays for detecting estrogen action Estrogenic activity can be detected by various methods, such as ligand-binding assay, reporter-gene assay, yeast two-hybrid assay, transcription assay, protein assay, cell assay, animal tests and signaling pathway analysis, which are based on the molecular and cellular mechanisms of estrogen action (Fig. 1). The assays used and the pathways identified for various estrogenic chemicals are summarized in Tables 1 and 2. Note that signaling pathway analysis is categorized separately from other assays because it usually consists of the assays categorized in other methods, and focuses on the identification of signaling pathways and functional outcomes rather than the evaluation of estrogenicity alone. Here, we briefly discuss the assays used to detect and characterize the estrogenic activity of chemicals. 4.1.1. Ligand-binding assay Ligand-binding assay is a well-established method to detect receptor–ligand interactions. An extract from hormonally responsive tissues, such as the uterus and liver (Song et al., 1999; Tollefsen and Nilsen, 2008), an extract from cultured cells expressing ERs (Olsen et al., 2003) or a recombinant receptor protein (Goodin et al., 2002) is used as a source of ERs. The assay quantifies the ability of a test chemical to compete with 3H-labeled 17β-E2 in binding to ERs, and the result is often expressed as the concentration showing 50% inhibition, or IC50. The result is also expressed as a relative binding affinity, the ratio of IC50 between the test and unlabeled E 2. In place of radioactive ligands, assays using non-radioactive ligands have been developed, such as the fluorescence polarization method (Jung et al., 2004; Hashimoto et al., 2001; Mersereau et al., 2008) and the competitive enzyme immunoassay (Nishizuka et al., 2004). While such assays are easy and fast to perform, they cannot distinguish between agonists and antagonists. Recently, McLachlan et al. developed a biosensor that can distinguish agonists and antagonists, where two halves of a split Venus fluorescent protein fused to either end of the ERα ligand-binding domain produce a fluorescent signal after conformational changes induced by binding estrogenic chemicals to the ligand-binding domain (McLachlan et al., 2011). The quantitative structure–activity relationship (QSAR) method has been developed on the basis of the molecular dynamic structure of the compound and used to predict estrogenic activity and to explore the interaction between ERs and ligands (Li and Gramatica, 2010). To obtain more detailed information about ER–ligand interactions at the atomic level, computational molecular modeling is a powerful tool. Li et al. carried out a molecular modeling study combining molecular docking, molecular dynamics stimulation and binding free energy calculation to examine the interaction between hydroxylated polychlorinated biphenyls (HO-PCBs) and ERs, and found that several amino acid residues formed hydrophobic and hydrogen–bond interactions with the ligand (Li et al., 2013d). Ligand-binding assay was used to characterize the estrogenicity of the chemicals (Tables 1 and 2), which are summarized below.

The list of estrogenic chemicals characterized by ligand-binding assay. Acetaminophen, acetylsalicylic acid, aldicarb, 3-alkyl naphthalenes, alkylphenols, anethole, benzo[a]pyrene, bisphenol A, boric acid, chlordecone, citral, dichlorophenyls, 9,10-dimethyl-m-carborane, diphenylamines, enterodiol, enterolactone, epigallocatechin 3-gallate, equilenin, geraniol, glabridin, glycitein, β-HCH, indole-3-carbinol, isocoumarins, isorhamnetin, kaempferide, kaempferol, metalloestrogens, 3-(4-methylbenzylidene) camphor, myricetin, nerol, PBDEs,

(continued) phenanthrenes, 2-phenylindoles, 2-phenyl-isoindole-1,3-dione, phthalates, quercetin, triazine, umbelliferone and zeranol (by means of competitive binding of ERs against 3H–E2); caffeic acid phenethyl ester (by means of recombinant hERα); auraptene, 3,9-benz[a]anthracene diols, carboranes, coumestrol, DDT, eugenol, glycinol, juglone, naringenin, naringin, PBDEs, psoralidin, phenanthrenes and tocotrienol (by means of molecular modeling); and arctigenin, bisphenol A, hexachlorophene, liquiritigenin and menadione (by means of fluorescence polarization).

4.1.2. Reporter-gene assay In a reporter-gene assay, the receptor, upon binding to ligands, binds to a specific response element on DNA and induces transcription of the downstream reporter gene. There are variations of this assay, such as in terms of the reporters: β-galactosidase (lacZ), chloramphenicol acetyltransferase (CAT), luciferase and green fluorescent protein (GFP); culture systems; receptor/reporter gene constructs; and the protocols for the transfection of reporter constructs into host cells. There are two types of culture system, dependent on the status of the expression of endogenous ERs. MVLN cells were developed from human breast cancer MCF-7 cells constitutively expressing ERs by introducing a reporter gene expressing firefly luciferase under the control of the estrogenresponsive element derived from the 5′-flanking region of the Xenopus vitellogenin A2 gene (Pons et al., 1990). New cell lines for luciferasebased reporter-gene assay have been developed to detect steroid hormones effectively: TGRM-Luc cells for glucocorticoids, TM-Luc cells for progestagens, TARN-Luc cells for androgens and MMV-Luc cells for estrogens (Willemsen et al., 2004). They were used to assess estrogenic and androgenic endocrine disruptors in sport supplements (Plotan et al., 2012). More recently, a panel of mammalian reporter cell-linebased CALUX (Chemically Activated LUciferase eXpression) bioassays was developed to detect chemicals with androgen, estrogen, progesterone and glucocorticoids (Sonneveld et al., 2005). The ER-CALUX bioassay utilizes human osteosarcoma (U2-OS) cells, which have been stably transformed with specific estrogen-response elements linked to a luciferase reporter gene, and evaluates estrogenicity by quantifying luciferase protein. When cells do not express endogenous receptors, it is necessary to transfect two different plasmids constitutively expressing either a receptor or a reporter gene. Yeast cells are frequently used in this type of assay because less time is required to detect the response with significant reproducibility. In the yeast estrogen screen (YES) assay, yeast cells (Saccharomyces cerevisiae) were stably transfected with DNA of two plasmid constructs containing the human ER gene and the estrogenresponse element-linked lacZ, and β-galactosidase activity was detected colorimetrically using chromogenic substrates, such as o-nitrophenyl-βD-galactoside (ONPG) (Arnold et al., 1996). However, the colorimetric as-

says take several days to perform and require cell lysis. These problems were solved by using fluorescence-based reporters, such as firefly luciferase (Leskinen et al., 2005) or GFP (Bovee et al., 2004). However, in yeast-based assays, the discrimination between agonists and antagonists is not effective, and the differences in membrane permeability, transport proteins and signal transduction pathways may cause differences in the response to chemicals between yeast cells and humans. Reporter-gene assay was used to characterize the estrogenicity of the chemicals (Tables 1 and 2), which are summarized below. The list of estrogenic chemicals characterized by reporter-gene assay. Acetaminophen, alkylanilines, caffeic acid phenethyl ester, chlordecone, epigallocatechin 3-gallate, fisetin, galangin, isocoumarins, luteolin, menadione, naringenin, naringin, parabens, pentachlorophenol and 3-phenoxybenzaldehyde (by means of β-galactosidase-based reporters); acteoside, anthraquinone, apigenin, auraptene, benz[a]acridine, benzanthrone, benzo[a]pyrene, biochanin A, butylated hydroxyanisole, cajanin, carboranes, β-carotene, daidzein, dieldrin, ephedrine, epigallocatechin 3-gallate, formononetin, genistein, ginsenoside Rg1, glycinol, glyceollins, glyphosate, β-HCH, hexachlorophene, hydroxychalcones, insecticides, γ-linolenic acid, liquiritigenin, luteolin, kaempferol, malathion, martynoside, metalloestrogens, naringenin, naringin, PBDEs, PCBs, perfluorinated compounds, phenanthrenes, 2-phenylindoles, phthalates, propyl gallate, psoralidin,

R. Kiyama, Y. Wada-Kiyama / Environment International 83 (2015) 11–40 (continued) rhodoeosein, sesamin/sesamolin/sesamol, tartrazine, tricresyl phosphate and zearalenone (by means of luciferase-based reporters); indole-3-carbinol and metalloestrogens (by means of CAT-based reporter genes); and bifenthrin, chloroxylenol, insecticides and taxifolin (by means of ER-CALUX).

4.1.3. Yeast two-hybrid assay Yeast two-hybrid assay was originally designed to detect protein– protein interaction in vivo and to identify the genes encoding the interacting proteins using transcriptional activators such as yeast GAL4 protein. To evaluate estrogenic activity, two plasmids are used: a plasmid carrying a gene encoding a fusion protein containing the GAL4 DNA-binding domain (GAL4DBD) and the human ERα/β ligandbinding domain (hERα/β LBD) and another plasmid containing a cDNA fragment encoding the ER-binding domain of a co-regulator with a region encoding GAL4 transactivation domain (GAL4AD) fused to the lacZ gene. Yeast cells are transformed with DNA of both plasmids, and the transformants are selected by growth on a medium lacking leucine and tryptophan. Test chemicals are added to the yeast cells to evaluate β-galactosidase activity. Since hERα/β LBD and the co-regulator interact with each other only in the presence of a ligand, the expression of the lacZ gene is dependent on the ligand binding. The assay revealed that the ER also binds to nuclear receptor co-regulators, such as RIP140, SRC-1, TIF1 and TIF2, in response to chemicals according to their estrogenic activity, and demonstrated that the interaction between steroid hormone receptors and co-regulators can be a useful tool for identifying chemicals that interact with the receptors (Nishikawa et al., 1999). The entire hERα in combination with the nuclear receptor-binding domain of co-regulators, SRC-1 or TIF2, resulted in a higher response to estrogen than GAL4DBD-hERαLBD (Lee et al., 2006). This suggests that the synergistic action of AF-1 and AF-2 of hERα mediates the recruitment of co-regulators, such as SRC-1, and also that a ligand-dependent direct interaction between the B domain in AF-1 and C-terminal domain can stabilize the cooperative interaction between ERα and co-regulators (Métivier et al., 2001). The yeast two-hybrid assay was compared with a commercial enzyme-linked immunosorbent assay (ELISA) kit to measure estrogenic activity or total estrogen concentrations, respectively, in natural and waste waters (Allinson et al., 2011). While the two assays showed a very good correlation and the ELISA kit is a reasonably rapid tool for preliminary screening of water samples, the yeast two-hybrid assay may not be accurate enough to represent mammalian or human systems, and ELISA may not be able to detect unknown compounds. Yeast two-hybrid assay was used to characterize the estrogenicity of acetaminophen, bisphenols, n-butyl benzyl phthalate, β-cyclodextrin, fenthion sulfoxide, hexachlorophene, 2-hydroxyanthraquinone, menadione, naringenin, naringin, PCBs and phlorizin (Tables 1 and 2). 4.1.4. Transcription assay Analysis of the transcripts of genes, or transcriptomic analysis, is one of the most effective approaches to predict the toxicity of chemicals, and various transcription assays, such as DNA microarray assay, Northern blotting, RNA-seq, RT-PCR and the serial analysis of gene expression (SAGE), have been developed (Kiyama and Zhu, 2014). These assays quantify the expression of ER genes or specific marker genes, such as APOA1 (ApoA-1), BRCA2, CCDN1 (cyclin D1), PGR and TFF1 (pS2) (by Northern blotting and RT-PCR), or sets of genes responding to estrogen or estrogen-responsive genes (by DNA microarray assay, RNA-seq and SAGE). DNA microarray-based evaluation of endocrine disruptors has been discussed previously (Tanji and Kiyama, 2004; Kiyama and Zhu, 2014). One of the advantages for DNA microarray assay over other transcription assays is that it can give gene-expression profiles of the chemicals examined, which could be used to compare the effects of chemicals by comparing the genes related to various cell functions. Comparative evaluation of DNA microarray, RT-PCR and real-time RT-PCR showed DNA microarray assay has the advantage over the others in effectiveness and quickness in diagnosis (Sultankulova et al.,

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2014). Gene expression datasets of different size and experimental design could be combined by the Generally Applicable Gene-set Enrichment (GAGE) method and used to predict estrogen signaling pathways (Luo et al., 2009). Recently, DNA microarrays have been developed for non-mammalian genes and used for evaluation of estrogenic chemicals (Baker et al., 2013; Hao et al., 2013). Transcription assay was used to characterize the estrogenicity of the chemicals (Tables 1 and 2), which are summarized below. The list of estrogenic chemicals characterized by transcription assay. Apigenin, arsenic, benzo[a]pyrene, biochanin A, curcumin, cyanidin-3-glycoside, daphnetin, DDT, dieldrin, epigallocatechin 3-gallate, esculetin, fenarimol, fluorotelomer alcohols, flutolanil, ginsenoside Rg1, glycinol, hydroxymatairesinol, insecticides, isorhamnetin, kaempferol, liquiritigenin, lycopene, myricetin, naringenin, naringin, irisolidone, parabens, perfluorobutanesulfonic acid, perfluorooctyl iodide, psoralidin, quercetin, sesamin/sesamolin/sesamol, silibinin, tartrazine, TCDD, tectorigenin, tocotrienol, zearalenone and zeranol (by RT-PCR); curcumin, genistein, juglone, phloretin and phthalates (by means of DNA microarray assay); and β-carotene, indole-3-carbinol, insecticides, lycopene and SERMs (by Northern blotting).

4.1.5. Protein assay Various analytical matrices for qualitative and quantitative screening of endocrine disruptors have been developed from large-scale physicochemical methods, such as mass spectrometry (MS), to bench-scale approaches, such as Western blotting and immunohistochemistry. In order to detect protein quantitatively, radio-, enzyme- and fluoro-based immunoassays (IAs), ELISA, liquid chromatography (LC), gas chromatography (GC), MS and combined MS with immunoassay (MSIA) are available. It should be noted that a single or several protein markers are often used in these assays, whereas sets of protein markers, such as those used for expressional profiling in transcription assays, are rarely used, mainly due to the difficulty in preparing tens or hundreds of antibodies or peptides at low cost and in predicting estrogen action by proteomic profiling. Thus, ER proteins and markers, such as APOA1 (ApoA-1), CCDN1 (cyclin D1), PGR (PR), TFF1 (pS2) and vitellogenin, are often detected alone by protein assay. Protein assay was used to characterize the estrogenicity of the chemicals (Tables 1 and 2), which are summarized below. The list of estrogenic chemicals characterized by protein assay. Acetaminophen, biochanin A, caffeic acid phenethyl ester, β-carotene, coumestrol, curcumin, daphnetin, epigallocatechin 3-gallate, esculetin, flutolanil, genistein, glyphosate, insecticides, irisolidone, metalloestrogens, myricetin, naringin, parabens, PCB3, tartrazine, tectorigenin, tocotrienol and zearalenone (by Western blotting); bisphenol A, β-cyclodextrin, genistein, insecticides, nothofagin, oxybenzone, SERMs, silibinin and triclopyr (by immunoassay); myricetin (by ELISA); and epigallocatechin 3-gallate, ginsenoside Rg1 and psoralidin (by ChIP assay).

4.1.6. Cell assay Cell growth and proliferation can be detected by a variety of methods: visualization of cell sizes and shapes by microscopy after appropriate staining, counting live cell numbers by the dye exclusion method using trypan blue or by cytometry, such as fluorescenceactivated cell sorting (FACS), distinguishing dead/viable cells, cell types, cell differentiation and biomarkers, and detecting metabolic or redox activity by colorimetric (MTT) or fluorimetric (resazurin) methods. The formazan-based MTT assay is a colorimetric assay for assessing cell viability. MTT, a yellow tetrazole derivative, is reduced to purple formazan by NAD(P)H-dependent oxidoreductase. In contrast, resazurin-based assays, such as alamarBlue assay (Desaulniers et al., 1998), exhibit greater sensitivity than cell counting, microfluorometric DNA determination assay and even MTT assay. Other colorimetric chemicals, such as MTS (a tetrazolium) and sulforhodamine B (SRB), have been used in cell assays. Cell lines derived from breast cancer have been used in cell assays. Estrogenic breast cancer cell lines, such as MCF-7, T-47D and MDAMB-231 cells, are commonly used to examine the effects of chemicals

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on cell functions, such as cell viability, cell proliferation, cell cycle, apoptosis and cell migration. For the determination of estrogenic activity, cell proliferation assays are widely used. The E-screen assay developed by Soto et al. (1995) is based on the growth promotion of MCF-7 cells in the presence of estrogen, and is widely used as a screening tool for estrogenic chemicals (Grünfeld and Bonefeld-Jorgensen, 2004; Maras et al., 2006; Resende et al., 2013). Cell assay was used to characterize the estrogenicity of the chemicals (Tables 1 and 2), which are summarized below. The list of estrogenic chemicals characterized by cell assay. Alachlor, anethole, arsenic, boric acid, citral, eugenol, geraniol, glyphosate, licochalcone A, metalloestrogens, nerol, nitrophenols, PCB118, 4-phenylphenol, phthalates and soysaponin I (by YES assay); 4-aryl-coumarin dimer, biochanin A, 2,6-dihydroxyanthraquinone, epigallocatechin 3-gallate, formononetin, glyceollins, 6-hydroxymusizin, insecticides, juglone, naringenin, naringin, pharmaceuticals, phlorizin, pinosylvin, propelargonidins, silibinin and β-sitosterol (by MTT assay); apigenin, epigallocatechin 3-gallate and naringin (by MTS assay); benzyl salicylate, conazoles, cyanidin-3-glycoside, dieldrin and SERMs (by SRB assay); cajanin (by alamarBlue assay); arsenic (by trypan blue assay); coumestrol and dieldrin (by using CellTiter); β-carotene, glyphosate, indole-3-carbinol, lycopene, metalloestrogens and phthalates (by using cell counters); bezafibrate, bisphenol A, daphnetin, esculetin, fenofibrate, fisetin, fluorotelomer alcohols, flutolanil, galangin, gemfibrozil, insecticides, irisolidone, isorhamnetin luteolin, kaempferol, metalloestrogens, PCBs, quercetin, semicarbazide and tectorigenin (by E-screen assay); and β-carotene, epigallocatechin 3-gallate, hydroxymatairesinol, juglone and lycopene (by flow cytometry).

4.1.7. Animal test Animal tests have been used for basic research, such as genetics, developmental biology and behavioral studies, as well as applied research, such as biomedical research, xenotransplantation, drug testing and toxicology tests. Some of the abnormality in animals used for aminal tests, such as ovotestis, was found originally by the observation of wild animals, such as alligators and fish. In vivo biomarkers, such as vitellogenin and aromatase, have been used as physiological indicators to estimate efficiently the impact of estrogenic chemicals, although careful interpretateion is needed (Nadzialek et al., 2011). Meanwhile, animal tests for toxicology testing have been conducted by pharmaceutical companies and animal testing facilities, and one million animals are used every year in Europe in toxicology tests (Commission of the European Communities, 2007), to examine industrial products, such as those listed in Table 2. Test results indicate acute, subchronic or chronic effects or the damage to specific organs, such as eye and skin irritancy, mutagenicity, carcinogenicity, teratogenicity and reproductive problems. The results are expressed using variables such as LD50, the concentration of chemicals at which 50% of the test animals are killed. Animal tests have several problems: they cost several million dollars per substance, take three or four years to complete, can potentially overestimate the risks, especially giving false-positive results, and show variability in the results between the effect of high doses of chemicals in animals and the effects of low doses in large numbers of humans, as well as in the rationale of how to use data on one species to predict the risk in another. Animal tests are useful to screen endocrine disruptors to evaluate adverse endocrine-mediated reproductive and/or developmental effects in multi-generation reproduction studies. In general, the use of living organisms allows the variation of assays based on a wide range of species with different end-points. The rodent uterotrophic bioassay is the most widely used in vivo screening assay, based on the response of the estrogen-sensitive uterus. Animals are injected with the test substances and uterotrophic activities are estimated by the uterine weight (Zacharewski et al., 1998; Tamir et al., 2000; Dang et al., 2007; Jiménez-Orozco et al., 2011). Similarly, Hershberger assay has been used to identify potential (anti-)androgenic compounds (Yamada et al., 2000) and frog embryo teratogenesis assay (FETAX) to detect developmental toxicants in the environment (Fort et al., 2001). These animal tests are time-consuming and most require the use of live

animals. Animal tests were used to characterize the estrogenicity of the chemicals (Tables 1 and 2), which are summarized below. The list of estrogenic chemicals characterized by animal tests. Acetaminophen, benzo[a]pyrene, boric acid, caffeic acid phenethyl ester, daphnetin, 2,4-dihydroxybenzophenone, esculetin, ephedrine, epigallocatechin 3-gallate, estrone 3-carboranylmethyl ether, fenarimol, fluoxetine, ginsenoside Rg1, glabridin, glycitein, insecticides, naringenin, naringin, 4-nitrophenol, PCBs, 2-phenylindoles, phthalates and zeranol (by rodent uterotrophic assay); pinosylvin and β-sitosterol (by rainbow trout feeding assay); 3-(4-methylbenzylidene) camphor and perfluorobutanesulfonic acid (by using Xenopus); and DDT, oxybenzone, perfluorooctyl iodide and phthalates (by using medaka).

4.1.8. Signaling pathway analysis Signaling pathway analysis consists of a variety of methods and protocols, which have variations depending on the signaling pathways, signaling networks and functional outcomes. Various types of cell signaling induced by estrogenic chemicals are summarized in Tables 1 to 3, and the signaling pathways related to apoptosis, carcinogenesis, cell growth/differentiation, differentiation/development and inflammation are discussed in Section 3. Signaling pathway analysis was used to characterize the estrogenicity of the chemicals (Tables 1 and 2), which are summarized below. The list of estrogenic chemicals characterized by signaling pathway analysis. Aroclor 1254, epigallocatechin 3-gallate, formononetin, geniposide, ginsenoside Rb1, methoxychlor/triclosan, naringenin, plumbagin, quercetin, raloxifene, withaferin A and wogonin (for apoptosis); cadmium, di(n-butyl) phthalate, methyl-amoorain + DMBA, testosterone and tocopherols (for carcinogenesis); baicalein, benzo[a]pyrene, bisphenol A, p,p′-DDE, o,p′-DDT, equol, 17α-ethinylestradiol, 17β-E2 valerate, dieldrin, ferulic acid, genistein, β-HCH, hydroxytyrosol, luteolin, methoxychlor, naringenin, oleuropein, piceatannol, procymidone, puerarin, quercetin and tributyltin (for cell growth and proliferation); adiponectin, androstenol, estradiolquinone, genistein, resveratrol, retinoic acid and tamoxifen (for differentiation/development); and baicalein, daidzein genistein, 4-hydroxyphenyl sulfonamides, niacin, p-n-nonylphenol, p-n-octylphenol and oroxylin-A (for inflammation).

4.2. Pathway-based risk assessment Replacing animal tests with in vitro assays has been accelerated in basic science as well as in the industrial technology field. In 2007, the US National Research Council (NRC) released a report “Toxicity Testing in the 21st Century: A Vision and a Strategy” (National Research Council, 2007), in which they called for a transformation of toxicity testing from animal tests to a system based on in vitro assays where perturbations in key toxicity pathways in response to chemicals can be evaluated. Current and future toxicity testing can be categorized into four options: status quo animal testing as Option I, animal testing partly assisted by in silico and in vitro screens as Option II, minimum in vivo testing largely assisted by in vitro screens as Option III and complete in vitro (in silico) testing without animal tests as Option IV. While this report had a profound impact for environmental scientists, toxicologists and pharmacologists as well as scientists and researchers in other fields, no practical protocol has ever been established. Although a number of toxicity pathways have already been identified, most are still partial and do not have sufficient annotations for their use for risk assessment, such as that in human exposure to chemicals. Although prototype protocols for risk assessment were examined for quercetin in DNA-damage-related signaling (Adeleye et al., 2015) and benzo[a]pyrene and dioxin in AhR signaling (National Research Council, US, 2010), other pathways for these chemicals (such as those shown in Tables 1 and 2) are not included, indicating the difficulty of such an approach. What is important to use pathway-based risk assessment is not how well such a strategy can mimic animal testing, but how to shift from outcome-based assessment, where only the result of assays or the fate of animals is evaluated, to mechanism-based assessment, where the process occurring in cells is evaluated before outcomes have emerged.

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This paradigm shift requires reliable assays, which are based on the predictability of the risk and are as valuable as the fate of animals. However, as mentioned above, the variability of signaling pathways is so limited at this moment that the variability of chemicals is restricted to limited numbers of categories, so the characteristics of each chemical cannot be properly evaluated. Interesting and suggestive approaches, however, can be found in cancer genomics, where pathway-based pharmacogenomics has been a key strategy for developing personalized cancer medicine (Chin et al., 2011), and in the US National Cancer Institute (NCI) 60 human tumor cell line anticancer drug screen (NCI60), where more than 100,000 chemicals were examined for screening candidate drugs using 60 human tumor cell lines (Shoemaker, 2006). The characteristics of each chemical could be evaluated to give sufficient predictability, which is also crucial for personalized medicine.

5. Conclusion and future prospects Here, we summarized estrogenic chemicals, which are categorized by structure (Table 1) or by characteristics other than structure (Table 2) (Section 2). Estrogenic activity is understood by the mechanism-based characterization of estrogenic chemicals as summarized in Fig. 1, so we characterized the signaling pathways in which each estrogenic chemical is involved and the methods by which each estrogenic chemical is assayed (Section 3). Signaling pathways are further characterized by the receptors and the networks involving other receptors and signaling pathways as well as the pathways involving autocrine/paracrine signaling and homeostatic networks (Table 3). We found here that a number of chemicals with quite diversified structures, phenolics and nonphenolics of natural or industrial origin, show estrogenicity, and a variety of signaling pathways and networks, owing not only to the differential roles of ERs but also to the complexity of pathways, effectors and cells/ tissues, are associated with estrogenicity. While this kind of diversity and complexity would be an obstacle to understand clearly the effect of estrogenic chemicals and to establish the methodology for risk assessment, pathway-based risk assessment would give superiority as a risk assessment technology, once established, because sensitivity would be higher due to multiple monitoring points in signaling pathways, which are then integrated into a single or a few outcomes, such as those detected by animal assay, cell-proliferation assay, ligandbinding assay, protein assay, reporter-gene assay and signaling pathway analysis (see Section 4). Furthermore, complex systems such as in animal tests are not required, providing less expensive, quick, highthroughput and highly sensitive assays. However, we still need to understand more about signaling pathways to utilize the information obtained by the analysis for risk assessment and to refine the methodology based on the pathways, which need to be reasonably developed in order to replace and reduce animal tests. First, the current information about genes is quite large, although it is mostly descriptive and explanatory, and lacks predictability. Meanwhile, pathway-based risk assessment could be used as a partial replacement of or as a preliminary screening step for animal tests, such as uterotrophic assay and life-cycle assay, to detect alterations at early stages before using the uterus and other tissues/organs. The combinations of chemicals, biological outcomes and assay systems would provide quite a large number of variations to distinguish predicted outcomes of potential risks.

Acknowledgments This research was supported partly by a Knowledge Cluster Initiative program and a Grant-in-aid for Basic Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by the Guideline Program for Medical Device Development from the Ministry of Economy, Trade and Industry of Japan.

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References Abdelrahim, M., Ariazi, E., Kim, K., Khan, S., Barhoumi, R., Burghardt, R., Liu, S., Hill, D., Finnell, R., Wlodarczyk, B., Jordan, V.C., Safe, S., 2006. 3-Methylcholanthrene and other aryl hydrocarbon receptor agonists directly activate estrogen receptor alpha. Cancer Res. 66 (4), 2459–2467. Adeleye, Y., Andersen, M., Clewell, R., Davies, M., Dent, M., Edwards, S., Fowler, P., Malcomber, S., Nicol, B., Scott, A., Scott, S., Sun, B., Westmoreland, C., White, A., Zhang, Q., Carmichael, P.L., 2015. Implementing Toxicity Testing in the 21st Century (TT21C): making safety decisions using toxicity pathways, and progress in a prototype risk assessment. Toxicology 332, 102–111. Ahmad, A., Banerjee, S., Wang, Z., Kong, D., Sarkar, F.H., 2008. Plumbagin-induced apoptosis of human breast cancer cells is mediated by inactivation of NF-kappaB and Bcl-2. J. Cell. Biochem. 105 (6), 1461–1471. Ahmed, S., Valen, E., Sandelin, A., Matthews, J., 2009. Dioxin increases the interaction between aryl hydrocarbon receptor and estrogen receptor alpha at human promoters. Toxicol. Sci. 111 (2), 254–266. Akama, K.T., Thompson, L.I., Milner, T.A., McEwen, B.S., 2013. Post-synaptic density95 (PSD-95) binding capacity of G-protein-coupled receptor 30 (GPR30), an estrogen receptor that can be identified in hippocampal dendritic spines. J. Biol. Chem. 288 (9), 6438–6450. Alarid, E.T., Preisler-Mashek, M.T., Solodin, N.M., 2003. Thyroid hormone is an inhibitor of estrogen-induced degradation of estrogen receptor-alpha protein: estrogendependent proteolysis is not essential for receptor transactivation function in the pituitary. Endocrinology 144 (8), 3469–3476. Ali, Z., Khan, S.I., Khan, I.A., 2009. Soyasaponin Bh, a triterpene saponin containing a unique hemiacetal-functional five-membered ring from Glycine max (soybeans). Planta Med. 75 (4), 371–374. Ali, I., Damdimopoulou, P., Stenius, U., Adamsson, A., Mäkelä, S.I., Åkesson, A., Berglund, M., Håkansson, H., Halldin, K., 2012. Cadmium-induced effects on cellular signaling pathways in the liver of transgenic estrogen reporter mice. Toxicol. Sci. 127 (1), 66–75. Alimirah, F., Peng, X., Yuan, L., Mehta, R.R., von Knethen, A., Choubey, D., Mehta, R.G., 2012. Crosstalk between the peroxisome proliferator-activated receptor γ (PPARγ) and the vitamin D receptor (VDR) in human breast cancer cells: PPARγ binds to VDR and inhibits 1α,25-dihydroxyvitamin D3 mediated transactivation. Exp. Cell Res. 318 (19), 2490–2497. Allinson, M., Shiraishi, F., Allinson, G., 2011. A comparison of recombinant receptorreporter gene bioassays and a total estrogen enzyme linked immunosorbent assay for the rapid screening of estrogenic activity in natural and waste waters. Bull. Environ. Contam. Toxicol. 86 (5), 461–464. Andersen, H.R., Vinggaard, A.M., Rasmussen, T.H., Gjermandsen, I.M., Bonefeld-Jørgensen, E.C., 2002. Effects of currently used pesticides in assays for estrogenicity, androgenicity, and aromatase activity in vitro. Toxicol. Appl. Pharmacol. 179 (1), 1–12. Andersen, H.R., Bonefeld-Jørgensen, E.C., Nielsen, F., Jarfeldt, K., Jayatissa, M.N., Vinggaard, A.M., 2006. Estrogenic effects in vitro and in vivo of the fungicide fenarimol. Toxicol. Lett. 163 (2), 142–152. Anita, Y., Radifar, M., Kardono, L.B., Hanafi, M., Istyastono, E.P., 2012. Structure-based design of eugenol analogs as potential estrogen receptor antagonists. Bioinformation 8 (19), 901–906. Anstead, G.M., Kym, P.R., 1995. Benz[a]anthracene diols: predicted carcinogenicity and structure–estrogen receptor binding affinity relationships. Steroids 60 (5), 383–394. Arbo, M.D., Franco, M.T., Larentis, E.R., Garcia, S.C., Sebben, V.C., Leal, M.B., Dallegrave, E., Limberger, R.P., 2009. Screening for in vivo (anti)estrogenic activity of ephedrine and p-synephrine and their natural sources Ephedra sinica Stapf. (Ephedraceae) and Citrus aurantium L. (Rutaceae) in rats. Arch. Toxicol. 83 (1), 95–99. Ariazi, E.A., Jordan, V.C., 2006. Estrogen-related receptors as emerging targets in cancer and metabolic disorders. Curr. Top. Med. Chem. 6 (3), 203–215. Armstrong, A.F., Valliant, J.F., 2007. The bioinorganic and medicinal chemistry of carboranes: from new drug discovery to molecular imaging and therapy. Dalton Trans. 38, 4240–4251. Arnold, S.F., Robinson, M.K., Notides, A.C., Guillette Jr., L.J., McLachlan, J.A., 1996. A yeast estrogen screen for examining the relative exposure of cells to natural and xenoestrogens. Environ. Health Perspect. 104 (5), 544–548. Arulmozhiraja, S., Shiraishi, F., Okumura, T., Iida, M., Takigami, H., Edmonds, J.S., Morita, M., 2005. Structural requirements for the interaction of 91 hydroxylated polychlorinated biphenyls with estrogen and thyroid hormone receptors. Toxicol. Sci. 84 (1), 49–62. Ashok, B.T., Chen, Y., Liu, X., Bradlow, H.L., Mittelman, A., Tiwari, R.K., 2001. Abrogation of estrogen-mediated cellular and biochemical effects by indole-3-carbinol. Nutr. Cancer 41 (1–2), 180–187. Axon, A., May, F.E., Gaughan, L.E., Williams, F.M., Blain, P.G., Wright, M.C., 2012. Tartrazine and sunset yellow are xenoestrogens in a new screening assay to identify modulators of human oestrogen receptor transcriptional activity. Toxicology 298 (1–3), 40–51. Babiker, F.A., De Windt, L.J., van Eickels, M., Thijssen, V., Bronsaer, R.J., Grohé, C., van Bilsen, M., Doevendans, P.A., 2004. 17beta-estradiol antagonizes cardiomyocyte hypertrophy by autocrine/paracrine stimulation of a guanylyl cyclase A receptor-cyclic guanosine monophosphate-dependent protein kinase pathway. Circulation 109 (2), 269–276. Bachmeier, B.E., Mirisola, V., Romeo, F., Generoso, L., Esposito, A., Dell'eva, R., Blengio, F., Killian, P.H., Albini, A., Pfeffer, U., 2010. Reference profile correlation reveals estrogen-like trancriptional activity of Curcumin. Cell. Physiol. Biochem. 26 (3), 471–482. Baker, M.E., 2013. What are the physiological estrogens? Steroids 78 (3), 337–340. Baker, M.E., Vidal-Dorsch, D.E., Ribecco, C., Sprague, L.J., Angert, M., Lekmine, N., Ludka, C., Martella, A., Ricciardelli, E., Bay, S.M., Gully, J.R., Kelley, K.M., Schlenk, D., Carnevali, O.,

32

R. Kiyama, Y. Wada-Kiyama / Environment International 83 (2015) 11–40

Šášik, R., Hardiman, G., 2013. Molecular analysis of endocrine disruption in hornyhead turbot at wastewater outfalls in southern california using a second generation multi-species microarray. PLoS One 8 (9), e75553. Ballaré, C., Vallejo, G., Vicent, G.P., Saragüeta, P., Beato, M., 2006. Progesterone signaling in breast and endometrium. J. Steroid Biochem. Mol. Biol. 102 (1–5), 2–10. Band, A.M., Laiho, M., 2011. Crosstalk of TGF-β and estrogen receptor signaling in breast cancer. J. Mammary Gland Biol. Neoplasia 16 (2), 109–115. Barbarisi, A., Petillo, O., Di Lieto, A., Melone, M.A., Margarucci, S., Cannas, M., Peluso, G., 2001. 17-Beta estradiol elicits an autocrine leiomyoma cell proliferation: evidence for a stimulation of protein kinase-dependent pathway. J. Cell. Physiol. 186 (3), 414–424. Belguise, K., Guo, S., Sonenshein, G.E., 2007. Activation of FOXO3a by the green tea polyphenol epigallocatechin-3-gallate induces estrogen receptor alpha expression reversing invasive phenotype of breast cancer cells. Cancer Res. 67 (12), 5763–5770. Berthier, A., Girard, C., Grandvuillemin, A., Muyard, F., Skaltsounis, A.L., Jouvenot, M., Delage-Mourroux, R., 2007. Effect of 7-O-beta-D-glucopyranosylchrysin and its aglycone chrysin isolated from Podocytisus caramanicus on estrogen receptor alpha transcriptional activity. Planta Med. 73 (14), 1447–1451. Bhargavan, B., Singh, D., Gautam, A.K., Mishra, J.S., Kumar, A., Goel, A., Dixit, M., Pandey, R., Manickavasagam, L., Dwivedi, S.D., Chakravarti, B., Jain, G.K., Ramachandran, R., Maurya, R., Trivedi, A., Chattopadhyay, N., Sanyal, S., 2012. Medicarpin, a legume phytoalexin, stimulates osteoblast differentiation and promotes peak bone mass achievement in rats: evidence for estrogen receptor β-mediated osteogenic action of medicarpin. J. Nutr. Biochem. 23 (1), 27–38. Bhavnani, B.R., Stanczyk, F.Z., 2014. Pharmacology of conjugated equine estrogens: efficacy, safety and mechanism of action. J. Steroid Biochem. Mol. Biol. 142, 16–29. Bhavnani, B.R., Tam, S.P., Lu, X., 2008. Structure activity relationships and differential interactions and functional activity of various equine estrogens mediated via estrogen receptors (ERs) ERalpha and ERbeta. Endocrinology 149 (10), 4857–4870. Biberger, C., von Angerer, E., 1996. 2-Phenylindoles with sulfur containing side chains. Estrogen receptor affinity, antiestrogenic potency, and antitumor activity. J. Steroid Biochem. Mol. Biol. 58 (1), 31–43. Boettger-Tong, H.L., Stancel, G.M., 1995. Retinoic acid inhibits estrogen-induced uterine stromal and myometrial cell proliferation. Endocrinology 136 (7), 2975–2983. Boldrin, P., Resende, F., Höhne, A., de Camargo, M., Espanha, L., Nogueira, C., Melo, M., Vilegas, W., Varanda, E., 2013. Estrogenic and mutagenic activities of Crotalaria pallida measured by recombinant yeast assay and Ames test. BMC Complement. Altern. Med. 13 (1), 216. Boudot, A., Kerdivel, G., Habauzit, D., Eeckhoute, J., Le Dily, F., Flouriot, G., Samson, M., Pakdel, F., 2011. Differential estrogen-regulation of CXCL12 chemokine receptors, CXCR4 and CXCR7, contributes to the growth effect of estrogens in breast cancer cells. PLoS One 6 (6), e20898. Boué, S.M., Tilghman, S.L., Elliott, S., Zimmerman, M.C., Williams, K.Y., Payton-Stewart, F., Miraflor, A.P., Howell, M.H., Shih, B.Y., Carter-Wientjes, C.H., Segar, C., Beckman, B.S., Wiese, T.E., Cleveland, T.E., McLachlan, J.A., Burow, M.E., 2009. Identification of the potent phytoestrogen glycinol in elicited soybean (Glycine max). Endocrinology 150 (5), 2446–2453. Bourque, M., Morissette, M., Di Paolo, T., 2014. Raloxifene activates G protein-coupled estrogen receptor 1/Akt signaling to protect dopamine neurons in 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine mice. Neurobiol. Aging 35 (10), 2347–2356. Bovee, T.F., Helsdingen, R.J., Rietjens, I.M., Keijer, J., Hoogenboom, R.L., 2004. Rapid yeast estrogen bioassays stably expressing human estrogen receptors alpha and beta, and green fluorescent protein: a comparison of different compounds with both receptor types. J. Steroid Biochem. Mol. Biol. 91 (3), 99–109. Brailoiu, G.C., Benamar, K., Arterburn, J.B., Gao, E., Rabinowitz, J.E., Koch, W.J., Brailoiu, E., 2013. Aldosterone increases cardiac vagal tone via G protein-coupled oestrogen receptor activation. J. Physiol. 591 (Pt 17), 4223–4235. Brander, S.M., He, G., Smalling, K.L., Denison, M.S., Cherr, G.N., 2012. The in vivo estrogenic and in vitro anti-estrogenic activity of permethrin and bifenthrin. Environ. Toxicol. Chem. 31 (12), 2848–2855. Brennan, J.C., Denison, M.S., Holstege, D.M., Magiatis, P., Dallas, J.L., Gutierrez, E.G., Soshilov, A.A., Millam, J.R., 2013. 2,3-Cis-2R,3R-(−)-epiafzelechin-3-O-p-coumarate, a novel flavan-3-ol isolated from Fallopia convolvulus seed, is an estrogen receptor agonist in human cell lines. BMC Complement. Altern. Med. 13, 133. Brinton, R.D., Proffitt, P., Tran, J., Luu, R., 1997. Equilin, a principal component of the estrogen replacement therapy premarin, increases the growth of cortical neurons via an NMDA receptor-dependent mechanism. Exp. Neurol. 147 (2), 211–220. Briz, V., Molina-Molina, J.M., Sánchez-Redondo, S., Fernández, M.F., Grimalt, J.O., Olea, N., Rodríguez-Farré, E., Suñol, C., 2011. Differential estrogenic effects of the persistent organochlorine pesticides dieldrin, endosulfan, and lindane in primary neuronal cultures. Toxicol. Sci. 120 (2), 413–427. Bulayeva, N.N., Watson, C.S., 2004. Xenoestrogen-induced ERK-1 and ERK-2 activation via multiple membrane-initiated signaling pathways. Environ. Health Perspect. 112 (15), 1481–1487. Bulzomi, P., Bolli, A., Galluzzo, P., Acconcia, F., Ascenzi, P., Marino, M., 2012a. The naringenin-induced proapoptotic effect in breast cancer cell lines holds out against a high bisphenol a background. IUBMB Life 64 (8), 690–696. Bulzomi, P., Galluzzo, P., Bolli, A., Leone, S., Acconcia, F., Marino, M., 2012b. The proapoptotic effect of quercetin in cancer cell lines requires ERβ-dependent signals. J. Cell. Physiol. 227 (5), 1891–1898. Burow, M.E., Boue, S.M., Collins-Burow, B.M., Melnik, L.I., Duong, B.N., Carter-Wientjes, C.H., Li, S., Wiese, T.E., Cleveland, T.E., McLachlan, J.A., 2001. Phytochemical glyceollins, isolated from soy, mediate antihormonal effects through estrogen receptor alpha and beta. J. Clin. Endocrinol. Metab. 86 (4), 1750–1758. Byrne, C., Divekar, S.D., Storchan, G.B., Parodi, D.A., Martin, M.B., 2013. Metals and breast cancer. J. Mammary Gland Biol. Neoplasia 18 (1), 63–73.

Cao, L., Gao, H., Li, P., Gui, S., Zhang, Y., 2014. The Wnt/β-catenin signaling pathway is involved in the antitumor effect of fulvestrant on rat prolactinoma MMQ cells. Tumour Biol. 35 (6), 5121–5127. Chalabi, N., Le Corre, L., Maurizis, J.C., Bignon, Y.J., Bernard-Gallon, D.J., 2004. The effects of lycopene on the proliferation of human breast cells and BRCA1 and BRCA2 gene expression. Eur. J. Cancer 40 (11), 1768–1775. Chalopin, M., Tesse, A., Martínez, M.C., Rognan, D., Arnal, J.F., Andriantsitohaina, R., 2010. Estrogen receptor alpha as a key target of red wine polyphenols action on the endothelium. PLoS One 5 (1), e8554. Chaloupka, K., Krishnan, V., Safe, S., 1992. Polynuclear aromatic hydrocarbon carcinogens as antiestrogens in MCF-7 human breast cancer cells: role of the Ah receptor. Carcinogenesis 13 (12), 2233–2239. Chan, H.Y., Yao, X., Tsang, S.Y., Bourreau, J.P., Chan, F.L., Huang, Y., 2002. Isoproterenol amplifies 17 beta-estradiol-mediated vasorelaxation: role of endothelium/nitric oxide and cyclic AMP. Cardiovasc. Res. 53 (3), 627–633. Chan, M.Y., Wai Man, G., Chen, Z.Y., Wang, J., Leung, L.K., 2007. Oestrogen receptor alpha is required for biochanin A-induced apolipoprotein A-1 mRNA expression in HepG2 cells. Br. J. Nutr. 98 (3), 534–539. Chandsawangbhuwana, C., Baker, M.E., 2014. 3D models of human ERα and ERβ complexed with coumestrol. Steroids 80, 37–43. Chang, E.J., Lee, W.J., Cho, S.H., Choi, S.W., 2003. Proliferative effects of flavan-3-ols and propelargonidins from rhizomes of Drynaria fortunei on MCF-7 and osteoblastic cells. Arch. Pharm. Res. 26 (8), 620–630. Chang, C.J., Chiu, J.H., Tseng, L.M., Chang, C.H., Chien, T.M., Wu, C.W., Lui, W.Y., 2006. Modulation of HER2 expression by ferulic acid on human breast cancer MCF7 cells. Eur. J. Clin. Investig. 36 (8), 588–596. Chatterjee, A., Chatterji, U., 2010. Arsenic abrogates the estrogen-signaling pathway in the rat uterus. Reprod. Biol. Endocrinol. 8, 80. Chatterjee, S., Ray, A., Bagchi, P., Deb, C., 1992. Estrogenic effects of aldrin and quinalphos in rats. Bull. Environ. Contam. Toxicol. 48 (1), 125–130. Chen, Y., 2012. Organophosphate-induced brain damage: mechanisms, neuropsychiatric and neurological consequences, and potential therapeutic strategies. Neurotoxicology 33 (3), 391–400. Chen, J., Sun, L., 2012. Formononetin-induced apoptosis by activation of Ras/p38 mitogenactivated protein kinase in estrogen receptor-positive human breast cancer cells. Horm. Metab. Res. 44 (13), 943–948. Chen, H., Xiao, J., Hu, G., Zhou, J., Xiao, H., Wang, X., 2002. Estrogenicity of organophosphorus and pyrethroid pesticides. J. Toxicol. Environ. Health A 65 (19), 1419–1435. Chen, W.F., Gao, Q.G., Dai, Z.J., Kung, A.W., Guo, D.A., Wong, M.S., 2012. Estrogenic effects of ginsenoside Rg1 in endometrial cells in vitro were not observed in immature CD-1 mice or ovariectomized mice model. Menopause 19 (9), 1052–1061. Chen, J., Zhao, X., Ye, Y., Wang, Y., Tian, J., 2013. Estrogen receptor beta-mediated proliferative inhibition and apoptosis in human breast cancer by calycosin and formononetin. Cell. Physiol. Biochem. 32 (6), 1790–1797. Chen, J., Hou, R., Zhang, X., Ye, Y., Wang, Y., Tian, J., 2014a. Calycosin suppresses breast cancer cell growth via ERβ-dependent regulation of IGF-1R, p38 MAPK and PI3K/ Akt pathways. PLoS One 9 (3), e91245. Chen, Y., Li, Z., He, Y., Shang, D., Pan, J., Wang, H., Chen, H., Zhu, Z., Wan, L., Wang, X., 2014b. Estrogen and pure antiestrogen fulvestrant (ICI 182 780) augment cell-matrigel adhesion of MCF-7 breast cancer cells through a novel G protein coupled estrogen receptor (GPR30)-to-calpain signaling axis. Toxicol. Appl. Pharmacol. 275 (2), 176–181. Chen, X., Xu, S., Tan, T., Lee, S.T., Cheng, S.H., Lee, F.W., Xu, S.J., Ho, K.C., 2014c. Toxicity and estrogenic endocrine disrupting activity of phthalates and their mixtures. Int. J. Environ. Res. Public Health 11 (3), 3156–3168. Cheng, P., Kanterewicz, B., Hershberger, P.A., McCarty Jr., K.S., Day, B.W., Nichols, M., 2004. Inhibition of estrogen receptor alpha-mediated transcription by antiestrogenic 1,1dichloro-2,2,3-triarylcyclopropanes. Mol. Pharmacol. 66 (4), 970–977. Chimento, A., Sirianni, R., Casaburi, I., Pezzi, V., 2014. Role of estrogen receptors and g protein-coupled estrogen receptor in regulation of hypothalamus–pituitary–testis axis and spermatogenesis. Front. Endocrinol. (Lausanne) 5, 1. Chin, L., Andersen, J.N., Futreal, P.A., 2011. Cancer genomics: from discovery science to personalized medicine. Nat. Med. 17 (3), 297–303. Choe, S.Y., Kim, S.J., Kim, H.G., Lee, J.H., Choi, Y., Lee, H., Kim, Y., 2003. Evaluation of estrogenicity of major heavy metals. Sci. Total Environ. 312 (1–3), 15–21. Choi, R.C., Zhu, J.T., Yung, A.W., Lee, P.S., Xu, S.L., Guo, A.J., Zhu, K.Y., Dong, T.T., Tsim, K.W., 2013. Synergistic action of flavonoids, baicalein, and daidzein in estrogenic and neuroprotective effects: a development of potential health products and therapeutic drugs against Alzheimer's disease. Evid. Based Complement. Alternat. Med. 2013, 635694. Chow, S.K., Chan, J.Y., Fung, K.P., 2004. Suppression of cell proliferation and regulation of estrogen receptor alpha signaling pathway by arsenic trioxide on human breast cancer MCF-7 cells. J. Endocrinol. 182 (2), 325–337. Chung, H., Jung, Y.M., Shin, D.H., Lee, J.Y., Oh, M.Y., Kim, H.J., Jang, K.S., Jeon, S.J., Son, K.H., Kong, G., 2008. Anticancer effects of wogonin in both estrogen receptor-positive and -negative human breast cancer cell lines in vitro and in nude mice xenografts. Int. J. Cancer 122 (4), 816–822. Collins-Burow, B.M., Burow, M.E., Duong, B.N., McLachlan, J.A., 2000. Estrogenic and antiestrogenic activities of flavonoid phytochemicals through estrogen receptor binding-dependent and -independent mechanisms. Nutr. Cancer 38 (2), 229–244. Collins-Burow, B.M., Antoon, J.W., Frigo, D.E., Elliott, S., Weldon, C.B., Boue, S.M., Beckman, B.S., Curiel, T.J., Alam, J., McLachlan, J.A., Burow, M.E., 2012. Antiestrogenic activity of flavonoid phytochemicals mediated via the c-Jun N-terminal protein kinase pathway. Cell-type specific regulation of estrogen receptor alpha. J. Steroid Biochem. Mol. Biol. 132 (1–2), 186–193. Comitato, R., Nesaretnam, K., Leoni, G., Ambra, R., Canali, R., Bolli, A., Marino, M., Virgili, F., 2009. A novel mechanism of natural vitamin E tocotrienol activity: involvement of ERbeta signal transduction. Am. J. Physiol. Endocrinol. Metab. 297 (2), E427–E437.

R. Kiyama, Y. Wada-Kiyama / Environment International 83 (2015) 11–40 Commission of the European Communities, 2007. Fifth report on the statistics on the number of animals used for experimental and other scientific purposes in the member states of the European Union. Report from the Commission to the Council and the European Parliament. COM(2007) 675 Final (November). Connor, K., Ramamoorthy, K., Moore, M., Mustain, M., Chen, I., Safe, S., Zacharewski, T., Gillesby, B., Joyeux, A., Balaguer, P., 1997. Hydroxylated polychlorinated biphenyls (PCBs) as estrogens and antiestrogens: structure–activity relationships. Toxicol. Appl. Pharmacol. 145 (1), 111–123. Coronado, M., De Haro, H., Deng, X., Rempel, M.A., Lavado, R., Schlenk, D., 2008. Estrogenic activity and reproductive effects of the UV-filter oxybenzone (2-hydroxy-4methoxyphenyl-methanone) in fish. Aquat. Toxicol. 90 (3), 182–187. Cos, S., González, A., Martínez-Campa, C., Mediavilla, M.D., Alonso-González, C., SánchezBarceló, E.J., 2008. Melatonin as a selective estrogen enzyme modulator. Curr. Cancer Drug Targets 8 (8), 691–702. Cosentino, M., Marino, F., Ferrari, M., Rasini, E., Bombelli, R., Luini, A., Legnaro, M., Delle Canne, M.G., Luzzani, M., Crema, F., Paracchini, S., Lecchini, S., 2007. Estrogenic activity of 7-hydroxymatairesinol potassium acetate (HMR/lignan) from Norway spruce (Picea abies) knots and of its active metabolite enterolactone in MCF-7 cells. Pharmacol. Res. 56 (2), 140–147. Dang, V.H., Choi, K.C., Jeung, E.B., 2007. Tetrabromodiphenyl ether (BDE 47) evokes estrogenicity and calbindin-D9k expression through an estrogen receptor-mediated pathway in the uterus of immature rats. Toxicol. Sci. 97 (2), 504–511. De Angelis, M., Stossi, F., Waibel, M., Katzenellenbogen, B.S., Katzenellenbogen, J.A., 2005. Isocoumarins as estrogen receptor beta selective ligands: isomers of isoflavone phytoestrogens and their metabolites. Bioorg. Med. Chem. 13 (23), 6529–6542. de Medina, P., Genovese, S., Paillasse, M.R., Mazaheri, M., Caze-Subra, S., Bystricky, K., Curini, M., Silvente-Poirot, S., Epifano, F., Poirot, M., 2010. Auraptene is an inhibitor of cholesterol esterification and a modulator of estrogen receptors. Mol. Pharmacol. 78 (5), 827–836. Denier, X., Hill, E.M., Rotchell, J., Minier, C., 2009. Estrogenic activity of cadmium, copper and zinc in the yeast estrogen screen. Toxicol. In Vitro 23 (4), 569–573. Deroo, B.J., Korach, K.S., 2006. Estrogen receptors and human disease. J. Clin. Invest. 116 (3), 561–570. Desaulniers, D., Leingartner, K., Zacharewski, T., Foster, W.G., 1998. Optimization of an MCF7-E3 cell proliferation assay and effects of environmental pollutants and industrial chemicals. Toxicol. In Vitro 12 (4), 409–422. Dietsch, V., Kalf, G.F., Hazel, B.A., 1996. Induction of granulocytic differentiation in myeloblasts by 17-beta-estradiol involves the leukotriene D4 receptor. Recept. Signal Transduct. 6 (2), 63–75. Dong, S., Terasaka, S., Kiyama, R., 2011. Bisphenol A induces a rapid activation of Erk1/2 through GPR30 in human breast cancer cells. Environ. Pollut. 159 (1), 212–218. Dong, S., Furutani, Y., Kimura, S., Zhu, Y., Kawabata, K., Furutani, M., Nishikawa, T., Tanaka, T., Masaki, T., Matsuoka, R., Kiyama, R., 2013a. Brefeldin A is an estrogenic, Erk1/2activating component in the extract of Agaricus blazei mycelia. J. Agric. Food Chem. 61 (1), 128–136. Dong, W.H., Chen, J.C., He, Y.L., Xu, J.J., Mei, Y.A., 2013b. Resveratrol inhibits K(v)2.2 currents through the estrogen receptor GPR30-mediated PKC pathway. Am. J. Physiol. Cell Physiol. 305 (5), C547–C557. Dorosh, A., Děd, L., Elzeinová, F., Pěknicová, J., 2011. Assessing oestrogenic effects of brominated flame retardants hexabromocyclododecane and tetrabromobisphenol A on MCF-7 cells. Folia Biol. (Praha) 57 (1), 35–39. Dowdy, J., Brower, S., Miller, M.R., 2003. Acetaminophen exhibits weak antiestrogenic activity in human endometrial adenocarcinoma (Ishikawa) cells. Toxicol. Sci. 72 (1), 57–65. Du, G., Shen, O., Sun, H., Fei, J., Lu, C., Song, L., Xia, Y., Wang, S., Wang, X., 2010. Assessing hormone receptor activities of pyrethroid insecticides and their metabolites in reporter gene assays. Toxicol. Sci. 116 (1), 58–66. DuSell, C.D., Nelson, E.R., Wang, X., Abdo, J., Mödder, U.I., Umetani, M., GestyPalmer, D., Javitt, N.B., Khosla, S., McDonnell, D.P., 2010. The endogenous selective estrogen receptor modulator 27-hydroxycholesterol is a negative regulator of bone homeostasis. Endocrinology 151 (8), 3675–3685. Eldridge, J.C., Stevens, J.T., Breckenridge, C.B., 2008. Atrazine interaction with estrogen expression systems. Rev. Environ. Contam. Toxicol. 196, 147–160. El-Halawany, A.M., Chung, M.H., Nakamura, N., Ma, C.M., Nishihara, T., Hattori, M., 2007. Estrogenic and anti-estrogenic activities of Cassia tora phenolic constituents. Chem. Pharm. Bull. (Tokyo) 55 (10), 1476–1482. Endo, Y., Iijima, T., Yamakoshi, Y., Fukasawa, H., Miyaura, C., Inada, M., Kubo, A., Itai, A., 2001. Potent estrogen agonists based on carborane as a hydrophobic skeletal structure. A new medicinal application of boron clusters. Chem. Biol. 8 (4), 341–355. Escande, A., Pillon, A., Servant, N., Cravedi, J.P., Larrea, F., Muhn, P., Nicolas, J.C., Cavaillès, V., Balaguer, P., 2006. Evaluation of ligand selectivity using reporter cell lines stably expressing estrogen receptor alpha or beta. Biochem. Pharmacol. 71 (10), 1459–1469. Etique, N., Grillier-Vuissoz, I., Lecomte, J., Flament, S., 2009. Crosstalk between adenosine receptor (A2A isoform) and ERalpha mediates ethanol action in MCF-7 breast cancer cells. Oncol. Rep. 21 (4), 977–981. Fan, G.W., Zhang, Y., Jiang, X., Zhu, Y., Wang, B., Su, L., Cao, W., Zhang, H., Gao, X., 2013. Anti-inflammatory activity of baicalein in LPS-stimulated RAW264.7 macrophages via estrogen receptor and NF-κB-dependent pathways. Inflammation 36 (6), 1584–1591. Fang, J., Akwabi-Ameyaw, A., Britton, J.E., Katamreddy, S.R., Navas III, F., Miller, A.B., Williams, S.P., Gray, D.W., Orband-Miller, L.A., Shearin, J., Heyer, D., 2008. Synthesis of 3-alkyl naphthalenes as novel estrogen receptor ligands. Bioorg. Med. Chem. Lett. 18 (18), 5075–5077.

33

Fang, C., Wu, X., Huang, Q., Liao, Y., Liu, L., Qiu, L., Shen, H., Dong, S., 2012. PFOS elicits transcriptional responses of the ER, AHR and PPAR pathways in Oryzias melastigma in a stage-specific manner. Aquat. Toxicol. 106–107, 9–19. Farabegoli, F., Barbi, C., Lambertini, E., Piva, R., 2007. (−)-Epigallocatechin-3-gallate downregulates estrogen receptor alpha function in MCF-7 breast carcinoma cells. Cancer Detect. Prev. 31 (6), 499–504. Feng, J., Shi, Z., Ye, Z., 2008. Effects of metabolites of the lignans enterolactone and enterodiol on osteoblastic differentiation of MG-63 cells. Biol. Pharm. Bull. 31 (6), 1067–1070. Fernandes, I., Faria, A., Azevedo, J., Soares, S., Calhau, C., De Freitas, V., Mateus, N., 2010. Influence of anthocyanins, derivative pigments and other catechol and pyrogalloltype phenolics on breast cancer cell proliferation. J. Agric. Food Chem. 58 (6), 3785–3792. Fernandez, J.W., Rezai-Zadeh, K., Obregon, D., Tan, J., 2010. EGCG functions through estrogen receptor-mediated activation of ADAM10 in the promotion of nonamyloidogenic processing of APP. FEBS Lett. 584 (19), 4259–4267. Fielden, M.R., Chen, I., Chittim, B., Safe, S.H., Zacharewski, T.R., 1997. Examination of the estrogenicity of 2,4,6,2′,6′-pentachlorobiphenyl (PCB 104), its hydroxylated metabolite 2,4,6,2′,6′-pentachloro-4-biphenylol (HO-PCB 104), and a further chlorinated derivative, 2,4,6,2′,4′,6′-hexachlorobiphenyl (PCB 155). Environ. Health Perspect. 105 (11), 1238–1248. Fillmore, C.M., Gupta, P.B., Rudnick, J.A., Caballero, S., Keller, P.J., Lander, E.S., Kuperwasser, C., 2010. Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling. Proc. Natl. Acad. Sci. U. S. A. 107 (50), 21737–21742. Finlay, G.A., Hunter, D.S., Walker, C.L., Paulson, K.E., Fanburg, B.L., 2003. Regulation of PDGF production and ERK activation by estrogen is associated with TSC2 gene expression. Am. J. Physiol. Cell Physiol. 285 (2), C409–C418. Fort, D.J., Rogers, R.L., Paul, R.R., Miller, M.F., Clark, P., Stover, E.L., Yoshioko, J., Quimby, F., Sower, S.A., Reed, K.L., Babbitt, K.J., Rolland, R., 2001. Effects of pond water, sediment and sediment extract samples from New Hampshire, USA on early Xenopus development and metamorphosis: comparison to native species. J. Appl. Toxicol. 21 (3), 199–209. Fox, E.M., Kuba, M.G., Miller, T.W., Davies, B.R., Arteaga, C.L., 2013. Autocrine IGF-I/insulin receptor axis compensates for inhibition of AKT in ER-positive breast cancer cells with resistance to estrogen deprivation. Breast Cancer Res. 15 (4), R55. Frazier-Jessen, M.R., Mott, F.J., Witte, P.L., Kovacs, E.J., 1996. Estrogen suppression of connective tissue deposition in a murine model of peritoneal adhesion formation. J. Immunol. 156 (8), 3036–3042. Furuta, C., Suzuki, A.K., Taneda, S., Kamata, K., Hayashi, H., Mori, Y., Li, C., Watanabe, G., Taya, K., 2004. Estrogenic activities of nitrophenols in diesel exhaust particles. Biol. Reprod. 70 (5), 1527–1533. Gaido, K.W., Leonard, L.S., Maness, S.C., Hall, J.M., McDonnell, D.P., Saville, B., Safe, S., 1999. Differential interaction of the methoxychlor metabolite 2,2-bis-(p-hydroxyphenyl)1,1,1-trichloroethane with estrogen receptors alpha and beta. Endocrinology 140 (12), 5746–5753. Gallet, M., Vanacker, J.M., 2010. ERR receptors as potential targets in osteoporosis. Trends Endocrinol. Metab. 21 (10), 637–641. Galluzzo, P., Ascenzi, P., Bulzomi, P., Marino, M., 2008. The nutritional flavanone naringenin triggers antiestrogenic effects by regulating estrogen receptor alphapalmitoylation. Endocrinology 149 (5), 2567–2575. Gantus, M.A., Alves, L.M., Stipursky, J., Souza, E.C., Teodoro, A.J., Alves, T.R., Carvalho, D.P., Martinez, A.M., Gomes, F.C., Nasciutti, L.E., 2011. Estradiol modulates TGF-β1 expression and its signaling pathway in thyroid stromal cells. Mol. Cell. Endocrinol. 337 (1–2), 71–79. Gao, Q.G., Chen, W.F., Xie, J.X., Wong, M.S., 2009. Ginsenoside Rg1 protects against 6OHDA-induced neurotoxicity in neuroblastoma SK-N-SH cells via IGF-I receptor and estrogen receptor pathways. J. Neurochem. 109 (5), 1338–1347. Gao, Y., Huang, E., Zhang, H., Wang, J., Wu, N., Chen, X., Wang, N., Wen, S., Nan, G., Deng, F., Liao, Z., Wu, D., Zhang, B., Zhang, J., Haydon, R.C., Luu, H.H., Shi, L.L., He, T.C., 2013. Crosstalk between Wnt/β-catenin and estrogen receptor signaling synergistically promotes osteogenic differentiation of mesenchymal progenitor cells. PLoS One 8 (12), e82436. Gao, Q.G., Chan, H.Y., Man, C.W., Wong, M.S., 2014. Differential ERα-mediated rapid estrogenic actions of ginsenoside Rg1 and estren in human breast cancer MCF-7 cells. J. Steroid Biochem. Mol. Biol. 141, 104–112. García, M.A., Peña, D., Alvarez, L., Cocca, C., Pontillo, C., Bergoc, R., de Pisarev, D.K., Randi, A., 2010. Hexachlorobenzene induces cell proliferation and IGF-I signaling pathway in an estrogen receptor alpha-dependent manner in MCF-7 breast cancer cell line. Toxicol. Lett. 192 (2), 195–205. Garcia-Segura, L.M., Diolez-Bojda, F., Lenoir, V., Naftolin, F., Kerdelhué, B., 1992. Estrogenlike effects of the mammary carcinogen 7,12-dimethylbenz(alpha)anthracene on hypothalamic neuronal membranes. Brain Res. Bull. 28 (4), 625–628. Garritano, S., Pinto, B., Calderisi, M., Cirillo, T., Amodio-Cocchieri, R., Reali, D., 2006. Estrogen-like activity of seafood related to environmental chemical contaminants. Environ. Health 5, 9. Ghisari, M., Bonefeld-Jorgensen, E.C., 2009. Effects of plasticizers and their mixtures on estrogen receptor and thyroid hormone functions. Toxicol. Lett. 189 (1), 67–77. Ghosh, D., Taylor, J.A., Green, J.A., Lubahn, D.B., 1999. Methoxychlor stimulates estrogenresponsive messenger ribonucleic acids in mouse uterus through a non-estrogen receptor (non-ER) alpha and non-ER beta mechanism. Endocrinology 140 (8), 3526–3533. Gilad, L.A., Schwartz, B., 2007. Association of estrogen receptor beta with plasmamembrane caveola components: implication in control of vitamin D receptor. J. Mol. Endocrinol. 38 (6), 603–618. Gilad, L.A., Bresler, T., Gnainsky, J., Smirnoff, P., Schwartz, B., 2005. Regulation of vitamin D receptor expression via estrogen-induced activation of the ERK 1/2 signaling pathway in colon and breast cancer cells. J. Endocrinol. 185 (3), 577–592.

34

R. Kiyama, Y. Wada-Kiyama / Environment International 83 (2015) 11–40

Gillies, G.E., McArthur, S., 2010. Estrogen actions in the brain and the basis for differential action in men and women: a case for sex-specific medicines. Pharmacol. Rev. 62 (2), 155–198. Giretti, M.S., Montt Guevara, M.M., Cecchi, E., Mannella, P., Palla, G., Spina, S., Bernacchi, G., Di Bello, S., Genazzani, A.R., Genazzani, A.D., Simoncini, T., 2014. Effects of estetrol on migration and invasion in T47-D breast cancer cells through the actin cytoskeleton. Front. Endocrinol. (Lausanne) 5, 80. Go, V., Garey, J., Wolff, M.S., Pogo, B.G., 1999. Estrogenic potential of certain pyrethroid compounds in the MCF-7 human breast carcinoma cell line. Environ. Health Perspect. 107 (3), 173–177. Goodin, M.G., Fertuck, K.C., Zacharewski, T.R., Rosengren, R.J., 2002. Estrogen receptormediated actions of polyphenolic catechins in vivo and in vitro. Toxicol. Sci. 69 (2), 354–361. Gorodeski, G.I., 2000. Role of nitric oxide and cyclic guanosine 3′,5′-monophosphate in the estrogen regulation of cervical epithelial permeability. Endocrinology 141 (5), 1658–1666. Gould, J.C., Leonard, L.S., Maness, S.C., Wagner, B.L., Conner, K., Zacharewski, T., Safe, S., McDonnell, D.P., Gaido, K.W., 1998. Bisphenol A interacts with the estrogen receptor alpha in a distinct manner from estradiol. Mol. Cell. Endocrinol. 142 (1–2), 203–214. Gozgit, J.M., Nestor, K.M., Fasco, M.J., Pentecost, B.T., Arcaro, K.F., 2004. Differential action of polycyclic aromatic hydrocarbons on endogenous estrogen-responsive genes and on a transfected estrogen-responsive reporter in MCF-7 cells. Toxicol. Appl. Pharmacol. 196 (1), 58–67. Gräns, J., Wassmur, B., Celander, M.C., 2010. One-way inhibiting cross-talk between arylhydrocarbon receptor (AhR) and estrogen receptor (ER) signaling in primary cultures of rainbow trout hepatocytes. Aquat. Toxicol. 100 (3), 263–270. Grünfeld, H.T., Bonefeld-Jorgensen, E.C., 2004. Effect of in vitro estrogenic pesticides on human oestrogen receptor alpha and beta mRNA levels. Toxicol. Lett. 151 (3), 467–480. Gunther, J.R., Moore, T.W., Collins, M.L., Katzenellenbogen, J.A., 2008. Amphipathic benzenes are designed inhibitors of the estrogen receptor alpha/steroid receptor coactivator interaction. ACS Chem. Biol. 3 (5), 282–286. Guo, D., Wang, J., Wang, X., Luo, H., Zhang, H., Cao, D., Chen, L., Huang, N., 2011. Double directional adjusting estrogenic effect of naringin from Rhizoma drynariae (Gusuibu). J. Ethnopharmacol. 138 (2), 451–457. Guo, A.J., Choi, R.C., Zheng, K.Y., Chen, V.P., Dong, T.T., Wang, Z.T., Vollmer, G., Lau, D.T., Tsim, K.W., 2012. Kaempferol as a flavonoid induces osteoblastic differentiation via estrogen receptor signaling. Chin. Med. 7, 10. Hall, J.M., Korach, K.S., 2003. Stromal cell-derived factor 1, a novel target of estrogen receptor action, mediates the mitogenic effects of estradiol in ovarian and breast cancer cells. Mol. Endocrinol. 17 (5), 792–803. Hamblen, E.L., Cronin, M.T., Schultz, T.W., 2003. Estrogenicity and acute toxicity of selected anilines using a recombinant yeast assay. Chemosphere 52 (7), 1173–1181. Hamelers, I.H., Van Schaik, R.F., Sussenbach, J.S., Steenbergh, P.H., 2003. 17beta-Estradiol responsiveness of MCF-7 laboratory strains is dependent on an autocrine signal activating the IGF type I receptor. Cancer Cell Int. 3 (1), 10. Han, D.H., Denison, M.S., Tachibana, H., Yamada, K., 2002. Relationship between estrogen receptor-binding and estrogenic activities of environmental estrogens and suppression by flavonoids. Biosci. Biotechnol. Biochem. 66 (7), 1479–1487. Han, S.I., Komatsu, Y., Murayama, A., Steffensen, K.R., Nakagawa, Y., Nakajima, Y., Suzuki, M., Oie, S., Parini, P., Vedin, L.L., Kishimoto, H., Shimano, H., Gustafsson, J.Å., Yanagisawa, J., 2014. Estrogen receptor ligands ameliorate fatty liver through a nonclassical estrogen receptor/Liver X receptor pathway in mice. Hepatology 59 (5), 1791–1802. Hao, R., Bondesson, M., Singh, A.V., Riu, A., McCollum, C.W., Knudsen, T.B., Gorelick, D.A., Gustafsson, J.Å., 2013. Identification of estrogen target genes during zebrafish embryonic development through transcriptomic analysis. PLoS One 8 (11), e79020. Härkönen, P.L., Väänänen, H.K., 2006. Monocyte–macrophage system as a target for estrogen and selective estrogen receptor modulators. Ann. N. Y. Acad. Sci. 1089, 218–227. Harnagea-Theophilus, E., Gadd, S.L., Knight-Trent, A.H., DeGeorge, G.L., Miller, M.R., 1999. Acetaminophen-induced proliferation of breast cancer cells involves estrogen receptors. Toxicol. Appl. Pharmacol. 155 (3), 273–279. Harris, C.A., Henttu, P., Parker, M.G., Sumpter, J.P., 1997. The estrogenic activity of phthalate esters in vitro. Environ. Health Perspect. 105 (8), 802–811. Harris, D.M., Besselink, E., Henning, S.M., Go, V.L., Heber, D., 2005. Phytoestrogens induce differential estrogen receptor alpha- or beta-mediated responses in transfected breast cancer cells. Exp. Biol. Med. (Maywood) 230 (8), 558–568. Hashimoto, Y., Moriguchi, Y., Oshima, H., Nishikawa, J., Nishihara, T., Nakamura, M., 2000. Estrogenic activity of chemicals for dental and similar use in vitro. J. Mater. Sci. Mater. Med. 11 (8), 465–468. Hashimoto, Y., Moriguchi, Y., Oshima, H., Kawaguchi, M., Miyazaki, K., Nakamura, M., 2001. Measurement of estrogenic activity of chemicals for the development of new dental polymers. Toxicol. In Vitro 15 (4–5), 421–425. Hashimoto, Y., Kawaguchi, M., Miyazaki, K., Nakamura, M., 2003. Estrogenic activity of tissue conditioners in vitro. Dent. Mater. 19 (4), 341–346. Hashimoto, R., Yu, J., Koizumi, H., Ouchi, Y., Okabe, T., 2012. Ginsenoside Rb1 prevents MPP(+)-induced apoptosis in PC12 cells by stimulating estrogen receptors with consequent activation of ERK1/2, Akt and inhibition of SAPK/JNK, p38 MAPK. Evid. Based Complement. Alternat. Med. 2012, 693717. Hattori, Y., Kojima, T., Kato, D., Matsubara, H., Takigawa, M., Ishiguro, N., 2012. A selective estrogen receptor modulator inhibits tumor necrosis factor-α-induced apoptosis through the ERK1/2 signaling pathway in human chondrocytes. Biochem. Biophys. Res. Commun. 421 (3), 418–424. Hazell, G.G., Yao, S.T., Roper, J.A., Prossnitz, E.R., O'Carroll, A.M., Lolait, S.J., 2009. Localisation of GPR30, a novel G protein-coupled oestrogen receptor, suggests multiple functions in rodent brain and peripheral tissues. J. Endocrinol. 202 (2), 223–236.

Hegazy, M.E., El-Hamd, H., Mohamed, A., El-Halawany, A.M., Djemgou, P.C., Shahat, A.A., Paré, P.W., 2011. Estrogenic activity of chemical constituents from Tephrosia candida. J. Nat. Prod. 74 (5), 937–942. Henke, B.R., Consler, T.G., Go, N., Hale, R.L., Hohman, D.R., Jones, S.A., Lu, A.T., Moore, L.B., Moore, J.T., Orband-Miller, L.A., Robinett, R.G., Shearin, J., Spearing, P.K., Stewart, E.L., Turnbull, P.S., Weaver, S.L., Williams, S.P., Wisely, G.B., Lambert, M.H., 2002. A new series of estrogen receptor modulators that display selectivity for estrogen receptor beta. J. Med. Chem. 45 (25), 5492–5505. Hernández-Díaz, F.J., Sánchez, J.J., Abreu, P., López-Coviella, I., Tabares, L., Prieto, L., Alonso, R., 2001. Estrogen modulates alpha(1)/beta-adrenoceptor-induced signaling and melatonin production in female rat pinealocytes. Neuroendocrinology 73 (2), 111–122. Hien, T.T., Kim, N.D., Pokharel, Y.R., Oh, S.J., Lee, M.Y., Kang, K.W., 2010. Ginsenoside Rg3 increases nitric oxide production via increases in phosphorylation and expression of endothelial nitric oxide synthase: essential roles of estrogen receptor-dependent PI3-kinase and AMP-activated protein kinase. Toxicol. Appl. Pharmacol. 246 (3), 171–183. Hien, T.T., Oh, W.K., Nguyen, P.H., Oh, S.J., Lee, M.Y., Kang, K.W., 2011. Nectandrin B activates endothelial nitric-oxide synthase phosphorylation in endothelial cells: role of the AMPactivated protein kinase/estrogen receptor α/phosphatidylinositol 3-kinase/Akt pathway. Mol. Pharmacol. 80 (6), 1166–1178. Hirahara, Y., Matsuda, K.I., Liu, Y.F., Yamada, H., Kawata, M., Boggs, J.M., 2013. 17βEstradiol and 17α-estradiol induce rapid changes in cytoskeletal organization in cultured oligodendrocytes. Neuroscience 235, 187–199. Hirsch, K., Atzmon, A., Danilenko, M., Levy, J., Sharoni, Y., 2007. Lycopene and other carotenoids inhibit estrogenic activity of 17beta-estradiol and genistein in cancer cells. Breast Cancer Res. Treat. 104 (2), 221–230. Hoekstra, P.F., Burnison, B.K., Garrison, A.W., Neheli, T., Muir, D.C., 2006. Estrogenic activity of dicofol with the human estrogen receptor: isomer- and enantiomer-specific implications. Chemosphere 64 (1), 174–177. Hong, Y.H., Wang, S.C., Hsu, C., Lin, B.F., Kuo, Y.H., Huang, C.J., 2011. Phytoestrogenic compounds in alfalfa sprout (Medicago sativa) beyond coumestrol. J. Agric. Food Chem. 59 (1), 131–137. Houtman, C.J., Van Oostveen, A.M., Brouwer, A., Lamoree, M.H., Legler, J., 2004. Identification of estrogenic compounds in fish bile using bioassay-directed fractionation. Environ. Sci. Technol. 38 (23), 6415–6423. Howes, M.J., Houghton, P.J., Barlow, D.J., Pocock, V.J., Milligan, S.R., 2002. Assessment of estrogenic activity in some common essential oil constituents. J. Pharm. Pharmacol. 54 (11), 1521–1528. Hu, J.Y., Aizawa, T., Ookubo, S., 2002. Products of aqueous chlorination of bisphenol A and their estrogenic activity. Environ. Sci. Technol. 36 (9), 1980–1987. Huang, Z., Fang, F., Wang, J., Wong, C.W., 2010. Structural activity relationship of flavonoids with estrogen-related receptor gamma. FEBS Lett. 584 (1), 22–26. Huang, P.H., Huang, C.Y., Chen, M.C., Lee, Y.T., Yue, C.H., Wang, H.Y., Lin, H., 2013. Emodin and aloe-emodin suppress breast cancer cell proliferation through ER α inhibition. Evid. Based Complement. Alternat. Med. 2013, 376123. Hwang, Y.P., Kim, H.G., Hien, T.T., Jeong, M.H., Jeong, T.C., Jeong, H.G., 2011. Puerarin activates endothelial nitric oxide synthase through estrogen receptor-dependent PI3-kinase and calcium-dependent AMP-activated protein kinase. Toxicol. Appl. Pharmacol. 257 (1), 48–58. Hwang, S.L., Lin, J.A., Shih, P.H., Yeh, C.T., Yen, G.C., 2012. Pro-cellular survival and neuroprotection of citrus flavonoid: the actions of hesperetin in PC12 cells. Food Funct. 3 (10), 1082–1090. Hwang, K.A., Park, M.A., Kang, N.H., Yi, B.R., Hyun, S.H., Jeung, E.B., Choi, K.C., 2013. Anticancer effect of genistein on BG-1 ovarian cancer growth induced by 17 β-estradiol or bisphenol A via the suppression of the crosstalk between estrogen receptor α and insulin-like growth factor-1 receptor signaling pathways. Toxicol. Appl. Pharmacol. 272 (3), 637–646. Innocenti, G., Vegeto, E., Dall'Acqua, S., Ciana, P., Giorgetti, M., Agradi, E., Sozzi, A., Fico, G., Tomè, F., 2007. In vitro estrogenic activity of Achillea millefolium L. Phytomedicine 14 (2–3), 147–152. Ise, R., Han, D., Takahashi, Y., Terasaka, S., Inoue, A., Tanji, M., Kiyama, R., 2005. Expression profiling of the estrogen responsive genes in response to phytoestrogens using a customized DNA microarray. FEBS Lett. 579 (7), 1732–1740. Ishibashi, H., Ishida, H., Matsuoka, M., Tominaga, N., Arizono, K., 2007. Estrogenic effects of fluorotelomer alcohols for human estrogen receptor isoforms alpha and beta in vitro. Biol. Pharm. Bull. 30 (7), 1358–1359. Ishikawa, T., Yuhanna, I.S., Umetani, J., Lee, W.R., Korach, K.S., Shaul, P.W., Umetani, M., 2013. LXRβ/estrogen receptor-α signaling in lipid rafts preserves endothelial integrity. J. Clin. Invest. 123 (8), 3488–3497. Isidori, M., Bellotta, M., Cangiano, M., Parrella, A., 2009. Estrogenic activity of pharmaceuticals in the aquatic environment. Environ. Int. 35 (5), 826–829. Jang, S.Y., Jang, S.W., Ko, J., 2011. Celastrol inhibits the growth of estrogen positive human breast cancer cells through modulation of estrogen receptor α. Cancer Lett. 300 (1), 57–65. Jazin, E.E., Dickerman, H.W., Henrikson, K.P., 1990. Estrogen regulation of a tissue factorlike procoagulant in the immature rat uterus. Endocrinology 126 (1), 176–185. Ji, Z.N., Zhao, W.Y., Liao, G.R., Choi, R.C., Lo, C.K., Dong, T.T., Tsim, K.W., 2006. In vitro estrogenic activity of formononetin by two bioassay systems. Gynecol. Endocrinol. 22 (10), 578–584. Jiang, S.Y., Shyu, R.Y., Yeh, M.Y., Jordan, V.C., 1995. Tamoxifen inhibits hepatoma cell growth through an estrogen receptor independent mechanism. J. Hepatol. 23 (6), 712–719. Jiménez-Orozco, F.A., Rosales, A.A., Vega-López, A., Domínguez-López, M.L., GarcíaMondragón, M.J., Maldonado-Espinoza, A., Lemini, C., Mendoza-Patiño, N., Mandoki,

R. Kiyama, Y. Wada-Kiyama / Environment International 83 (2015) 11–40 J.J., 2011. Differential effects of esculetin and daphnetin on in vitro cell proliferation and in vivo estrogenicity. Eur. J. Pharmacol. 668 (1–2), 35–41. Jin, J.S., Lee, J.H., Hattori, M., 2013. Ligand binding affinities of arctigenin and its demethylated metabolites to estrogen receptor alpha. Molecules 18 (1), 1122–1127. Journe, F., Laurent, G., Chaboteaux, C., Nonclercq, D., Durbecq, V., Larsimont, D., Body, J.J., 2008. Farnesol, a mevalonate pathway intermediate, stimulates MCF-7 breast cancer cell growth through farnesoid-X-receptor-mediated estrogen receptor activation. Breast Cancer Res. Treat. 107 (1), 49–61. Jung, J., Ishida, K., Nishihara, T., 2004. Anti-estrogenic activity of fifty chemicals evaluated by in vitro assays. Life Sci. 74 (25), 3065–3074. Jung, B.I., Kim, M.S., Kim, H.A., Kim, D., Yang, J., Her, S., Song, Y.S., 2010. Caffeic acid phenethyl ester, a component of beehive propolis, is a novel selective estrogen receptor modulator. Phytother. Res. 24 (2), 295–300. Kajta, M., Rzemieniec, J., Litwa, E., Lason, W., Lenartowicz, M., Krzeptowski, W., Wojtowicz, A.K., 2013. The key involvement of estrogen receptor β and G-protein-coupled receptor 30 in the neuroprotective action of daidzein. Neuroscience 238, 345–360. Kamiya, M., Toriba, A., Onoda, Y., Kizu, R., Hayakawa, K., 2005. Evaluation of estrogenic activities of hydroxylated polycyclic aromatic hydrocarbons in cigarette smoke condensate. Food Chem. Toxicol. 43 (7), 1017–1027. Kang, L., Guo, Y., Zhang, X., Meng, J., Wang, Z.Y., 2011. A positive cross-regulation of HER2 and ER-α36 controls ALDH1 positive breast cancer cells. J. Steroid Biochem. Mol. Biol. 127 (3–5), 262–268. Kang, N.H., Hwang, K.A., Lee, H.R., Choi, D.W., Choi, K.C., 2013. Resveratrol regulates the cell viability promoted by 17β-estradiol or bisphenol A via down-regulation of the cross-talk between estrogen receptor α and insulin growth factor-1 receptor in BG1 ovarian cancer cells. Food Chem. Toxicol. 59, 373–379. Karpeta, A., Ptak, A., Gregoraszczuk, E.L., 2014. Different action of 2,2′,4,4′tetrabromodiphenyl ether (BDE-47) and its hydroxylated metabolites on ERα and ERβ gene and protein expression. Toxicol. Lett. 229 (1), 250–256. Kashima, H., Shiozawa, T., Miyamoto, T., Suzuki, A., Uchikawa, J., Kurai, M., Konishi, I., 2009. Autocrine stimulation of IGF1 in estrogen-induced growth of endometrial carcinoma cells: involvement of the mitogen-activated protein kinase pathway followed by up-regulation of cyclin D1 and cyclin E. Endocr. Relat. Cancer 16 (1), 113–122. Kassem, M., Okazaki, R., Harris, S.A., Spelsberg, T.C., Conover, C.A., Riggs, B.L., 1998. Estrogen effects on insulin-like growth factor gene expression in a human osteoblastic cell line with high levels of estrogen receptor. Calcif. Tissue Int. 62 (1), 60–66. Katzenellenbogen, B.S., 2000. Mechanisms of action and cross-talk between estrogen receptor and progesterone receptor pathways. J. Soc. Gynecol. Investig. 7 (1 Suppl.), S33–S37. Kauss, M.A., Reiterer, G., Bunaciu, R.P., Yen, A., 2008. Human myeloblastic leukemia cells (HL-60) express a membrane receptor for estrogen that signals and modulates retinoic acid-induced cell differentiation. Exp. Cell Res. 314 (16), 2999–3006. Kavlock, R.J., Daston, G.P., DeRosa, C., Fenner-Crisp, P., Gray, L.E., Kaattari, S., Lucier, G., Luster, M., Mac, M.J., Maczka, C., Miller, R., Moore, J., Rolland, R., Scott, G., Sheehan, D.M., Sinks, T., Tilson, H.A., 1996. Research needs for the risk assessment of health and environmental effects of endocrine disruptors: a report of the U.S. EPAsponsored workshop. Environ. Health Perspect. 104 (Suppl. 4), 715–740. Kiefer, T.L., Lai, L., Yuan, L., Dong, C., Burow, M.E., Hill, S.M., 2005. Differential regulation of estrogen receptor alpha, glucocorticoid receptor and retinoic acid receptor alpha transcriptional activity by melatonin is mediated via different G proteins. J. Pineal Res. 38 (4), 231–239. Kim, S., Park, T.I., 2013. Naringenin: a partial agonist on estrogen receptor in T47D-KBluc breast cancer cells. Int. J. Clin. Exp. Med. 6 (10), 890–899. Kim, S.S., Kwack, S.J., Lee, R.D., Lim, K.J., Rhee, G.S., Seok, J.H., Kim, B.H., Won, Y.H., Lee, G.S., Jeung, E.B., Lee, B.M., Park, K.L., 2005. Assessment of estrogenic and androgenic activities of tetramethrin in vitro and in vivo assays. J. Toxicol. Environ. Health A 68 (23–24), 2277–2289. Kim, J.Y., Yi, B.R., Go, R.E., Hwang, K.A., Nam, K.H., Choi, K.C., 2014. Methoxychlor and triclosan stimulates ovarian cancer growth by regulating cell cycle- and apoptosisrelated genes via an estrogen receptor-dependent pathway. Environ. Toxicol. Pharmacol. 37 (3), 1264–1274. Kirkegaard, T., Hansen, S.K., Larsen, S.L., Reiter, B.E., Sørensen, B.S., Lykkesfeldt, A.E., 2014. T47D breast cancer cells switch from ER/HER to HER/c-Src signaling upon acquiring resistance to the antiestrogen fulvestrant. Cancer Lett. 344 (1), 90–100. Kirkiacharian, S., Lormier, A.T., Chidiack, H., Bouchoux, F., Cérède, E., 2004. Synthesis and binding affinity to human alpha and beta estrogen receptors of various 7hydroxycoumarins substituted at 4- and 3,4-positions. Farmaco 59 (12), 981–986. Kiyama, R., Zhu, Y., 2014. DNA microarray-based gene expression profiling of estrogenic chemicals. Cell. Mol. Life Sci. 71 (11), 2065–2082. Kiyama, R., Zhu, Y., Kawaguchi, K., Iitake, N., Wada-Kiyama, Y., Dong, S., 2014. Estrogenresponsive genes for environmental studies. Environ. Technol. Innov. 1–2, 16–28. Kjærstad, M.B., Taxvig, C., Nellemann, C., Vinggaard, A.M., Andersen, H.R., 2010. Endocrine disrupting effects in vitro of conazole antifungals used as pesticides and pharmaceuticals. Reprod. Toxicol. 30 (4), 573–582. Kjeldsen, L.S., Bonefeld-Jørgensen, E.C., 2013. Perfluorinated compounds affect the function of sex hormone receptors. Environ. Sci. Pollut. Res. Int. 20 (11), 8031–8044. Kjeldsen, L.S., Ghisari, M., Bonefeld-Jørgensen, E.C., 2013. Currently used pesticides and their mixtures affect the function of sex hormone receptors and aromatase enzyme activity. Toxicol. Appl. Pharmacol. 272 (2), 453–464. Klann, A., Levy, G., Lutz, I., Müller, C., Kloas, W., Hildebrandt, J.P., 2005. Estrogen-like effects of ultraviolet screen 3-(4-methylbenzylidene)-camphor (Eusolex 6300) on cell proliferation and gene induction in mammalian and amphibian cells. Environ. Res. 97 (3), 274–281. Klein-Hitpass, L., Schorpp, M., Wagner, U., Ryffel, G.U., 1986. An estrogen-responsive element derived from the 5' flanking region of the Xenopus vitellogenin A2 gene functions in transfected human cells. Cell 46 (7), 1053–1061.

35

Klinge, C.M., Blankenship, K.A., Risinger, K.E., Bhatnagar, S., Noisin, E.L., Sumanasekera, W.K., Zhao, L., Brey, D.M., Keynton, R.S., 2005. Resveratrol and estradiol rapidly activate MAPK signaling through estrogen receptors alpha and beta in endothelial cells. J. Biol. Chem. 280 (9), 7460–7468. Klotz, D.M., Beckman, B.S., Hill, S.M., McLachlan, J.A., Walters, M.R., Arnold, S.F., 1996. Identification of environmental chemicals with estrogenic activity using a combination of in vitro assays. Environ. Health Perspect. 104 (10), 1084–1089. Klotz, D.M., Arnold, S.F., McLachlan, J.A., 1997. Inhibition of 17 beta-estradiol and progesterone activity in human breast and endometrial cancer cells by carbamate insecticides. Life Sci. 60 (17), 1467–1475. Kohno, Y., Kitamura, S., Sanoh, S., Sugihara, K., Fujimoto, N., Ohta, S., 2005. Metabolism of the alpha, beta-unsaturated ketones, chalcone and trans-4-phenyl-3-buten-2-one, by rat liver microsomes and estrogenic activity of the metabolites. Drug Metab. Dispos. 33 (8), 1115–1123. Kojima, H., Katsura, E., Takeuchi, S., Niiyama, K., Kobayashi, K., 2004. Screening for estrogen and androgen receptor activities in 200 pesticides by in vitro reporter gene assays using Chinese hamster ovary cells. Environ. Health Perspect. 112 (5), 524–531. Kojima, M., Fukunaga, K., Sasaki, M., Nakamura, M., Tsuji, M., Nishiyama, T., 2005. Evaluation of estrogenic activities of pesticides using an in vitro reporter gene assay. Int. J. Environ. Health Res. 15 (4), 271–280. Kojima, H., Takeuchi, S., Itoh, T., Iida, M., Kobayashi, S., Yoshida, T., 2013. In vitro endocrine disruption potential of organophosphate flame retardants via human nuclear receptors. Toxicology 314 (1), 76–83. Kovalchuk, S.N., Kozhemyako, V.B., Atopkina, L.N., Silchenko, A.S., Avilov, S.A., Kalinin, V.I., Rasskazov, V.A., Aminin, D.L., 2006. Estrogenic activity of triterpene glycosides in yeast two-hybrid assay. J. Steroid Biochem. Mol. Biol. 101 (4–5), 226–231. Krishnan, V., Safe, S., 1993. Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), and dibenzofurans (PCDFs) as antiestrogens in MCF-7 human breast cancer cells: quantitative structure–activity relationships. Toxicol. Appl. Pharmacol. 120 (1), 55–61. Krishnan, V., Porter, W., Santostefano, M., Wang, X., Safe, S., 1995. Molecular mechanism of inhibition of estrogen-induced cathepsin D gene expression by 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD) in MCF-7 cells. Mol. Cell. Biol. 15 (12), 6710–6719. Kuiper, G.G., Lemmen, J.G., Carlsson, B., Corton, J.C., Safe, S.H., van der Saag, P.T., van der Burg, B., Gustafsson, J.A., 1998. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 139 (10), 4252–4263. Kummer, V., Masková, J., Zralý, Z., Neca, J., Simecková, P., Vondrácek, J., Machala, M., 2008. Estrogenic activity of environmental polycyclic aromatic hydrocarbons in uterus of immature Wistar rats. Toxicol. Lett. 180 (3), 212–221. Kung Sutherland, M.S., Lipps, S.G., Patnaik, N., Gayo-Fung, L.M., Khammungkune, S., Xie, W., Brady, H.A., Barbosa, M.S., Anderson, D.W., Stein, B., 2003. SP500263, a novel SERM, blocks osteoclastogenesis in a human bone cell model: role of IL-6 and GMCSF. Cytokine 23 (1–2), 1–14. Kurihara, R., Shiraishi, F., Tanaka, N., Hashimoto, S., 2005. Presence and estrogenicity of anthracene derivatives in coastal Japanese waters. Environ. Toxicol. Chem. 24 (8), 1984–1993. Kuruto-Niwa, R., Inoue, S., Ogawa, S., Muramatsu, M., Nozawa, R., 2000. Effects of tea catechins on the ERE-regulated estrogenic activity. J. Agric. Food Chem. 48 (12), 6355–6361. La Rosa, P., Pellegrini, M., Totta, P., Acconcia, F., Marino, M., 2014. Xenoestrogens alter estrogen receptor (ER) α intracellular levels. PLoS One 9 (2), e88961. Lappano, R., Recchia, A.G., De Francesco, E.M., Angelone, T., Cerra, M.C., Picard, D., Maggiolini, M., 2011. The cholesterol metabolite 25-hydroxycholesterol activates estrogen receptor α-mediated signaling in cancer cells and in cardiomyocytes. PLoS One 6 (1), e16631. Laschke, M.W., Schwender, C., Scheuer, C., Vollmar, B., Menger, M.D., 2008. Epigallocatechin-3-gallate inhibits estrogen-induced activation of endometrial cells in vitro and causes regression of endometriotic lesions in vivo. Hum. Reprod. 23 (10), 2308–2318. Lee, S.O., Nadiminty, N., Wu, X.X., Lou, W., Dong, Y., Ip, C., Onate, S.A., Gao, A.C., 2005. Selenium disrupts estrogen signaling by altering estrogen receptor expression and ligand binding in human breast cancer cells. Cancer Res. 65 (8), 3487–3492. Lee, H.S., Sasagawa, S., Kato, S., Fukuda, R., Horiuchi, H., Ohta, A., 2006. Yeast two-hybrid detection systems that are highly sensitive to a certain kind of endocrine disruptors. Biosci. Biotechnol. Biochem. 70 (2), 521–524. Lee, H.J., Ju, J., Paul, S., So, J.Y., DeCastro, A., Smolarek, A., Lee, M.J., Yang, C.S., Newmark, H.L., Suh, N., 2009. Mixed tocopherols prevent mammary tumorigenesis by inhibiting estrogen action and activating PPAR-gamma. Clin. Cancer Res. 15 (12), 4242–4249. Lee, S.A., Kim, E.Y., Jeon, W.K., Woo, C.H., Choe, J., Han, S., Kim, B.C., 2011. The inhibitory effect of raloxifene on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells is mediated through a ROS/p38 MAPK/CREB pathway to the upregulation of heme oxygenase-1 independent of estrogen receptor. Biochimie 93 (2), 168–174. Lee, H.R., Hwang, K.A., Park, M.A., Yi, B.R., Jeung, E.B., Choi, K.C., 2012. Treatment with bisphenol A and methoxychlor results in the growth of human breast cancer cells and alteration of the expression of cell cycle-related genes, cyclin D1 and p21, via an estrogen receptor-dependent signaling pathway. Int. J. Mol. Med. 29 (5), 883–890. Lee, H.R., Hwang, K.A., Choi, K.C., 2014. The estrogen receptor signaling pathway activated by phthalates is linked with transforming growth factor-β in the progression of LNCaP prostate cancer models. Int. J. Oncol. 45 (2), 595–602. Lemaire, G., Mnif, W., Mauvais, P., Balaguer, P., Rahmani, R., 2006. Activation of alpha- and beta-estrogen receptors by persistent pesticides in reporter cell lines. Life Sci. 79 (12), 1160–1169.

36

R. Kiyama, Y. Wada-Kiyama / Environment International 83 (2015) 11–40

Leskinen, P., Michelini, E., Picard, D., Karp, M., Virta, M., 2005. Bioluminescent yeast assays for detecting estrogenic and androgenic activity in different matrices. Chemosphere 61 (2), 259–266. Letellier, K., Azeddine, B., Parent, S., Labelle, H., Rompré, P.H., Moreau, A., Moldovan, F., 2008. Estrogen cross-talk with the melatonin signaling pathway in human osteoblasts derived from adolescent idiopathic scoliosis patients. J. Pineal Res. 45 (4), 383–393. Leung, K.W., Leung, F.P., Mak, N.K., Tombran-Tink, J., Huang, Y., Wong, R.N., 2009. Protopanaxadiol and protopanaxatriol bind to glucocorticoid and oestrogen receptors in endothelial cells. Br. J. Pharmacol. 156 (4), 626–637. Lewis-Wambi, J.S., Jordan, V.C., 2009. Estrogen regulation of apoptosis: how can one hormone stimulate and inhibit? Breast Cancer Res. 11 (3), 206. Li, J., Gramatica, P., 2010. The importance of molecular structures, endpoints' values, and predictivity parameters in QSAR research: QSAR analysis of a series of estrogen receptor binders. Mol. Divers. 14 (4), 687–696. Li, C., Taneda, S., Suzuki, A.K., Furuta, C., Watanabe, G., Taya, K., 2006. Estrogenic and antiandrogenic activities of 4-nitrophenol in diesel exhaust particles. Toxicol. Appl. Pharmacol. 217 (1), 1–6. Li, Y., Yuan, Y.Y., Meeran, S.M., Tollefsbol, T.O., 2010a. Synergistic epigenetic reactivation of estrogen receptor-α (ERα) by combined green tea polyphenol and histone deacetylase inhibitor in ERα-negative breast cancer cells. Mol. Cancer 9, 274. Li, J., Ma, M., Wang, Z., 2010b. In vitro profiling of endocrine disrupting effects of phenols. Toxicol. In Vitro 24 (1), 201–207. Li, Y., Burns, K.A., Arao, Y., Luh, C.J., Korach, K.S., 2012. Differential estrogenic actions of endocrine-disrupting chemicals bisphenol A, bisphenol AF, and zearalenone through estrogen receptor α and β in vitro. Environ. Health Perspect. 120 (7), 1029–1035. Li, Y.C., Ding, X.S., Li, H.M., Zhang, C., 2013a. Icariin attenuates high glucose-induced type IV collagen and fibronectin accumulation in glomerular mesangial cells by inhibiting transforming growth factor-β production and signalling through G protein-coupled oestrogen receptor 1. Clin. Exp. Pharmacol. Physiol. 40 (9), 635–643. Li, X., Gao, Y., Guo, L.H., Jiang, G., 2013b. Structure-dependent activities of hydroxylated polybrominated diphenyl ethers on human estrogen receptor. Toxicology 309, 15–22. Li, Q., Sullivan, N.R., McAllister, C.E., Van de Kar, L.D., Muma, N.A., 2013c. Estradiol accelerates the effects of fluoxetine on serotonin 1A receptor signaling. Psychoneuroendocrinology 38 (7), 1145–1157. Li, X., Ye, L., Wang, X., Shi, W., Qian, X., Zhu, Y., Yu, H., 2013d. Molecular modeling and molecular dynamics simulation studies on the interactions of hydroxylated polychlorinated biphenyls with estrogen receptor-β. Arch. Environ. Contam. Toxicol. 65 (3), 357–367. Li, Y.C., Ding, X.S., Li, H.M., Zhang, Y., Bao, J., 2014a. Role of G protein-coupled estrogen receptor 1 in modulating transforming growth factor-β stimulated mesangial cell extracellular matrix synthesis and migration. Mol. Cell. Endocrinol. 391 (1–2), 50–59. Li, J., Wang, F., Ding, H., Jin, C., Chen, J., Zhao, Y., Li, X., Chen, W., Sun, P., Tan, Y., Zhang, Q., Wang, X., Fan, A., Hua, Q., 2014b. Geniposide, the component of the Chinese herbal formula Tongluojiunao, protects amyloid-β peptide (1-42-mediated death of hippocampal neurons via the non-classical estrogen signaling pathway. Neural Regen. Res. 9 (5), 474–480. Liao, M.H., Tai, Y.T., Cherng, Y.G., Liu, S.H., Chang, Y.A., Lin, P.I., Chen, R.M., 2014. Genistein induces oestrogen receptor-α gene expression in osteoblasts through the activation of mitogen-activated protein kinases/NF-κB/activator protein-1 and promotes cell mineralisation. Br. J. Nutr. 111 (1), 55–63. Lim, S.H., Ha, T.Y., Ahn, J., Kim, S., 2011. Estrogenic activities of Psoralea corylifolia L. seed extracts and main constituents. Phytomedicine 18 (5), 425–430. Lin, C.W., Yang, L.Y., Shen, S.C., Chen, Y.C., 2007. IGF-I plus E2 induces proliferation via activation of ROS-dependent ERKs and JNKs in human breast carcinoma cells. J. Cell. Physiol. 212 (3), 666–674. Lin, S.L., Yan, L.Y., Liang, X.W., Wang, Z.B., Wang, Z.Y., Qiao, J., Schatten, H., Sun, Q.Y., 2009. A novel variant of ER-alpha, ER-alpha36 mediates testosterone-stimulated ERK and Akt activation in endometrial cancer Hec1A cells. Reprod. Biol. Endocrinol. 7, 102. Liu, S., Sugimoto, Y., Kulp, S.K., Jiang, J., Chang, H.L., Park, K.Y., Kashida, Y., Lin, Y.C., 2002. Estrogenic down-regulation of protein tyrosine phosphatase gamma (PTP gamma) in human breast is associated with estrogen receptor alpha. Anticancer Res. 22 (6C), 3917–3923. Liu, S., Abdelrahim, M., Khan, S., Ariazi, E., Jordan, V.C., Safe, S., 2006. Aryl hydrocarbon receptor agonists directly activate estrogen receptor alpha in MCF-7 breast cancer cells. Biol. Chem. 387 (9), 1209–1213. Liu, J., Li, J., Sidell, N., 2007. Modulation by phenylacetate of early estrogen-mediated events in MCF-7 breast cancer cells. Cancer Chemother. Pharmacol. 59 (2), 217–225. Liu, T., Jin, H., Sun, Q.R., Xu, J.H., Hu, H.T., 2010a. Neuroprotective effects of emodin in rat cortical neurons against beta-amyloid-induced neurotoxicity. Brain Res. 1347, 149–160. Liu, H., Du, J., Hu, C., Qi, H., Wang, X., Wang, S., Liu, Q., Li, Z., 2010b. Delayed activation of extracellular-signal-regulated kinase 1/2 is involved in genistein- and equol-induced cell proliferation and estrogen-receptor-alpha-mediated transcription in MCF-7 breast cancer cells. J. Nutr. Biochem. 21 (5), 390–396. Liu, X., Nam, J.W., Song, Y.S., Viswanath, A.N., Pae, A.N., Kil, Y.S., Kim, H.D., Park, J.H., Seo, E.K., Chang, M., 2014. Psoralidin, a coumestan analogue, as a novel potent estrogen receptor signaling molecule isolated from Psoralea corylifolia. Bioorg. Med. Chem. Lett. 24 (5), 1403–1406. Lopes Costa, A., Le Bachelier, C., Mathieu, L., Rotig, A., Boneh, A., De Lonlay, P., Tarnopolsky, M.A., Thorburn, D.R., Bastin, J., Djouadi, F., 2014. Beneficial effects of resveratrol on respiratory chain defects in patients' fibroblasts involve estrogen receptor and estrogenrelated receptor alpha signaling. Hum. Mol. Genet. 23 (8), 2106–2119. Lou, Q.Q., Zhang, Y.F., Zhou, Z., Shi, Y.L., Ge, Y.N., Ren, D.K., Xu, H.M., Zhao, Y.X., Wei, W.J., Qin, Z.F., 2013. Effects of perfluorooctanesulfonate and perfluorobutanesulfonate on

the growth and sexual development of Xenopus laevis. Ecotoxicology 22 (7), 1133–1144. Luo, W., Friedman, M.S., Shedden, K., Hankenson, K.D., Woolf, P.J., 2009. GAGE: generally applicable gene set enrichment for pathway analysis. BMC Bioinforma. 10, 161. Luo, L.J., Liu, F., Lin, Z.K., Xie, Y.F., Xu, J.L., Tong, Q.C., Shu, R., 2012. Genistein regulates the IL-1 beta induced activation of MAPKs in human periodontal ligament cells through G protein-coupled receptor 30. Arch. Biochem. Biophys. 522 (1), 9–16. Ma, H.R., Wang, J., Chen, Y.F., Chen, H., Wang, W.S., Aisa, H.A., 2014. Icariin and icaritin stimulate the proliferation of SKBr3 cells through the GPER1-mediated modulation of the EGFR-MAPK signaling pathway. Int. J. Mol. Med. 33 (6), 1627–1634. Machala, M., Ciganek, M., Bláha, L., Minksová, K., Vondráck, J., 2001. Aryl hydrocarbon receptor-mediated and estrogenic activities of oxygenated polycyclic aromatic hydrocarbons and azaarenes originally identified in extracts of river sediments. Environ. Toxicol. Chem. 20 (12), 2736–2743. Machida, K., Abe, T., Arai, D., Okamoto, M., Shimizu, I., de Voogd, N.J., Fusetani, N., Nakao, Y., 2014. Cinanthrenol A, an estrogenic steroid containing phenanthrene nucleus, from a marine sponge Cinachyrella sp. Org. Lett. 16 (6), 1539–1541. Maggiolini, M., Statti, G., Vivacqua, A., Gabriele, S., Rago, V., Loizzo, M., Menichini, F., Amdò, S., 2002. Estrogenic and antiproliferative activities of isoliquiritigenin in MCF7 breast cancer cells. J. Steroid Biochem. Mol. Biol. 82 (4–5), 315–322. Maggiolini, M., Vivacqua, A., Fasanella, G., Recchia, A.G., Sisci, D., Pezzi, V., Montanaro, D., Musti, A.M., Picard, D., Andò, S., 2004. The G protein-coupled receptor GPR30 mediates c-fos up-regulation by 17beta-estradiol and phytoestrogens in breast cancer cells. J. Biol. Chem. 279 (26), 27008–27016. Maggiolini, M., Recchia, A.G., Bonofiglio, D., Catalano, S., Vivacqua, A., Carpino, A., Rago, V., Rossi, R., Andò, S., 2005. The red wine phenolics piceatannol and myricetin act as agonists for estrogen receptor alpha in human breast cancer cells. J. Mol. Endocrinol. 35 (2), 269–281. Mahmoodzadeh, S., Fritschka, S., Dworatzek, E., Pham, T.H., Becher, E., Kuehne, A., Davidson, M.M., Regitz-Zagrosek, V., 2009. Nuclear factor-kappaB regulates estrogen receptoralpha transcription in the human heart. J. Biol. Chem. 284 (37), 24705–24714. Mahmoodzadeh, S., Leber, J., Zhang, X., Jaisser, F., Messaoudi, S., Morano, I., Furth, P.A., Dworatzek, E., Regitz-Zagrosek, V., 2014. Cardiomyocyte-specific estrogen receptor alpha increases angiogenesis, lymphangiogenesis and reduces fibrosis in the female mouse heart post-myocardial infarction. J. Cell Sci. Ther. 5 (1), 153. Mak, P., Leung, Y.K., Tang, W.Y., Harwood, C., Ho, S.M., 2006. Apigenin suppresses cancer cell growth through ERbeta. Neoplasia 8 (11), 896–904. Manabe, M., Kanda, S., Fukunaga, K., Tsubura, A., Nishiyama, T., 2006. Evaluation of the estrogenic activities of some pesticides and their combinations using MtT/Se cell proliferation assay. Int. J. Hyg. Environ. Health 209 (5), 413–421. Mandal, A., Bhatia, D., Bishayee, A., 2013. Simultaneous disruption of estrogen receptor and Wnt/β-catenin signaling is involved in methyl amooranin-mediated chemoprevention of mammary gland carcinogenesis in rats. Mol. Cell. Biochem. 384 (1–2), 239–250. Mann, V., Huber, C., Kogianni, G., Collins, F., Noble, B., 2007. The antioxidant effect of estrogen and Selective Estrogen Receptor Modulators in the inhibition of osteocyte apoptosis in vitro. Bone 40 (3), 674–684. Maranghi, F., Tassinari, R., Marcoccia, D., Altieri, I., Catone, T., De Angelis, G., Testai, E., Mastrangelo, S., Evandri, M.G., Bolle, P., Lorenzetti, S., 2010. The food contaminant semicarbazide acts as an endocrine disrupter: evidence from an integrated in vivo/ in vitro approach. Chem. Biol. Interact. 183 (1), 40–48. Maras, M., Vanparys, C., Muylle, F., Robbens, J., Berger, U., Barber, J.L., Blust, R., De Coen, W., 2006. Estrogen-like properties of fluorotelomer alcohols as revealed by mcf-7 breast cancer cell proliferation. Environ. Health Perspect. 114 (1), 100–105. Marconett, C.N., Singhal, A.K., Sundar, S.N., Firestone, G.L., 2012. Indole-3-carbinol disrupts estrogen receptor-alpha dependent expression of insulin-like growth factor-1 receptor and insulin receptor substrate-1 and proliferation of human breast cancer cells. Mol. Cell. Endocrinol. 363 (1–2), 74–84. Marino, M., Pellegrini, M., La Rosa, P., Acconcia, F., 2012. Susceptibility of estrogen receptor rapid responses to xenoestrogens: physiological outcomes. Steroids 77 (10), 910–917. Martin, M.B., Reiter, R., Pham, T., Avellanet, Y.R., Camara, J., Lahm, M., Pentecost, E., Pratap, K., Gilmore, B.A., Divekar, S., Dagata, R.S., Bull, J.L., Stoica, A., 2003. Estrogen-like activity of metals in MCF-7 breast cancer cells. Endocrinology 144 (6), 2425–2436. Matsuda, H., Shimoda, H., Morikawa, T., Yoshikawa, M., 2001. Phytoestrogens from the roots of Polygonum cuspidatum (Polygonaceae): structure-requirement of hydroxyanthraquinones for estrogenic activity. Bioorg. Med. Chem. Lett. 11 (14), 1839–1842. Maximov, P.Y., Lee, T.M., Jordan, V.C., 2013. The discovery and development of selective estrogen receptor modulators (SERMs) for clinical practice. Curr. Clin. Pharmacol. 8 (2), 135–155. McAllister, C.E., Creech, R.D., Kimball, P.A., Muma, N.A., Li, Q., 2012. GPR30 is necessary for estradiol-induced desensitization of 5-HT1A receptor signaling in the paraventricular nucleus of the rat hypothalamus. Psychoneuroendocrinology 37 (8), 1248–1260. McCarthy, A.R., Thomson, B.M., Shaw, I.C., Abell, A.D., 2006. Estrogenicity of pyrethroid insecticide metabolites. J. Environ. Monit. 8 (1), 197–202. McLachlan, M.J., Katzenellenbogen, J.A., Zhao, H., 2011. A new fluorescence complementation biosensor for detection of estrogenic compounds. Biotechnol. Bioeng. 108 (12), 2794–2803. McPherson, S.J., Ellem, S.J., Risbridger, G.P., 2008. Estrogen-regulated development and differentiation of the prostate. Differentiation 76 (6), 660–670. Medjakovic, S., Jungbauer, A., 2008. Red clover isoflavones biochanin A and formononetin are potent ligands of the human aryl hydrocarbon receptor. J. Steroid Biochem. Mol. Biol. 108 (1–2), 171–177. Medjakovic, S., Zoechling, A., Gerster, P., Ivanova, M.M., Teng, Y., Klinge, C.M., Schildberger, B., Gartner, M., Jungbauer, A., 2014. Effect of nonpersistent pesticides

R. Kiyama, Y. Wada-Kiyama / Environment International 83 (2015) 11–40 on estrogen receptor, androgen receptor, and aryl hydrocarbon receptor. Environ. Toxicol. 29 (10), 1201–1216. Meerts, I.A., Letcher, R.J., Hoving, S., Marsh, G., Bergman, A., Lemmen, J.G., van der Burg, B., Brouwer, A., 2001. In vitro estrogenicity of polybrominated diphenyl ethers, hydroxylated PDBEs, and polybrominated bisphenol A compounds. Environ. Health Perspect. 109 (4), 399–407. Mellanen, P., Petänen, T., Lehtimäki, J., Mäkelä, S., Bylund, G., Holmbom, B., Mannila, E., Oikari, A., Santti, R., 1996. Wood-derived estrogens: studies in vitro with breast cancer cell lines and in vivo in trout. Toxicol. Appl. Pharmacol. 136 (2), 381–388. Menendez, J.A., Colomer, R., Lupu, R., 2004. Omega-6 polyunsaturated fatty acid gammalinolenic acid (18:3n-6) is a selective estrogen-response modulator in human breast cancer cells: gamma-linolenic acid antagonizes estrogen receptor-dependent transcriptional activity, transcriptionally represses estrogen receptor expression and synergistically enhances tamoxifen and ICI 182,780 (Faslodex) efficacy in human breast cancer cells. Int. J. Cancer 109 (6), 949–954. Meng, R., Tang, H.Y., Westfall, J., London, D., Cao, J.H., Mousa, S.A., Luidens, M., Hercbergs, A., Davis, F.B., Davis, P.J., Lin, H.Y., 2011. Crosstalk between integrin αvβ3 and estrogen receptor-α is involved in thyroid hormone-induced proliferation in human lung carcinoma cells. PLoS One 6 (11), e27547. Meng, X., Sun, G., Ye, J., Xu, H., Wang, H., Sun, X., 2014. Notoginsenoside R1-mediated neuroprotection involves estrogen receptor-dependent crosstalk between Akt and ERK1/ 2 pathways: a novel mechanism of Nrf2/ARE signaling activation. Free Radic. Res. 48 (4), 445–460. Mense, S.M., Singh, B., Remotti, F., Liu, X., Bhat, H.K., 2009. Vitamin C and alphanaphthoflavone prevent estrogen-induced mammary tumors and decrease oxidative stress in female ACI rats. Carcinogenesis 30 (7), 1202–1208. Mercado-Feliciano, M., Bigsby, R.M., 2008. Hydroxylated metabolites of the polybrominated diphenyl ether mixture DE-71 are weak estrogen receptor-alpha ligands. Environ. Health Perspect. 116 (10), 1315–1321. Mersereau, J.E., Levy, N., Staub, R.E., Baggett, S., Zogovic, T., Chow, S., Ricke, W.A., Tagliaferri, M., Cohen, I., Bjeldanes, L.F., Leitman, D.C., 2008. Liquiritigenin is a plantderived highly selective estrogen receptor beta agonist. Mol. Cell. Endocrinol. 283 (1–2), 49–57. Métivier, R., Penot, G., Flouriot, G., Pakdel, F., 2001. Synergism between ERalpha transactivation function 1 (AF-1) and AF-2 mediated by steroid receptor coactivator protein-1: requirement for the AF-1 alpha-helical core and for a direct interaction between the N- and C-terminal domains. Mol. Endocrinol. 15 (11), 1953–1970. Meyers, M.J., Sun, J., Carlson, K.E., Marriner, G.A., Katzenellenbogen, B.S., Katzenellenbogen, J.A., 2001. Estrogen receptor-beta potency-selective ligands: structure–activity relationship studies of diarylpropionitriles and their acetylene and polar analogues. J. Med. Chem. 44 (24), 4230–4251. Micevych, P.E., Kelly, M.J., 2012. Membrane estrogen receptor regulation of hypothalamic function. Neuroendocrinology 96 (2), 103–110. Migliaccio, A., Piccolo, D., Castoria, G., Di Domenico, M., Bilancio, A., Lombardi, M., Gong, W., Beato, M., Auricchio, F., 1998. Activation of the Src/p21ras/Erk pathway by progesterone receptor via cross-talk with estrogen receptor. EMBO J. 17 (7), 2008–2018. Migliaccio, A., Castoria, G., Di Domenico, M., Ciociola, A., Lombardi, M., De Falco, A., Nanayakkara, M., Bottero, D., De Stasio, R., Varricchio, L., Auricchio, F., 2006. Crosstalk between EGFR and extranuclear steroid receptors. Ann. N. Y. Acad. Sci. 1089, 194–200. Min, G., 2010. Estrogen modulates transactivations of SXR-mediated liver × receptor response element and CAR-mediated phenobarbital response element in HepG2 cells. Exp. Mol. Med. 42 (11), 731–738. Min, G., Kim, H., Bae, Y., Petz, L., Kemper, J.K., 2002. Inhibitory cross-talk between estrogen receptor (ER) and constitutively activated androstane receptor (CAR). CAR inhibits ER-mediated signaling pathway by squelching p160 coactivators. J. Biol. Chem. 277 (37), 34626–34633. Misiewicz, B., Griebler, C., Gomez, M., Raybourne, R., Zelazowska, E., Gold, P.W., Sternberg, E.M., 1996. The estrogen antagonist tamoxifen inhibits carrageenan induced inflammation in LEW/N female rats. Life Sci. 58 (16), L281–L286. Moggs, J.G., Orphanides, G., 2001. Estrogen receptors: orchestrators of pleiotropic cellular responses. EMBO Rep. 2 (9), 775–781. Morrissey, C., Bektic, J., Spengler, B., Galvin, D., Christoffel, V., Klocker, H., Fitzpatrick, J.M., Watson, R.W., 2004. Phytoestrogens derived from Belamcanda chinensis have an antiproliferative effect on prostate cancer cells in vitro. J. Urol. 172 (6 Pt 1), 2426–2433. Mortensen, A.S., Arukwe, A., 2008. Estrogenic effect of dioxin-like aryl hydrocarbon receptor (AhR) agonist (PCB congener 126) in salmon hepatocytes. Mar. Environ. Res. 66 (1), 119–120. Muchekehu, R.W., Harvey, B.J., 2008. 17Beta-estradiol rapidly mobilizes intracellular calcium from ryanodine-receptor-gated stores via a PKC-PKA-Erk-dependent pathway in the human eccrine sweat gland cell line NCL-SG3. Cell Calcium 44 (3), 276–288. Mueller, S.O., 2004. Xenoestrogens: mechanisms of action and detection methods. Anal. Bioanal. Chem. 378 (3), 582–587. Müller, J.C., Imazaki, P.H., Boareto, A.C., Lourenço, E.L., Golin, M., Vechi, M.F., Lombardi, N.F., Minatovicz, B.C., Scippo, M.L., Martino-Andrade, A.J., Dalsenter, P.R., 2012. In vivo and in vitro estrogenic activity of the antidepressant fluoxetine. Reprod. Toxicol. 34 (1), 80–85. Nadal, A., Rovira, J.M., Laribi, O., Leon-quinto, T., Andreu, E., Ripoll, C., Soria, B., 1998. Rapid insulinotropic effect of 17beta-estradiol via a plasma membrane receptor. FASEB J. 12 (13), 1341–1348. Nadzialek, S., Depiereux, S., Mandiki, S.N., Kestemont, P., 2011. In vivo biomarkers of estrogenicity: limitation of interpretation in wild environment. Arch. Environ. Contam. Toxicol. 60 (3), 471–478. Nakaya, M., Tachibana, H., Yamada, K., 2005. Isoflavone genistein and daidzein upregulate LPS-induced inducible nitric oxide synthase activity through estrogen receptor pathway in RAW264.7 cells. Biochem. Pharmacol. 71 (1–2), 108–114.

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Nakaya, Y., Mawatari, K., Takahashi, A., Harada, N., Hata, A., Yasui, S., 2007. The phytoestrogen ginsensoside Re activates potassium channels of vascular smooth muscle cells through PI3K/Akt and nitric oxide pathways. J. Med. Invest. 54 (3–4), 381–384. Namgoong, G.M., Khanal, P., Cho, H.G., Lim, S.C., Oh, Y.K., Kang, B.S., Shim, J.H., Yoo, J.C., Choi, H.S., 2010. The prolyl isomerase Pin1 induces LC-3 expression and mediates tamoxifen resistance in breast cancer. J. Biol. Chem. 285 (31), 23829–23841. National Research Council (US), 2007. Toxicity Testing in the 21st Century: A Vision and a Strategy. National Academies Press (US), Washington, DC. National Research Council (US), 2010. Toxicity-Pathway-Based Risk Assessment: Preparing for Paradigm Change: A Symposium Summary. National Academies Press (US), Washington, DC. Ndebele, K., Graham, B., Tchounwou, P.B., 2010. Estrogenic activity of coumestrol, DDT, and TCDD in human cervical cancer cells. Int. J. Environ. Res. Public Health 7 (5), 2045–2056. Nejati-Koshki, K., Zarghami, N., Pourhassan-Moghaddam, M., Rahmati-Yamchi, M., Mollazade, M., Nasiri, M., Esfahlan, R.J., Barkhordari, A., Tayefi-Nasrabadi, H., 2012. Inhibition of leptin gene expression and secretion by silibinin: possible role of estrogen receptors. Cytotechnology 64 (6), 719–726. Nethrapalli, I.S., Tinnikov, A.A., Krishnan, V., Lei, C.D., Toran-Allerand, C.D., 2005. Estrogen activates mitogen-activated protein kinase in native, nontransfected CHO-K1, COS-7, and RAT2 fibroblast cell lines. Endocrinology 146 (1), 56–63. Nilsson, S., Mäkelä, S., Treuter, E., Tujague, M., Thomsen, J., Andersson, G., Enmark, E., Pettersson, K., Warner, M., Gustafsson, J.A., 2001. Mechanisms of estrogen action. Physiol. Rev. 81 (4), 1535–1565. Nishiguchi, T., Kobayashi, T., Sugimura, M., Kobayashi, H., Terao, T., 1999. Upregulation of thrombomodulin antigen levels in U937 cells by combined stimulation with estradiol-17beta and vitamin K2 (menaquinone 4). Semin. Thromb. Hemost. 25 (5), 509–517. Nishikawa, J., Saito, K., Goto, J., Dakeyama, F., Matsuo, M., Nishihara, T., 1999. New screening methods for chemicals with hormonal activities using interaction of nuclear hormone receptor with coactivator. Toxicol. Appl. Pharmacol. 154 (1), 76–83. Nishimura, S., Taki, M., Takaishi, S., Iijima, Y., Akiyama, T., 2000. Structures of 4-arylcoumarin (neoflavone) dimers isolated from Pistacia chinensis BUNGE and their estrogen-like activity. Chem. Pharm. Bull. (Tokyo) 48 (4), 505–508. Nishizuka, M., Heitaku, S., Maekawa, S., Nishikawa, j, Imagawa, M., 2004. Development of standardized in vitro assay system for estrogen receptors and species specificity of binding ability of 4-nonylphenol and p-octylphenol. J. Health Sci. 50 (5), 511–517. Novensa, L., Selent, J., Pastor, M., Sandberg, K., Heras, M., Dantas, A.P., 2010. Equine estrogens impair nitric oxide production and endothelial nitric oxide synthase transcription in human endothelial cells compared with the natural 17βestradiol. Hypertension 56 (3), 405–411. Nwachukwu, J.C., Srinivasan, S., Bruno, N.E., Parent, A.A., Hughes, T.S., Pollock, J.A., Gjyshi, O., Cavett, V., Nowak, J., Garcia-Ordonez, R.D., Houtman, R., Griffin, P.R., Kojetin, D.J., Katzenellenbogen, J.A., Conkright, M.D., Nettles, K.W., 2014. Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network. Elife 3, e02057. Obrero, M., Yu, D.V., Shapiro, D.J., 2002. Estrogen receptor-dependent and estrogen receptor-independent pathways for tamoxifen and 4-hydroxytamoxifen-induced programmed cell death. J. Biol. Chem. 277 (47), 45695–45703. Oda, K., Nishimura, T., Higuchi, K., Ishido, N., Ochi, K., Iizasa, H., Sai, Y., Tomi, M., Nakashima, E., 2013. Estrogen receptor α induction by mitoxantrone increases Abcg2 expression in placental trophoblast cells. J. Pharm. Sci. 102 (9), 3364–3372. Oh, S.M., Chung, K.H., 2004. Estrogenic activities of Ginkgo biloba extracts. Life Sci. 74 (11), 1325–1335. Oh, Y.J., Jung, Y.J., Kang, J.W., Yoo, Y.S., 2007. Investigation of the estrogenic activities of pesticides from Pal-dang reservoir by in vitro assay. Sci. Total Environ. 388 (1–3), 8–15. Ohta, K., Chiba, Y., Ogawa, T., Endo, Y., 2008. Promising core structure for nuclear receptor ligands: design and synthesis of novel estrogen receptor ligands based on diphenylamine skeleton. Bioorg. Med. Chem. Lett. 18 (18), 5050–5053. Ohta, R., Takagi, A., Ohmukai, H., Marumo, H., Ono, A., Matsushima, Y., Inoue, T., Ono, H., Kanno, J., 2012. Ovariectomized mouse uterotrophic assay of 36 chemicals. J. Toxicol. Sci. 37 (5), 879–889. Ohta, K., Ogawa, T., Kaise, A., Endo, Y., 2014. Novel estrogen receptor (ER) modulators containing various hydrophobic bent-core structures. Bioorg. Med. Chem. 22 (13), 3508–3514. Ohtani-Kaneko, R., 2006. Mechanisms underlying estrogen-induced sexual differentiation in the hypothalamus. Histol. Histopathol. 21 (3), 317–324. Oishi, K., Toyao, K., Kawano, Y., 2008. Suppression of estrogenic activity of 17-betaestradiol by beta-cyclodextrin. Chemosphere 73 (11), 1788–1792. Okubo, T., Yokoyama, Y., Kano, K., Soya, Y., Kano, I., 2004. Estimation of estrogenic and antiestrogenic activities of selected pesticides by MCF-7 cell proliferation assay. Arch. Environ. Contam. Toxicol. 46 (4), 445–453. Olsen, C.M., Meussen-Elholm, E.T., Samuelsen, M., Holme, J.A., Hongslo, J.K., 2003. Effects of the environmental oestrogens bisphenol A, tetrachlorobisphenol A, tetrabromobisphenol A, 4-hydroxybiphenyl and 4,′4′-dihydroxybiphenyl on oestrogen receptor binding, cell proliferation and regulation of oestrogen sensitive proteins in the human breast cancer cell line MCF-7. Pharmacol. Toxicol. 92 (4), 180–188. Ombra, M.N., Di Santi, A., Abbondanza, C., Migliaccio, A., Avvedimento, E.V., Perillo, B., 2013. Retinoic acid impairs estrogen signaling in breast cancer cells by interfering with activation of LSD1 via PKA. Biochim. Biophys. Acta 1829 (5), 480–486. Ong, E.T., Hwang, T.L., Huang, Y.L., Lin, C.F., Wu, W.B., 2011. Vitisin B, a resveratrol tetramer, inhibits migration through inhibition of PDGF signaling and enhancement of cell adhesiveness in cultured vascular smooth muscle cells. Toxicol. Appl. Pharmacol. 256 (2), 198–208.

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Ono, M., Yin, P., Navarro, A., Moravek, M.B., Coon V, J.S., Druschitz, S.A., Serna, V.A., Qiang, W., Brooks, D.C., Malpani, S.S., Ma, J., Ercan, C.M., Mittal, N., Monsivais, D., Dyson, M.T., Yemelyanov, A., Maruyama, T., Chakravarti, D., Kim, J.J., Kurita, T., Gottardi, C.J., Bulun, S.E., 2013. Paracrine activation of WNT/β-catenin pathway in uterine leiomyoma stem cells promotes tumor growth. Proc. Natl. Acad. Sci. U. S. A. 110 (42), 17053–17058. Onorato, J., Henion, J.D., 2001. Evaluation of triterpene glycoside estrogenic activity using LC/MS and immunoaffinity extraction. Anal. Chem. 73 (19), 4704–4710. Osborne, C.K., Shou, J., Massarweh, S., Schiff, R., 2005. Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer. Clin. Cancer Res. 11 (2 Pt 2), 865s–870s. Palmieri, D., Perego, P., Palombo, D., 2014. Estrogen receptor activation protects against TNF-α-induced endothelial dysfunction. Angiology 65 (1), 17–21. Pang, W.Y., Wang, X.L., Mok, S.K., Lai, W.P., Chow, H.K., Leung, P.C., Yao, X.S., Wong, M.S., 2010. Naringin improves bone properties in ovariectomized mice and exerts oestrogen-like activities in rat osteoblast-like (UMR-106) cells. Br. J. Pharmacol. 159 (8), 1693–1703. Panno, M.L., Giordano, F., Rizza, P., Pellegrino, M., Zito, D., Giordano, C., Mauro, L., Catalano, S., Aquila, S., Sisci, D., De Amicis, F., Vivacqua, A., Fuqua, S.W., Andò, S., 2012. Bergapten induces ER depletion in breast cancer cells through SMAD4-mediated ubiquitination. Breast Cancer Res. Treat. 136 (2), 443–455. Papoutsi, Z., Kassi, E., Mitakou, S., Aligiannis, N., Tsiapara, A., Chrousos, G.P., Moutsatsou, P., 2006. Acteoside and martynoside exhibit estrogenic/antiestrogenic properties. J. Steroid Biochem. Mol. Biol. 98 (1), 63–71. Park, S.H., Kim, K.Y., An, B.S., Choi, J.H., Jeung, E.B., Leung, P.C., Choi, K.C., 2009. Cell growth of ovarian cancer cells is stimulated by xenoestrogens through an estrogendependent pathway, but their stimulation of cell growth appears not to be involved in the activation of the mitogen-activated protein kinases ERK-1 and p38. J. Reprod. Dev. 55 (1), 23–29. Park, S.B., Bae, J.W., Kim, J.M., Lee, S.G., Han, M., 2012. Antiproliferative and apoptotic effect of epigallocatechin-3-gallate on Ishikawa cells is accompanied by sex steroid receptor downregulation. Int. J. Mol. Med. 30 (5), 1211–1218. Parker, M.G., 1998. Transcriptional activation by oestrogen receptors. Biochem. Soc. Symp. 63, 45–50. Parveen, M., Inoue, A., Ise, R., Tanji, M., Kiyama, R., 2008. Evaluation of estrogenic activity of phthalate esters by gene expression profiling using a focused microarray (EstrArray). Environ. Toxicol. Chem. 27 (6), 1416–1425. Pazaiti, A., Kontos, M., Fentiman, I.S., 2012. ZEN and the art of breast health maintenance. Int. J. Clin. Pract. 66 (1), 28–36. Pearl, C.A., Mason, H., Roser, J.F., 2011. Immunolocalization of estrogen receptor alpha, estrogen receptor beta and androgen receptor in the pre-, peri- and post-pubertal stallion testis. Anim. Reprod. Sci. 125 (1–4), 103–111. Penttinen, P., Jaehrling, J., Damdimopoulos, A.E., Inzunza, J., Lemmen, J.G., van der Saag, P., Pettersson, K., Gauglitz, G., Mäkelä, S., Pongratz, I., 2007. Diet-derived polyphenol metabolite enterolactone is a tissue-specific estrogen receptor activator. Endocrinology 148 (10), 4875–4886. Petit, F., Le Goff, P., Cravédi, J.P., Valotaire, Y., Pakdel, F., 1997. Two complementary bioassays for screening the estrogenic potency of xenobiotics: recombinant yeast for trout estrogen receptor and trout hepatocyte cultures. J. Mol. Endocrinol. 19 (3), 321–335. Pianjing, P., Thiantanawat, A., Rangkadilok, N., Watcharasit, P., Mahidol, C., Satayavivad, J., 2011. Estrogenic activities of sesame lignans and their metabolites on human breast cancer cells. J. Agric. Food Chem. 59 (1), 212–221. Picard, K., Lhuguenot, J.C., Lavier-Canivenc, M.C., Chagnon, M.C., 2001. Estrogenic activity and metabolism of n-butyl benzyl phthalate in vitro: identification of the active molecule(s). Toxicol. Appl. Pharmacol. 172 (2), 108–118. Piccolella, M., Crippa, V., Messi, E., Tetel, M.J., Poletti, A., 2014. Modulators of estrogen receptor inhibit proliferation and migration of prostate cancer cells. Pharmacol. Res. 79, 13–20. Plísková, M., Vondrácek, J., Kren, V., Gazák, R., Sedmera, P., Walterová, D., Psotová, J., Simánek, V., Machala, M., 2005. Effects of silymarin flavonolignans and synthetic silybin derivatives on estrogen and aryl hydrocarbon receptor activation. Toxicology 215 (1–2), 80–89. Plotan, M., Elliott, C.T., Oplatowska, M., Connolly, L., 2012. Validation and application of reporter gene assays for the determination of estrogenic and androgenic endocrine disruptor activity in sport supplements. Anal. Bioanal. Chem. 403 (10), 3057–3067. Pons, M., Gagne, D., Nicolas, J.C., Mehtali, M., 1990. A new cellular model of response to estrogens: a bioluminescent test to characterize (anti) estrogen molecules. Biotechniques 9 (4), 450–459. Prakash, P., Russell, R.M., Krinsky, N.I., 2001. In vitro inhibition of proliferation of estrogen-dependent and estrogen-independent human breast cancer cells treated with carotenoids or retinoids. J. Nutr. 131 (5), 1574–1580. Prifti, S., Mall, P., Rabe, T., 2003. Synthetic estrogen-mediated activation of ERK 2 intracellular signaling molecule. Gynecol. Endocrinol. 17 (5), 423–428. Ptak, A., Ludewig, G., Gregoraszczuk, E.Ł., 2008. A low halogenated biphenyl (PCB3) increases CYP1A1 expression and activity via the estrogen receptor beta in the porcine ovary. J. Physiol. Pharmacol. 59 (3), 577–588. Qu, J., Liu, W., Huang, C., Xu, C., Du, G., Gu, A., Wang, X., 2014. Estrogen receptors are involved in polychlorinated biphenyl-induced apoptosis on mouse spermatocyte GC-2 cell line. Toxicol. In Vitro 28 (3), 373–380. Radice, S., Chiesara, E., Frigerio, S., Fumagalli, R., Parolaro, D., Rubino, T., Marabini, L., 2006. Estrogenic effect of procymidone through activation of MAPK in MCF-7 breast carcinoma cell line. Life Sci. 78 (23), 2716–2723. Rafi, M.M., Rosen, R.T., Vassil, A., Ho, C.T., Zhang, H., Ghai, G., Lambert, G., DiPaola, R.S., 2000. Modulation of bcl-2 and cytotoxicity by licochalcone-A, a novel estrogenic flavonoid. Anticancer Res. 20 (4), 2653–2658.

Rahal, O.M., Simmen, R.C., 2011. Paracrine-acting adiponectin promotes mammary epithelial differentiation and synergizes with genistein to enhance transcriptional response to estrogen receptor β signaling. Endocrinology 152 (9), 3409–3421. Randall, C., et al., 2013. National Pesticide Applicator Certification Core Manual. National Association of State Departments of Agriculture Research Foundation, Washington, DC. Rao, J., Jiang, X., Wang, Y., Chen, B., 2011. Advances in the understanding of the structure and function of ER-α36, a novel variant of human estrogen receptor-alpha. J. Steroid Biochem. Mol. Biol. 127 (3–5), 231–237. Renoir, J.M., Marsaud, V., Lazennec, G., 2013. Estrogen receptor signaling as a target for novel breast cancer therapeutics. Biochem. Pharmacol. 85 (4), 449–465. Resende, F.A., de Oliveira, A.P., de Camargo, M.S., Vilegas, W., Varanda, E.A., 2013. Evaluation of estrogenic potential of flavonoids using a recombinant yeast strain and MCF7/ BUS cell proliferation assay. PLoS One 8 (10), e74881. Ribeiro, J.R., Freiman, R.N., 2014. Estrogen signaling crosstalk: implications for endocrine resistance in ovarian cancer. J. Steroid Biochem. Mol. Biol. 143, 160–173. Riby, J.E., Feng, C., Chang, Y.C., Schaldach, C.M., Firestone, G.L., Bjeldanes, L.F., 2000. The major cyclic trimeric product of indole-3-carbinol is a strong agonist of the estrogen receptor signaling pathway. Biochemistry 39 (5), 910–918. Riverso, M., Kortenkamp, A., Silva, E., 2014. Non-tumorigenic epithelial cells secrete MCP1 and other cytokines that promote cell division in breast cancer cells by activating ERα via PI3K/Akt/mTOR signaling. Int. J. Biochem. Cell Biol. 53C, 281–294. Robb, E.L., Stuart, J.A., 2014. The stilbenes resveratrol, pterostilbene and piceid affect growth and stress resistance in mammalian cells via a mechanism requiring estrogen receptor beta and the induction of Mn-superoxide dismutase. Phytochemistry 98, 164–173. Rosario, E.R., Carroll, J., Pike, C.J., 2010. Testosterone regulation of Alzheimer-like neuropathology in male 3xTg-AD mice involves both estrogen and androgen pathways. Brain Res. 1359, 281–290. Routledge, E.J., Sumpter, J.P., 1997. Structural features of alkylphenolic chemicals associated with estrogenic activity. J. Biol. Chem. 272 (6), 3280–3288. Rowlands, D.J., Chapple, S., Siow, R.C., Mann, G.E., 2011. Equol-stimulated mitochondrial reactive oxygen species activate endothelial nitric oxide synthase and redox signaling in endothelial cells: roles for F-actin and GPR30. Hypertension 57 (4), 833–840. Ruh, M.F., Zacharewski, T., Connor, K., Howell, J., Chen, I., Safe, S., 1995. Naringenin: a weakly estrogenic bioflavonoid that exhibits antiestrogenic activity. Biochem. Pharmacol. 50 (9), 1485–1493. Sabatucci, J.P., Ashwell, M.A., Trybulski, E., O'Donnell, M.M., Moore, W.J., Harnish, D.C., Chadwick, C.C., 2006. Substituted 4-hydroxyphenyl sulfonamides as pathwayselective estrogen receptor ligands. Bioorg. Med. Chem. Lett. 16 (4), 854–858. Safe, S., 2001. Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-Sp1 interactions. Vitam. Horm. 62, 231–252. Safe, S., Wormke, M., 2003. Inhibitory aryl hydrocarbon receptor-estrogen receptor alpha cross-talk and mechanisms of action. Chem. Res. Toxicol. 16 (7), 807–816. Safe, S.H., Pallaroni, L., Yoon, K., Gaido, K., Ross, S., Saville, B., McDonnell, D., 2001. Toxicology of environmental estrogens. Reprod. Fertil. Dev. 13 (4), 307–315. Saggar, J.K., Chen, J., Corey, P., Thompson, L.U., 2010. The effect of secoisolariciresinol diglucoside and flaxseed oil, alone and in combination, on MCF-7 tumor growth and signaling pathways. Nutr. Cancer 62 (4), 533–542. Santen, R.J., Fan, P., Zhang, Z., Bao, Y., Song, R.X., Yue, W., 2009. Estrogen signals via an extra-nuclear pathway involving IGF-1R and EGFR in tamoxifen-sensitive and -resistant breast cancer cells. Steroids 74 (7), 586–594. Santolla, M.F., De Francesco, E.M., Lappano, R., Rosano, C., Abonante, S., Maggiolini, M., 2014. Niacin activates the G protein estrogen receptor (GPER)-mediated signalling. Cell. Signal. 26 (7), 1466–1475. Sauvé, K., Lepage, J., Sanchez, M., Heveker, N., Tremblay, A., 2009. Positive feedback activation of estrogen receptors by the CXCL12–CXCR4 pathway. Cancer Res. 69 (14), 5793–5800. Schlange, T., Matsuda, Y., Lienhard, S., Huber, A., Hynes, N.E., 2007. Autocrine WNT signaling contributes to breast cancer cell proliferation via the canonical WNT pathway and EGFR transactivation. Breast Cancer Res. 9 (5), R63. Schmidt, J.M., Mercure, J., Tremblay, G.B., Pagé, M., Kalbakji, A., Feher, M., Dunn-Dufault, R., Peter, M.G., Redden, P.R., 2003. De novo design, synthesis, and evaluation of novel nonsteroidal phenanthrene ligands for the estrogen receptor. J. Med. Chem. 46 (8), 1408–1418. Schultz, T.W., Sinks, G.D., Cronin, M.T., 2002. Structure–activity relationships for gene activation oestrogenicity: evaluation of a diverse set of aromatic chemicals. Environ. Toxicol. 17 (1), 14–23. Schwartz-Mittelman, A., Baruch, A., Neufeld, T., Buchner, V., Rishpon, J., 2005. Electrochemical detection of xenoestrogenic and antiestrogenic compounds using a yeast two-hybrid-17-beta-estradiol system. Bioelectrochemistry 65 (2), 149–156. Sharan, S., Nikhil, K., Roy, P., 2013. Effects of low dose treatment of tributyltin on the regulation of estrogen receptor functions in MCF-7 cells. Toxicol. Appl. Pharmacol. 269 (2), 176–186. Shelly, W., Draper, M.W., Krishnan, V., Wong, M., Jaffe, R.B., 2008. Selective estrogen receptor modulators: an update on recent clinical findings. Obstet. Gynecol. Surv. 63 (3), 163–181. Shen, K., Leung, S.W., Ji, L., Huang, Y., Hou, M., Xu, A., Wang, Z., Vanhoutte, P.M., 2014. Notoginsenoside Ft1 activates both glucocorticoid and estrogen receptors to induce endothelium-dependent, nitric oxide-mediated relaxations in rat mesenteric arteries. Biochem. Pharmacol. 88 (1), 66–74. Shi, C., Zheng, D.D., Fang, L., Wu, F., Kwong, W.H., Xu, J., 2012. Ginsenoside Rg1 promotes nonamyloidgenic cleavage of APP via estrogen receptor signaling to MAPK/ERK and PI3K/Akt. Biochim. Biophys. Acta 1820 (4), 453–460. Shimamura, N., Miyase, T., Umehara, K., Warashina, T., Fujii, S., 2006. Phytoestrogens from Aspalathus linearis. Biol. Pharm. Bull. 29 (6), 1271–1274.

R. Kiyama, Y. Wada-Kiyama / Environment International 83 (2015) 11–40 Shin, J.E., Bae, E.A., Lee, Y.C., Ma, J.Y., Kim, D.H., 2006. Estrogenic effect of main components kakkalide and tectoridin of Puerariae Flos and their metabolites. Biol. Pharm. Bull. 29 (6), 1202–1206. Shoemaker, R.H., 2006. The NCI60 human tumour cell line anticancer drug screen. Nat. Rev. Cancer 6 (10), 813–823. Sibonga, J.D., Bell, N.H., Turner, R.T., 1998. Evidence that ibuprofen antagonizes selective actions of estrogen and tamoxifen on rat bone. J. Bone Miner. Res. 13 (5), 863–870. Silva, E., Kabil, A., Kortenkamp, A., 2010. Cross-talk between non-genomic and genomic signalling pathways—distinct effect profiles of environmental estrogens. Toxicol. Appl. Pharmacol. 245 (2), 160–170. Simões, B.M., Vivanco, M.D., 2011. Cancer stem cells in the human mammary gland and regulation of their differentiation by estrogen. Future Oncol. 7 (8), 995–1006. Simoncini, T., Lenzi, E., Zöchling, A., Gopal, S., Goglia, L., Russo, E., Polak, K., Casarosa, E., Jungbauer, A., Genazzani, A.D., Genazzani, A.R., 2011. Estrogen-like effects of wine extracts on nitric oxide synthesis in human endothelial cells. Maturitas 70 (2), 169–175. Sirianni, R., Chimento, A., De Luca, A., Casaburi, I., Rizza, P., Onofrio, A., Iacopetta, D., Puoci, F., Andò, S., Maggiolini, M., Pezzi, V., 2010. Oleuropein and hydroxytyrosol inhibit MCF-7 breast cancer cell proliferation interfering with ERK1/2 activation. Mol. Nutr. Food Res. 54 (6), 833–840. Soltysik, K., Czekaj, P., 2013. Membrane estrogen receptors — is it an alternative way of estrogen action? J. Physiol. Pharmacol. 64 (2), 129–142. Somers-Edgar, T.J., Scandlyn, M.J., Stuart, E.C., Le Nedelec, M.J., Valentine, S.P., Rosengren, R.J., 2008. The combination of epigallocatechin gallate and curcumin suppresses ER alpha-breast cancer cell growth in vitro and in vivo. Int. J. Cancer 122 (9), 1966–1971. Somjen, D., Knoll, E., Vaya, J., Stern, N., Tamir, S., 2004a. Estrogen-like activity of licorice root constituents: glabridin and glabrene, in vascular tissues in vitro and in vivo. J. Steroid Biochem. Mol. Biol. 91 (3), 147–155. Somjen, D., Kohen, F., Gayer, B., Knoll, E., Limor, R., Baz, M., Sharon, O., Posner, G.H., Stern, N., 2004b. A non-calcemic Vitamin D analog modulates both nuclear and putative membranal estrogen receptors in cultured human vascular smooth muscle cells. J. Steroid Biochem. Mol. Biol. 89–90 (1–5), 397–399. Somjen, D., Katzburg, S., Knoll, E., Hendel, D., Stern, N., Kaye, A.M., Yoles, I., 2007. DT56a (Femarelle): a natural selective estrogen receptor modulator (SERM). J. Steroid Biochem. Mol. Biol. 104 (3–5), 252–258. Song, T.T., Hendrich, S., Murphy, P.A., 1999. Estrogenic activity of glycitein, a soy isoflavone. J. Agric. Food Chem. 47 (4), 1607–1610. Song, L.H., Pan, W., Yu, Y.H., Quarles, L.D., Zhou, H.H., Xiao, Z.S., 2006. Resveratrol prevents CsA inhibition of proliferation and osteoblastic differentiation of mouse bone marrow-derived mesenchymal stem cells through an ER/NO/cGMP pathway. Toxicol. In Vitro 20 (6), 915–922. Song, L., Zhao, J., Zhang, X., Li, H., Zhou, Y., 2013. Icariin induces osteoblast proliferation, differentiation and mineralization through estrogen receptor-mediated ERK and JNK signal activation. Eur. J. Pharmacol. 714 (1–3), 15–22. Sonneveld, E., Jansen, H.J., Riteco, J.A., Brouwer, A., van der Burg, B., 2005. Development of androgen- and estrogen-responsive bioassays, members of a panel of human cell line-based highly selective steroid-responsive bioassays. Toxicol. Sci. 83 (1), 136–148. Soto, A.M., Sonnenschein, C., Chung, K.L., Fernandez, M.F., Olea, N., Serrano, F.O., 1995. The E-SCREEN assay as a tool to identify estrogens: an update on estrogenic environmental pollutants. Environ. Health Perspect. 103 (Suppl. 7), 113–122. Sotoca, A.M., Gelpke, M.D., Boeren, S., Ström, A., Gustafsson, J.Å., Murk, A.J., Rietjens, I.M., Vervoort, J., 2011. Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol. Cell. Proteomics 10 (1) (M110.002170). Stauffer, S.R., Coletta, C.J., Tedesco, R., Nishiguchi, G., Carlson, K., Sun, J., Katzenellenbogen, B.S., Katzenellenbogen, J.A., 2000. Pyrazole ligands: structure–affinity/activity relationships and estrogen receptor-alpha-selective agonists. J. Med. Chem. 43 (26), 4934–4947. Steinmetz, R., Young, P.C., Caperell-Grant, A., Gize, E.A., Madhukar, B.V., Ben-Jonathan, N., Bigsby, R.M., 1996. Novel estrogenic action of the pesticide residue betahexachlorocyclohexane in human breast cancer cells. Cancer Res. 56 (23), 5403–5409. Stice, J.P., Mbai, F.N., Chen, L., Knowlton, A.A., 2012. Rapid activation of nuclear factor κB by 17β-estradiol and selective estrogen receptor modulators: pathways mediating cellular protection. Shock 38 (2), 128–136. Stratton, R.C., Squires, P.E., Green, A.K., 2010. 17Beta-estradiol elevates cGMP, and via plasma membrane recruitment of protein kinase GIalpha, stimulates Ca2+ efflux from rat hepatocytes. J. Biol. Chem. 285 (35), 27201–27212. Suenaga, F., Hatsushika, K., Takano, S., Ando, T., Ohnuma, Y., Ogawa, H., Nakao, A., 2008. A possible link between resveratrol and TGF-beta: resveratrol induction of TGF-beta expression and signaling. FEBS Lett. 582 (5), 586–590. Sultankulova, K.T., Chervyakova, O.V., Kozhabergenov, N.S., Shorayeva, K.A., Strochkov, V.M., Orynbayev, M.B., Sandybayev, N.T., Sansyzbay, A.R., Vasin, A.V., 2014. Comparative evaluation of effectiveness of IAVchip DNA microarray in influenza A diagnosis. Sci. World J. 2014, 620580. Sun, H., Chen, W., Xu, X., Ding, Z., Chen, X., Wang, X., 2014. Pyrethroid and their metabolite, 3-phenoxybenzoic acid showed similar (anti)estrogenic activity in human and rat estrogen receptor α-mediated reporter gene assays. Environ. Toxicol. Pharmacol. 37 (1), 371–377. Swami, S., Krishnan, A.V., Peng, L., Lundqvist, J., Feldman, D., 2013. Transrepression of the estrogen receptor promoter by calcitriol in human breast cancer cells via two negative vitamin D response elements. Endocr. Relat. Cancer 20 (4), 565–577. Swedenborg, E., Rüegg, J., Hillenweck, A., Rehnmark, S., Faulds, M.H., Zalko, D., Pongratz, I., Pettersson, K., 2008. 3-Methylcholanthrene displays dual effects on estrogen receptor (ER) alpha and ER beta signaling in a cell-type specific fashion. Mol. Pharmacol. 73 (2), 575–586. Sweet, F., 1981. Boron estrogens: synthesis, biochemical and biological testing of estrone and estradiol-17 beta 3-carboranylmethyl ethers. Steroids 37 (2), 223–238.

39

Takahashi, Y., Hursting, S.D., Perkins, S.N., Wang, T.C., Wang, T.T., 2006. Genistein affects androgen-responsive genes through both androgen- and estrogen-induced signaling pathways. Mol. Carcinog. 45 (1), 18–25. Takeda, S., 2014. Δ(9)-tetrahydrocannabinol targeting estrogen receptor signaling: the possible mechanism of action coupled with endocrine disruption. Biol. Pharm. Bull. 37 (9), 1435–1438. Takemura, H., Shim, J.Y., Sayama, K., Tsubura, A., Zhu, B.T., Shimoi, K., 2007. Characterization of the estrogenic activities of zearalenone and zeranol in vivo and in vitro. J. Steroid Biochem. Mol. Biol. 103 (2), 170–177. Tamir, S., Eizenberg, M., Somjen, D., Stern, N., Shelach, R., Kaye, A., Vaya, J., 2000. Estrogenic and antiproliferative properties of glabridin from licorice in human breast cancer cells. Cancer Res. 60 (20), 5704–5709. Taneda, S., Mori, Y., Kamata, K., Hayashi, H., Furuta, C., Li, C., Seki, K., Sakushima, A., Yoshino, S., Yamaki, K., Watanabe, G., Taya, K., Suzuki, A.K., 2004. Estrogenic and anti-androgenic activity of nitrophenols in diesel exhaust particles (DEP). Biol. Pharm. Bull. 27 (6), 835–837. Tange, S., Fujimoto, N., Uramaru, N., Sugihara, K., Ohta, S., Kitamura, S., 2014. In vitro metabolism of cis- and trans-permethrin by rat liver microsomes, and its effect on estrogenic and anti-androgenic activities. Environ. Toxicol. Pharmacol. 37 (3), 996–1005. Tanji, M., Kiyama, R., 2004. Expression profiling of estrogen responsive genes using genomic and proteomic techniqes for the evaluation of endocrine disruptors. Curr. Pharmacogenomics 2 (3), 255–266. Taylor, S.E., Martin-Hirsch, P.L., Martin, F.L., 2010. Oestrogen receptor splice variants in the pathogenesis of disease. Cancer Lett. 288 (2), 133–148. ter Veld, M.G., Schouten, B., Louisse, J., van Es, D.S., van der Saag, P.T., Rietjens, I.M., Murk, A.J., 2006. Estrogenic potency of food-packaging-associated plasticizers and antioxidants as detected in ERalpha and ERbeta reporter gene cell lines. J. Agric. Food Chem. 54 (12), 4407–4416. Thakkar, J.P., Mehta, D.G., 2011. A review of an unfavorable subset of breast cancer: estrogen receptor positive progesterone receptor negative. Oncologist 16 (3), 276–285. Thasni, K.A., Rakesh, S., Rojini, G., Ratheeshkumar, T., Srinivas, G., Priya, S., 2008. Estrogendependent cell signaling and apoptosis in BRCA1-blocked BG1 ovarian cancer cells in response to plumbagin and other chemotherapeutic agents. Ann. Oncol. 19 (4), 696–705. Thasni, K.A., Ratheeshkumar, T., Rojini, G., Sivakumar, K.C., Nair RS, G.S., Banerji, A., Somasundaram, V., Srinivas, P., 2013. Structure activity relationship of plumbagin in BRCA1 related cancer cells. Mol. Carcinog. 52 (5), 392–403. Thomas, P., Dong, J., 2006. Binding and activation of the seven-transmembrane estrogen receptor GPR30 by environmental estrogens: a potential novel mechanism of endocrine disruption. J. Steroid Biochem. Mol. Biol. 102 (1–5), 175–179. Thongprakaisang, S., Thiantanawat, A., Rangkadilok, N., Suriyo, T., Satayavivad, J., 2013. Glyphosate induces human breast cancer cells growth via estrogen receptors. Food Chem. Toxicol. 59, 129–136. Tian, Y., Ke, S., Thomas, T., Meeker, R.J., Gallo, M.A., 1998. Regulation of estrogen receptor mRNA by 2,3,7,8-tetrachlorodibenzo-p-dioxin as measured by competitive RT-PCR. J. Biochem. Mol. Toxicol. 12 (2), 71–77. Tian, H., Ru, S., Wang, Z., Cai, W., Wang, W., 2009. Estrogenic effects of monocrotophos evaluated by vitellogenin mRNA and protein induction in male goldfish (Carassius auratus). Comp. Biochem. Physiol. C Toxicol. Pharmacol. 150 (2), 231–236. Tian, J., Berton, T.R., Shirley, S.H., Lambertz, I., Gimenez-Conti, I.B., DiGiovanni, J., Korach, K.S., Conti, C.J., Fuchs-Young, R., 2012. Developmental stage determines estrogen receptor alpha expression and non-genomic mechanisms that control IGF-1 signaling and mammary proliferation in mice. J. Clin. Invest. 122 (1), 192–204. Tilley, A.J., Zanatta, S.D., Qin, C.X., Kim, I.K., Seok, Y.M., Stewart, A., Woodman, O.L., Williams, S.J., 2012. 2-Morpholinoisoflav-3-enes as flexible intermediates in the synthesis of phenoxodiol, isophenoxodiol, equol and analogues: vasorelaxant properties, estrogen receptor binding and Rho/RhoA kinase pathway inhibition. Bioorg. Med. Chem. 20 (7), 2353–2361. Tohno, H., Horii, C., Fuse, T., Okonogi, A., Yomoda, S., 2010. Evaluation of estrogen receptor Beta binding of pruni cortex and its constituents. Yakugaku Zasshi 130 (7), 989–997. Tolba, M.F., Esmat, A., Al-Abd, A.M., Azab, S.S., Khalifa, A.E., Mosli, H.A., Abdel-Rahman, S.Z., Abdel-Naim, A.B., 2013. Caffeic acid phenethyl ester synergistically enhances docetaxel and paclitaxel cytotoxicity in prostate cancer cells. IUBMB Life 65 (8), 716–729. Tollefsen, K.E., Nilsen, A.J., 2008. Binding of alkylphenols and alkylated non-phenolics to rainbow trout (Oncorhynchus mykiss) hepatic estrogen receptors. Ecotoxicol. Environ. Saf. 69 (2), 163–172. Toran-Allerand, C.D., Guan, X., MacLusky, N.J., Horvath, T.L., Diano, S., Singh, M., Connolly Jr., E.S., Nethrapalli, I.S., Tinnikov, A.A., 2002. ER-X: a novel, plasma membrane-associated, putative estrogen receptor that is regulated during development and after ischemic brain injury. J. Neurosci. 22 (19), 8391–8401. Toran-Allerand, C.D., Tinnikov, A.A., Singh, R.J., Nethrapalli, I.S., 2005. 17Alpha-estradiol: a brain-active estrogen? Endocrinology 146 (9), 3843–3850. Totta, P., Acconcia, F., Leone, S., Cardillo, I., Marino, M., 2004. Mechanisms of naringenininduced apoptotic cascade in cancer cells: involvement of estrogen receptor alpha and beta signalling. IUBMB Life 56 (8), 491–499. Tran, D.Q., Ide, C.F., McLachlan, J.A., Arnold, S.F., 1996. The anti-estrogenic activity of selected polynuclear aromatic hydrocarbons in yeast expressing human estrogen receptor. Biochem. Biophys. Res. Commun. 229 (1), 101–108. Tsai, K.S., Yang, R.S., Liu, S.H., 2004. Benzo[a]pyrene regulates osteoblast proliferation through an estrogen receptor-related cyclooxygenase-2 pathway. Chem. Res. Toxicol. 17 (5), 679–684. Uchida, M., Nakamura, H., Kagami, Y., Kusano, T., Arizono, K., 2010. Estrogenic effects of o, p′-DDT exposure in Japanese medaka (Oryzias latipes). J. Toxicol. Sci. 35 (4), 605–608. Ullrich, J.W., Unwalla, R.J., Singhaus Jr., R.R., Harris, H.A., Mewshaw, R.E., 2007. Estrogen receptor beta ligands: design and synthesis of new 2-phenyl-isoindole-1,3-diones. Bioorg. Med. Chem. Lett. 17 (1), 118–122.

40

R. Kiyama, Y. Wada-Kiyama / Environment International 83 (2015) 11–40

Ullrich, N.D., Krust, A., Collins, P., MacLeod, K.T., 2008. Genomic deletion of estrogen receptors ERalpha and ERbeta does not alter estrogen-mediated inhibition of Ca2+ influx and contraction in murine cardiomyocytes. Am. J. Physiol. Heart Circ. Physiol. 294 (6), H2421–H2427. Umehara, K., Nemoto, K., Kimijima, K., Matsushita, A., Terada, E., Monthakantirat, O., DeEknamkul, W., Miyase, T., Warashina, T., Degawa, M., Noguchi, H., 2008. Estrogenic constituents of the heartwood of Dalbergia parviflora. Phytochemistry 69 (2), 546–552. Uslu, U., Sandal, S., Cumbul, A., Yildiz, S., Aydin, M., Yilmaz, B., 2013. Evaluation of estrogenic effects of polychlorinated biphenyls and organochlorinated pesticides using immature rat uterotrophic assay. Hum. Exp. Toxicol. 32 (5), 476–482. Valero, M.S., Pereboom, D., Barcelo-Batllory, S., Brines, L., Garay, R.P., Alda, J.O., 2011. Protein kinase A signalling is involved in the relaxant responses to the selective β-oestrogen receptor agonist diarylpropionitrile in rat aortic smooth muscle in vitro. J. Pharm. Pharmacol. 63 (2), 222–229. Vallejo, G., Ballaré, C., Barañao, J.L., Beato, M., Saragüeta, P., 2005. Progestin activation of nongenomic pathways via cross talk of progesterone receptor with estrogen receptor beta induces proliferation of endometrial stromal cells. Mol. Endocrinol. 19 (12), 3023–3037. van Aswegen, C., Dirksen van Schalkwyk, J.C., Roux, L.J., Becker, P.J., Du Plessis, D.J., 1992. A novel study on the effect of acetylsalicylic acid on the binding capacity of estrogen receptors from MCF-7 cells. Clin. Physiol. Biochem. 9 (4), 145–149. Vasconsuelo, A., Pronsato, L., Ronda, A.C., Boland, R., Milanesi, L., 2011. Role of 17βestradiol and testosterone in apoptosis. Steroids 76 (12), 1223–1231. Ventura, C., Núñez, M., Miret, N., Martinel Lamas, D., Randi, A., Venturino, A., Rivera, E., Cocca, C., 2012. Differential mechanisms of action are involved in chlorpyrifos effects in estrogen-dependent or -independent breast cancer cells exposed to low or high concentrations of the pesticide. Toxicol. Lett. 213 (2), 184–193. Vermerris, W., Nicholson, R.L., 2008. Phenolic Compound Biochemistry. Springer. Villa, E., 2008. Role of estrogen in liver cancer. Womens Health (Lond. Engl.) 4, 41–50. Virgili, F., Acconcia, F., Ambra, R., Rinna, A., Totta, P., Marino, M., 2004. Nutritional flavonoids modulate estrogen receptor alpha signaling. IUBMB Life 56 (3), 145–151. Vo, N.T., Madlener, S., Bago-Horvath, Z., Herbacek, I., Stark, N., Gridling, M., Probst, P., Giessrigl, B., Bauer, S., Vonach, C., Saiko, P., Grusch, M., Szekeres, T., Fritzer-Szekeres, M., Jäger, W., Krupitza, G., Soleiman, A., 2010. Pro- and anticarcinogenic mechanisms of piceatannol are activated dose dependently in MCF-7 breast cancer cells. Carcinogenesis 31 (12), 2074–2081. Vo, T.T., Jung, E.M., Choi, K.C., Yu, F.H., Jeung, E.B., 2011. Estrogen receptor α is involved in the induction of Calbindin-D(9 k) and progesterone receptor by parabens in GH3 cells: a biomarker gene for screening xenoestrogens. Steroids 76 (7), 675–681. von Angerer, E., Kranzfelder, G., Taneja, A.K., Schönenberger, H., 1980. N, N′dialkylbis(dichlorophenyl)ethylenediamines and -imidazolidines: relationship between structure and estradiol receptor affinity. J. Med. Chem. 23 (12), 1347–1350. Wada, H., Tarumi, H., Imazato, S., Narimatsu, M., Ebisu, S., 2004. In vitro estrogenicity of resin composites. J. Dent. Res. 83 (3), 222–226. Wagner, J., Lehmann, L., 2006. Estrogens modulate the gen\e expression of Wnt-7a in cultured endometrial adenocarcinoma cells. Mol. Nutr. Food Res. 50 (4–5), 368–372. Walters, M.R., Sharma, R., 2003. Cross-talk between beta-adrenergic stimulation and estrogen receptors: isoproterenol inhibits 17beta-estradiol-induced gene transcription in A7r5 cells. J. Cardiovasc. Pharmacol. 42 (2), 266–274. Wang, L.Q., 2002. Mammalian phytoestrogens: enterodiol and enterolactone. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 777 (1–2), 289–309. Wang, R.Y., Needham, L.L., 2007. Environmental chemicals: from the environment to food, to breast milk, to the infant. J. Toxicol. Environ. Health B Crit. Rev. 10 (8), 597–609. Wang, L.H., Yang, X.Y., Mihalic, K., Xiao, W., Li, D., Farrar, W.L., 2001. Activation of estrogen receptor blocks interleukin-6-inducible cell growth of human multiple myeloma involving molecular cross-talk between estrogen receptor and STAT3 mediated by co-regulator PIAS3. J. Biol. Chem. 276 (34), 31839–31844. Wang, X., Masri, S., Phung, S., Chen, S., 2008a. The role of amphiregulin in exemestaneresistant breast cancer cells: evidence of an autocrine loop. Cancer Res. 68 (7), 2259–2265. Wang, Y., Zhao, Y., Chen, X., 2008b. Experimental study on the estrogen-like effect of boric Acid. Biol. Trace Elem. Res. 121 (2), 160–170. Wang, J., Chung, M.H., Xue, B., Ma, H., Ma, C., Hattori, M., 2010. Estrogenic and antiestrogenic activities of phloridzin. Biol. Pharm. Bull. 33 (4), 592–597. Wang, L.M., Xie, K.P., Huo, H.N., Shang, F., Zou, W., Xie, M.J., 2012. Luteolin inhibits proliferation induced by IGF-1 pathway dependent ERα in human breast cancer MCF-7 cells. Asian Pac. J. Cancer Prev. 13 (4), 1431–1437. Wang, Y., Wang, W.L., Xie, W.L., Li, L.Z., Sun, J., Sun, W.J., Gong, H.Y., 2013a. Puerarin stimulates proliferation and differentiation and protects against cell death in human osteoblastic MG-63 cells via ER-dependent MEK/ERK and PI3K/Akt activation. Phytomedicine 20 (10), 787–796. Wang, X., Deng, H., Zou, F., Fu, Z., Chen, Y., Wang, Z., Liu, L., 2013b. ER-α36-mediated gastric cancer cell proliferation via the c-Src pathway. Oncol. Lett. 6 (2), 329–335. Wang, H., Guo, Y., Zhao, X., Li, H., Fan, G., Mao, H., Miao, L., Gao, X., 2013c. An estrogen receptor dependent mechanism of Oroxylin A in the repression of inflammatory response. PLoS One 8 (7), e69555. Wang, Y., Zhou, Q., Wang, C., Yin, N., Li, Z., Liu, J., Jiang, G., 2013d. Estrogen-like response of perfluorooctyl iodide in male medaka (Oryzias latipes) based on hepatic vitellogenin induction. Environ. Toxicol. 28 (10), 571–578. Wang, H., Gao, M., Wang, J., 2013e. Kaempferol inhibits cancer cell growth by antagonizing estrogen-related receptor α and γ activities. Cell Biol. Int. 37 (11), 1190–1196. Wang, C., Xu, C.X., Bu, Y., Bottum, K.M., Tischkau, S.A., 2014. Beta-naphthoflavone (DB06732) mediates estrogen receptor-positive breast cancer cell cycle arrest through AhR-dependent regulation of PI3K/AKT and MAPK/ERK signaling. Carcinogenesis 35 (3), 703–713.

Watson, C.S., Jeng, Y.J., Kochukov, M.Y., 2008. Nongenomic actions of estradiol compared with estrone and estriol in pituitary tumor cell signaling and proliferation. FASEB J. 22 (9), 3328–3336. Willemsen, P., Scippo, M.L., Kausel, G., Figueroa, J., Maghuin-Rogister, G., Martial, J.A., Muller, M., 2004. Use of reporter cell lines for detection of endocrine–disrupter activity. Anal. Bioanal. Chem. 378 (3), 655–663. Wintermantel, T.M., Campbell, R.E., Porteous, R., Bock, D., Gröne, H.J., Todman, M.G., Korach, K.S., Greiner, E., Pérez, C.A., Schütz, G., Herbison, A.E., 2006. Definition of estrogen receptor pathway critical for estrogen positive feedback to gonadotropinreleasing hormone neurons and fertility. Neuron 52 (2), 271–280. Wormke, M., Stoner, M., Saville, B., Walker, K., Abdelrahim, M., Burghardt, R., Safe, S., 2003. The aryl hydrocarbon receptor mediates degradation of estrogen receptor alpha through activation of proteasomes. Mol. Cell. Biol. 23 (6), 1843–1855. Wu, K.L., Chen, C.H., Shih, C.D., 2012. Nontranscriptional activation of PI3K/Akt signaling mediates hypotensive effect following activation of estrogen receptor β in the rostral ventrolateral medulla of rats. J. Biomed. Sci. 19 (1), 76. Wungsintaweekul, B., Umehara, K., Miyase, T., Noguchi, H., 2011. Estrogenic and antiestrogenic compounds from the Thai medicinal plant, Smilax corbularia (Smilacaceae). Phytochemistry 72 (6), 495–502. Xie, L., Thrippleton, K., Irwin, M.A., Siemering, G.S., Mekebri, A., Crane, D., Berry, K., Schlenk, D., 2005. Evaluation of estrogenic activities of aquatic herbicides and surfactants using an rainbow trout vitellogenin assay. Toxicol. Sci. 87 (2), 391–398. Xing, D., Nozell, S., Chen, Y.F., Hage, F., Oparil, S., 2009. Estrogen and mechanisms of vascular protection. Arterioscler. Thromb. Vasc. Biol. 29 (3), 289–295. Xu, H., Qin, S., Carrasco, G.A., Dai, Y., Filardo, E.J., Prossnitz, E.R., Battaglia, G., Doncarlos, L.L., Muma, N.A., 2009. Extra-nuclear estrogen receptor GPR30 regulates serotonin function in rat hypothalamus. Neuroscience 158 (4), 1599–1607. Yamada, T., Kunimatsu, T., Sako, H., Yabushita, S., Sukata, T., Okuno, Y., Matsuo, M., 2000. Comparative evaluation of a 5-day Hershberger assay utilizing mature male rats and a pubertal male assay for detection of flutamide's antiandrogenic activity. Toxicol. Sci. 53 (2), 289–296. Yamada, K., Terasaki, M., Makino, M., 2010. A novel estrogenic compound transformed from fenthion under UV-A irradiation. J. Hazard. Mater. 176 (1–3), 685–691. Yang, C., Chen, S., 1999. Two organochlorine pesticides, toxaphene and chlordane, are antagonists for estrogen-related receptor alpha-1 orphan receptor. Cancer Res. 59 (18), 4519–4524. Yao, Y., Brodie, A.M., Davidson, N.E., Kensler, T.W., Zhou, Q., 2010. Inhibition of estrogen signaling activates the NRF2 pathway in breast cancer. Breast Cancer Res. Treat. 124 (2), 585–591. Yeo, S.H., Herbison, A.E., 2014. Estrogen-negative feedback and estrous cyclicity are critically dependent upon estrogen receptor-α expression in the arcuate nucleus of adult female mice. Endocrinology 155 (8), 2986–2995. Yoon, K., Pallaroni, L., Stoner, M., Gaido, K., Safe, S., 2001. Differential activation of wild-type and variant forms of estrogen receptor alpha by synthetic and natural estrogenic compounds using a promoter containing three estrogen-responsive elements. J. Steroid Biochem. Mol. Biol. 78 (1), 25–32. Yoshitake, J., Kato, K., Yoshioka, D., Sueishi, Y., Sawa, T., Akaike, T., Yoshimura, T., 2008. Suppression of NO production and 8-nitroguanosine formation by phenol-containing endocrine-disrupting chemicals in LPS-stimulated macrophages: involvement of estrogen receptor-dependent or -independent pathways. Nitric Oxide 18 (3), 223–228. Yue, W., Yager, J.D., Wang, J.P., Jupe, E.R., Santen, R.J., 2013. Estrogen receptor-dependent and independent mechanisms of breast cancer carcinogenesis. Steroids 78 (2), 161–170. Zacharewski, T.R., Meek, M.D., Clemons, J.H., Wu, Z.F., Fielden, M.R., Matthews, J.B., 1998. Examination of the in vitro and in vivo estrogenic activities of eight commercial phthalate esters. Toxicol. Sci. 46 (2), 282–293. Zhang, X., Wang, Y., Zhao, Y., Chen, X., 2008. Experimental study on the estrogen-like effect of mercuric chloride. Biometals 21 (2), 143–150. Zhang, X., Mukerji, R., Samadi, A.K., Cohen, M.S., 2011. Down-regulation of estrogen receptor-alpha and rearranged during transfection tyrosine kinase is associated with withaferin a-induced apoptosis in MCF-7 breast cancer cells. BMC Complement. Altern. Med. 11, 84. Zhang, S.Q., Sawmiller, D., Li, S., Rezai-Zadeh, K., Hou, H., Zhou, S., Shytle, D., Giunta, B., Fernandez, F., Mori, T., Tan, J., 2013. Octyl gallate markedly promotes antiamyloidogenic processing of APP through estrogen receptor-mediated ADAM10 activation. PLoS One 8 (8), e71913. Zhang, Q., Lu, M., Wang, C., Du, J., Zhou, P., Zhao, M., 2014a. Characterization of estrogen receptor α activities in polychlorinated biphenyls by in vitro dual-luciferase reporter gene assay. Environ. Pollut. 189, 169–175. Zhang, X., Li, J.H., Duan, S.X., Lin, Q.J., Ke, S., Ma, L., Huang, T.H., Jiang, X.W., 2014b. G protein-coupled estrogen receptor–protein kinase A–ERK–CREB signaling pathway is involved in the regulation of mouse gubernaculum testis cells by diethylstilbestrol. Arch. Environ. Contam. Toxicol. 67 (1), 97–103. Zhang, X., Deng, H., Wang, Z.Y., 2014c. Estrogen activation of the mitogen-activated protein kinase is mediated by ER-α36 in ER-positive breast cancer cells. J. Steroid Biochem. Mol. Biol. 143C, 434–443. Zhou, Y., Zhu, Z.L., Guan, X.X., Hou, W.W., Yu, H.Y., 2009. Reciprocal roles between caffeine and estrogen on bone via differently regulating cAMP/PKA pathway: the possible mechanism for caffeine-induced osteoporosis in women and estrogen's antagonistic effects. Med. Hypotheses 73 (1), 83–85. Zhu, Y., Sullivan, L.L., Nair, S.S., Williams, C.C., Pandey, A.K., Marrero, L., Vadlamudi, R.K., Jones, F.E., 2006. Coregulation of estrogen receptor by ERBB4/HER4 establishes a growth-promoting autocrine signal in breast tumor cells. Cancer Res. 66 (16), 7991–7998.