- Email: [email protected]
The potential role of endocrine disrupting chemicals in cellulite
Accepted Manuscript The potential role of endocrine disrupting chemicals in cellulite Maria Mazioti PII: DOI: Reference:
S0306-9877(18)30058-6 https://doi.org/10.1016/j.mehy.2018.05.008 YMEHY 8874
To appear in:
Medical Hypotheses
Received Date: Revised Date: Accepted Date:
13 January 2018 18 April 2018 13 May 2018
Please cite this article as: M. Mazioti, The potential role of endocrine disrupting chemicals in cellulite, Medical Hypotheses (2018), doi: https://doi.org/10.1016/j.mehy.2018.05.008
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
TITLE PAGE
Title: The potential role of endocrine disrupting chemicals in cellulite
Author: Maria Mazioti, MD, PhD
Corresponding author: Maria Mazioti, MD, PhD 26, Perikleous Street, Salamina, 18900 Telephone: +306942252660 email: [email protected]
Sources of support: None
1
ABSTRACT
Cellulite constitutes a major aesthetic concern affecting the majority of post-adolescent women. Current epidemiological evidence supports that the prevalence of cellulite is significantly higher in industrialized societies indicating that environmental factors have crucial role in its pathogenesis and perpetuation. Endocrine disrupting chemicals, which exist ubiquitously in the environment, are able to alter hormonal and homeostatic systems. Several of them exert agonist effects by binding to estrogen receptors and mimicking the biological activity of estrogens. Since elevated estrogen concentration is prerequisite for cellulite, the present article suggests that endocrine disrupting chemicals may be key determinants in the initiation and deterioration of cellulite either by stimulating estrogen receptors or increasing their circulating levels due to interference with enzymes and binding proteins.
2
MAIN TEXT
INTRODUCTION Cellulite, which represents a major aesthetic problem, is considered as the final result of various disorders like enlargement of fat lobules, alteration of the microcirculation, destruction of the architecture of the connective tissue and fluid retention. According to many scientists cellulite is a normal state which guarantees the availability of the stored adipose tissue during pregnancy and lactation (1). The pathogenesis of cellulite is multifactorial and the essential role of estrogens in its initiation and aggravation has been recognized a long ago. This relation is supported by observations showing that cellulite appears in women, its onset is at puberty and it is deteriorated during pregnancy, menstruation and hormone replacement treatment (2). Estrogens possess a complex role in the pathogenesis of cellulite due to their concomitant effects on adipose and connective tissues. Human subcutaneous adipocytes express estrogen receptors type a and type β (ERa, ERβ) (3). Novel clues have been provided indicating that estradiol may stimulate the differentiation and proliferation of pre-adipocytes and the increasing number of anti-lipolytic a2 adrenergic receptors in subcutaneous adipocytes, through ERa-mediated mechanism (4). In addition several studies have confirmed the expression of both ERa and ERβ in human fibroblasts, the activation of which leads to the synthesis of metalloproteinases (MMPs). During menstruation the level of MMPs is high in order endometrial bleeding to be achieved. The collagen destruction that they cause is not limited only in endometrium, but it also concerns the connective tissue and the dermis (5). The consequent attraction of polymorphonuclear white blood cells, macrophages and eosinophils contributes to chronic inflammation, which in combination with estrogens foster structural alterations in glycozaminoglycans, making them more hydrophilic and resulting to augmented interstitial osmotic pressure and edema (2).
3
Endocrine disrupting chemicals (EDCs) are defined as exogenous factors interfering with synthesis, secretion, transport, binding, metabolism and excretion of natural hormones. They are widely used in the production of industrial, pharmaceuticals and personal care products. Their ubiquitous presence, long half-life, low metabolic rate and accumulation in adipose tissue contribute to constant human exposure to them. EDCs are associated with many metabolic diseases like obesity, diabetes mellitus and several of them may cause imbalance of sex hormones. Of particular importance are EDCs that exert agonist effects by binding to estrogen receptors (ERs) and mimicking the biological activity of endogenous estrogens, leading to amplified cellular responses (6).
THE HYPOTHESIS Epidemiological evidence suggests that the prevalence of cellulite is considerably higher in Westernized societies (7). Genetic predisposition has failed to fully justify that difference, indicating that changes in lifestyle and environmental impact may be additional precipitating factors. Several EDCs, which extensively exist in the environment act as ERs agonists (Table 1). Since estrogens play pivotal role in cellulite, the present article suggests that exposure to EDCs, in combination with other agents, may be a crucial factor for the pathogenesis or perpetuation of cellulite (Figure 1).
EVALUATION OF THE HYPOTHESIS Bisphenol A (BPA) is a compound diversely used in the manufacture of daily products and its annual production reaches to 3.6 million tones. Of concern is its detection not only in serum and urine samples of adults but also in breast milk, fetal serum and amniotic fluid (6,8). BPA binds to both ERa and ERβ, even though its affinity to ERβ is greater, and exerts agonist effects (9,10).
4
Phthalates represent a group of chemicals interfering with ERs. Most of phthalates and their metabolites bind and activate both the subtypes of ERs although there are data suggesting that several of them may exhibit estrogenic and anti-estrogenic activity after binding to ERa and ERβ respectively (11-13). Permethrin belongs to pyrethroids, which are synthetic compounds similar to pyrethrins derived from the flower chrysanthemum. Due to the widespread use of permethrin in agriculture, its residues contaminate the soil and the water, remain in the corps and finally they incorporate in the food chain. Moreover, permethrin is one of the main ingredients of many household or industrial insecticides, insect-repellents and it is also used in the treatment of head lice and scabies (14). Accumulating evidence supports that permethrin possesses weak estrogenic activity (15,16). Another pesticide, endrin, which is banned but is still detected in humans and animals due to its low biodegradability and its high bioaccumulation, is also documented to act as ERs agonist (17,18). Particularly important are the results of in vitro studies exploring the interference of parabens with ERs. Parabens are alkyl esters of p-hydroxybenzoic acid and are used in almost all the cosmetic products as well as foods and drugs because of their bactericidal and fungicidal properties (19). Significant number of studies suggests that parabens exhibit estrogenic activity, but the activation of ERs is significantly lower than that of estradiol (20,21). Increasing attention has been focused on the endocrine disrupting potency of phytoestrogens, which are plant-derived compounds with structural and functional similarities to natural estrogens. Phytoestrogens include isoflavones, lignans and coumestans. The main isoflavone, genistein, which is abundantly found in soy products, has been added to diet because of its favorable actions on preventing atherosclerosis, osteoporosis and even carcinogenesis (22). A growing body of studies has shown that genistein binds to ERs and exhibits estrogenic or antiestrogenic activity depending on the target tissue (23,24).
5
Nonylphenol (NP) is a compound derived from the degradation of alkyphenols ethoxylates, which are used in detergents, paints, pesticides, plastics and personal care products. High levels of NP in air, wastewater and sediment, its toxicity and its endocrine disrupting potency have recently become causes of great concern for human health. NP is reported to exhibit estrogenic activity, although that activity is considered weak enough in comparison with estradiol (25,26). Tributyltin (TBT) is a highly toxic chemical that has been extensively used as biocide in order to prevent the growth of marine organisms on the ship hulls. Although it is prohibited, TBT remains one of the most significant pollutants of the marine and aquatic environment. It is worth noting that it has been detected in human blood and liver. The impact of TBT on sex hormones balance has been long acknowledged due to the development of male characteristics (imposex) in female gastropods, but recently was documented that this effect can be suspended after the simultaneous exposure to TBT and synthetic estrogens (27). It is demonstrated that TBT may activate ERa and ERβ of adipocytes in both in vitro and in vivo experiments (28). It has been suggested that several heavy metals represent an additional group of environmental pollutants interfering with endocrine system (6). Cadmium is a metal to which human exposure is high because it is broadly used in the industrial production of batteries, pigments and electroplating. Furthermore, cadmium is detected in sedimentary rocks, marine phosphates and in atmosphere because of volcanic activity and forest fires. Cigarette smoking is an additional source of cadmium. Few in vitro studies document that cadmium binds and activates ERs (29,30). Ultra violet filters (UV filters) are chemicals widely used in cosmetics and mainly in sunscreens in order to protect the skin from the deleterious effects of sunlight. Their residues have been found in wastewater, lakes and fishes and the extent of human exposure to them is revealed by their detection in human urine samples and breast milk (31,32). Regarding the interference of
6
UV filters with ERs, increasing number of studies show their potency to act as ERs agonists (3335). Current studies suggest that EDCs may lead to substantial increase of natural estrogen concentration by interacting with enzymes or binding proteins involved in the metabolic pathways of sex hormones. Many hydroxylated metabolites of polychlorinated biphenyls (PCBs), polyhalogenated aromatic hydrocarbons (PHAHs) and BPA or its broadly used derivatives TeCBPA and TeBBPA, were shown to induce inhibition of estrogen sulfotransferase (SULT1E1), an enzyme which participates in estrogen metabolism (36). Circulating estrogens are bound to albumin and sex hormone binding globulin (SHBG), which is the major transport protein for sex steroids. Several EDCs like NP, BPA, genistein and O-hydroxybiphenyl which is used in plastic industry, may cause dose-depend displacement of estradiol from SHBG, leading to elevated levels of free estrogens (37).
DISCUSSION Elimination of orange-peel appearance is one of the main aesthetic concerns due to the consideration that the slim and flawless feminine body is absolutely desirable. The present article suggests that exposure to EDCs may indirectly contribute to the pathogenesis of cellulite. There are no scientific data that directly verify or refute the effects of EDCs on its initiation and deterioration. Cellulite results from disorders in adipose and connective tissues. Despite the existence of evidence which confirms the induction hypertrophy and hyperplasia of adipocytes by EDCs, lack of information about their effects on fibroblasts is an essential limiting factor in drawing conclusions (38). The potential contribution of EDCs to cellulite is examined due to their wide spectrum of uses. EDCs are contained in a huge variety of consumer goods like pharmaceutical pills, personal care products, detergents, food products, textiles and even children’s toys. It is certain that a
7
causal relationship between EDCs and cellulite can not be established, but exposure to these environmental agents may play determinant role in triggering cellulite. It is still debatable if the prevailing concentrations of EDCs can lead to any disease. This dose response relation has arisen controversies because of the relatively low amounts of EDCs in the environment. Human exposure to EDCs, even in low concentration, is observed during critical stages of development like pregnancy and infancy. EDCs initiate affecting adipose and connective tissues early enough unlike to endogenous estrogens which start their action in puberty (6). EDCs have many modes of action and humans are simultaneously exposed to a huge number of them. It is not possible to foresee the results of their co-existence on human adipose and connective tissues because many of them may interact and cause additive effects. Moreover, EDCs may induce nongenomic responses leading to redundant, synergistic or antagonist effects (39). Also, as previously mentioned several compounds may act as ERs agonists, whereas other studies document their antagonistic activity (Table 1). ERs are also expressed in vascular endothelial and smooth muscle cells and macrophages (40). Indisputably the exact role of ERs agonists in cellulite can be elucidated only through a thorough and overall examination of their impact on each cell type. In conclusion, the present article is based on the constant interaction of humans with the environment and underlines the potential contribution of EDCs to ERs activation and possibly to the pathogenesis and perpetuation of cellulite. This perspective may stimulate the design of large scale studies in order to obtain in depth knowledge, identify unknown precipitating factors and develop effective therapies.
8
ACKNOWLEDGMENTS None
CONFLICT OF INTEREST STATEMENT None
9
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10
9. Gould JC, Leonard LS, Maness SC, Wagner BL, Conner K, Zacharewski T et al. Bisphenol A interacts with the estrogen receptor alpha in a distinct manner from estradiol. Molecular and cellular endocrinology 1998;142:203-14. 10. Richter CA, Birnbaum LS, Farabollini F, Newbold RR, Rubin BS, Talsness CE et al. In vivo effects of bisphenol A in laboratory rodent studies. Reproductive toxicology 2007;24:199-224. 11. Jobling S, Reynolds T, White R, Parker MG, Sumpter JP. A variety of environmentally persistent chemicals, including some phthalate plasticizers, are weakly estrogenic. Environmental health perspectives 1995;103:582-7. 12. Harris CA, Henttu P, Parker MG, Sumpter JP. The estrogenic activity of phthalate esters in vitro. Environmental health perspectives 1997;105:802-11. 13. Takeuchi S, Iida M, Kobayashi S, Jin K, Matsuda T, Kojima H. Differential effects of phthalate esters on transcriptional activities via human estrogen receptors alpha and beta, and androgen receptor. Toxicology 2005;210:223-33. 14. Casida JE. Pyrethrum flowers and pyrethroid insecticides. Environmental health perspectives 1980;34:189-202. 15. Go V, Garey J, Wolff MS, Pogo BG. Estrogenic potential of certain pyrethroid compounds in the MCF-7 human breast carcinoma cell line. Environmental health perspectives 1999;107:173-7. 16. Garey J, Wolff MS. Estrogenic and antiprogestagenic activities of pyrethroid insecticides. Biochemical and biophysical research communications 1998;251:855-9. 17. Lemaire G, Mnif W, Mauvais P, Balaguer P, Rahmani R. Activation of alpha- and betaestrogen receptors by persistent pesticides in reporter cell lines. Life sciences 2006;79:1160-9. 18. Sargis RM, Johnson DN, Choudhury RA, Brady MJ. Environmental endocrine disruptors promote adipogenesis in the 3T3-L1 cell line through glucocorticoid receptor activation. Obesity 2010;18:1283-8.
11
19. Darbre PD, Harvey PW. Paraben esters: review of recent studies of endocrine toxicity, absorption, esterase and human exposure, and discussion of potential human health risks. Journal of applied toxicology : JAT 2008;28:561-78. 20. Byford JR, Shaw LE, Drew MG, Pope GS, Sauer MJ, Darbre PD. Oestrogenic activity of parabens in MCF7 human breast cancer cells. The Journal of steroid biochemistry and molecular biology 2002;80:49-60. 21. Routledge EJ, Parker J, Odum J, Ashby J, Sumpter JP. Some alkyl hydroxy benzoate preservatives (parabens) are estrogenic. Toxicology and applied pharmacology 1998;153:12-9. 22. Cassidy A, Albertazzi P, Lise Nielsen I, Hall W, Williamson G, Tefens I et al. Critical review of health effects of soyabean phyto-oestrogens in post-menopausal women. The Proceedings of the Nutrition Society 2006;65:76-92. 23. Casanova M, You L, Gaido KW, Archibeque-Engle S, Janszen DB, Heck HA. Developmental effects of dietary phytoestrogens in Sprague-Dawley rats and interactions of genistein and daidzein with rat estrogen receptors alpha and beta in vitro. Toxicological sciences : an official journal of the Society of Toxicology 1999;51:236-44. 24. Ju YH, Allred CD, Allred KF, Karko KL, Doerge DR, Helferich WG. Physiological concentrations of dietary genistein dose-dependently stimulate growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in athymic nude mice. The Journal of nutrition 2001;131:2957-62. 25. Vivacqua A, Recchia AG, Fasanella G, Gabriele S, Caprino A, Rago V et al. The food contaminants bisphenol A and 4-nonylphenol act as agonists for estrogen receptor alpha in MCF7 breast cancer cells. Endocrine 2003;22:275-84. 26. Laws SC, Carey SA, Ferrell JM, Bodman GJ, Cooper RL. Estrogenic activity of octylphenol, nonylphenol, bisphenol A and methoxychlor in rats. Toxicological sciences : an official journal of the Society of Toxicology 2000;54:154-67.
12
27. Santos MM, Micael J, Carvalho AP, Morabito R, Booy P, Massanisso P et al. Estrogens counteract the masculinizing effect of tributyltin in zebrafish. Comparative biochemistry and physiology Toxicology & pharmacology : CBP 2006;142:151-5. 28. Penza M, Jeremic M, Marrazzo E, Maggi A, Ciana P, Rando G et al. The environmental chemical tributyltin chloride (TBT) shows both estrogenic and adipogenic activities in mice which might depend on the exposure dose. Toxicology and applied pharmacology 2011;255:6575. 29. Brama M, Gnessi L, Basciani S, Cerulli N, Politi L, Speza G et al. Cadmium induces mitogenic signaling in breast cancer cell by an ERalpha-dependent mechanism. Molecular and cellular endocrinology 2007;264:102-8. 30. Stoica A, Katzenellenbogen BS, Martin MB. Activation of estrogen receptor-alpha by the heavy metal cadmium. Molecular endocrinology 2000;14:545-53. 31. Felix T, Hall BJ, Brodbelt JS. Determination of benzophenone-3 and metabolites in water and human urine by solid-phase microextraction and quadrupole ion trap GC–MS. Analytica chimica acta 1998;371:195-203. 32. Hany J, Nagel R. Nachweis von UV-filtersubstanzen in muttermilch. Deutsche LebensmittelRundschau 1995;91:341-5. 33. Schreurs RH, Sonneveld E, Jansen JH, Seinen W, van der Burg B. Interaction of polycyclic musks and UV filters with the estrogen receptor (ER), androgen receptor (AR), and progesterone receptor (PR) in reporter gene bioassays. Toxicological sciences : an official journal of the Society of Toxicology 2005;83:264-72. 34. Blair RM, Fang H, Branham WS, Hass BS, Dial SL, Moland CL et al. The estrogen receptor relative binding affinities of 188 natural and xenochemicals: structural diversity of ligands. Toxicological sciences : an official journal of the Society of Toxicology 2000;54:138-53.
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35. Schlumpf M, Jarry H, Wuttke W, Ma R, Lichtensteiger W. Estrogenic activity and estrogen receptor beta binding of the UV filter 3-benzylidene camphor. Comparison with 4methylbenzylidene camphor. Toxicology 2004;199:109-20. 36. Kester MH, Bulduk S, van Toor H, Tibboel D, Meinl W, Glatt H et al. Potent inhibition of estrogen sulfotransferase by hydroxylated metabolites of polyhalogenated aromatic hydrocarbons reveals alternative mechanism for estrogenic activity of endocrine disrupters. The Journal of clinical endocrinology and metabolism 2002;87:1142-50. 37. Dechaud H, Ravard C, Claustrat F, de la Perriere AB, Pugeat M. Xenoestrogen interaction with human sex hormone-binding globulin (hSHBG). Steroids 1999;64:328-34. 38. Regnier SM, Sargis RM. Adipocytes under assault: environmental disruption of adipose physiology. Biochimica et biophysica acta 2014;1842:520-33. 39. Watson CS, Bulayeva NN, Wozniak AL, Alyea RA. Xenoestrogens are potent activators of nongenomic estrogenic responses. Steroids 2007;72:124-34. 40. Cutolo M, Sulli A, Seriolo B, Accardo S, Masi A. Estrogens, the immune response and autoimmunity. Clinical and experimental rheumatology 1994;13:217-26.
14
Table 1. Agonist/Antagonist effect of endocrine disrupting chemicals by binding to estrogen receptors Endocrine
Binding
disrupting
to
chemical
estrogen receptor
Bisphenol A
Effect
Reference
ERa, ERβ
agonist
Gould et al 9, Richter et al 10
ERa, ERβ
agonist
Jobling et al 11, Harris et al 12, Takeuchi et al 13
ERβ
antagonist
Takeuchi et al 13
ERs
agonist
Go et al 15, Garey et al 16
ERa
agonist
Phthalates
Permethrin
Lemaire et al 18
Endrin ERβ
antagonist
Parabens
ERs
agonist
Byford et al 20, Routledge et al 21
Genistein
ERs
agonist
Casanova et al 23, Ju et al 24
Nonylphenol
ERs
agonist
Vivacqua et al 25, Laws et al 26
Tributyltin
ERs
agonist
Penza et al 28
Cadmium
ERa
agonist
Brama et al 29, Stoica et al 30
UV filters
ERa, ERβ
agonist
Felix et al 31, Hany et al 32, Schreurs et al 33
15
Figure 1 shows the hypothesis of the present article suggesting that endocrine disrupting chemicals, which exist ubiquitously in the environment, may be key determinants in the pathogenesis of cellulite either by stimulating estrogen receptors or increasing their circulating levels due to interference with enzymes and binding proteins.
16
S0306-9877(18)30058-6 https://doi.org/10.1016/j.mehy.2018.05.008 YMEHY 8874
To appear in:
Medical Hypotheses
Received Date: Revised Date: Accepted Date:
13 January 2018 18 April 2018 13 May 2018
Please cite this article as: M. Mazioti, The potential role of endocrine disrupting chemicals in cellulite, Medical Hypotheses (2018), doi: https://doi.org/10.1016/j.mehy.2018.05.008
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
TITLE PAGE
Title: The potential role of endocrine disrupting chemicals in cellulite
Author: Maria Mazioti, MD, PhD
Corresponding author: Maria Mazioti, MD, PhD 26, Perikleous Street, Salamina, 18900 Telephone: +306942252660 email: [email protected]
Sources of support: None
1
ABSTRACT
Cellulite constitutes a major aesthetic concern affecting the majority of post-adolescent women. Current epidemiological evidence supports that the prevalence of cellulite is significantly higher in industrialized societies indicating that environmental factors have crucial role in its pathogenesis and perpetuation. Endocrine disrupting chemicals, which exist ubiquitously in the environment, are able to alter hormonal and homeostatic systems. Several of them exert agonist effects by binding to estrogen receptors and mimicking the biological activity of estrogens. Since elevated estrogen concentration is prerequisite for cellulite, the present article suggests that endocrine disrupting chemicals may be key determinants in the initiation and deterioration of cellulite either by stimulating estrogen receptors or increasing their circulating levels due to interference with enzymes and binding proteins.
2
MAIN TEXT
INTRODUCTION Cellulite, which represents a major aesthetic problem, is considered as the final result of various disorders like enlargement of fat lobules, alteration of the microcirculation, destruction of the architecture of the connective tissue and fluid retention. According to many scientists cellulite is a normal state which guarantees the availability of the stored adipose tissue during pregnancy and lactation (1). The pathogenesis of cellulite is multifactorial and the essential role of estrogens in its initiation and aggravation has been recognized a long ago. This relation is supported by observations showing that cellulite appears in women, its onset is at puberty and it is deteriorated during pregnancy, menstruation and hormone replacement treatment (2). Estrogens possess a complex role in the pathogenesis of cellulite due to their concomitant effects on adipose and connective tissues. Human subcutaneous adipocytes express estrogen receptors type a and type β (ERa, ERβ) (3). Novel clues have been provided indicating that estradiol may stimulate the differentiation and proliferation of pre-adipocytes and the increasing number of anti-lipolytic a2 adrenergic receptors in subcutaneous adipocytes, through ERa-mediated mechanism (4). In addition several studies have confirmed the expression of both ERa and ERβ in human fibroblasts, the activation of which leads to the synthesis of metalloproteinases (MMPs). During menstruation the level of MMPs is high in order endometrial bleeding to be achieved. The collagen destruction that they cause is not limited only in endometrium, but it also concerns the connective tissue and the dermis (5). The consequent attraction of polymorphonuclear white blood cells, macrophages and eosinophils contributes to chronic inflammation, which in combination with estrogens foster structural alterations in glycozaminoglycans, making them more hydrophilic and resulting to augmented interstitial osmotic pressure and edema (2).
3
Endocrine disrupting chemicals (EDCs) are defined as exogenous factors interfering with synthesis, secretion, transport, binding, metabolism and excretion of natural hormones. They are widely used in the production of industrial, pharmaceuticals and personal care products. Their ubiquitous presence, long half-life, low metabolic rate and accumulation in adipose tissue contribute to constant human exposure to them. EDCs are associated with many metabolic diseases like obesity, diabetes mellitus and several of them may cause imbalance of sex hormones. Of particular importance are EDCs that exert agonist effects by binding to estrogen receptors (ERs) and mimicking the biological activity of endogenous estrogens, leading to amplified cellular responses (6).
THE HYPOTHESIS Epidemiological evidence suggests that the prevalence of cellulite is considerably higher in Westernized societies (7). Genetic predisposition has failed to fully justify that difference, indicating that changes in lifestyle and environmental impact may be additional precipitating factors. Several EDCs, which extensively exist in the environment act as ERs agonists (Table 1). Since estrogens play pivotal role in cellulite, the present article suggests that exposure to EDCs, in combination with other agents, may be a crucial factor for the pathogenesis or perpetuation of cellulite (Figure 1).
EVALUATION OF THE HYPOTHESIS Bisphenol A (BPA) is a compound diversely used in the manufacture of daily products and its annual production reaches to 3.6 million tones. Of concern is its detection not only in serum and urine samples of adults but also in breast milk, fetal serum and amniotic fluid (6,8). BPA binds to both ERa and ERβ, even though its affinity to ERβ is greater, and exerts agonist effects (9,10).
4
Phthalates represent a group of chemicals interfering with ERs. Most of phthalates and their metabolites bind and activate both the subtypes of ERs although there are data suggesting that several of them may exhibit estrogenic and anti-estrogenic activity after binding to ERa and ERβ respectively (11-13). Permethrin belongs to pyrethroids, which are synthetic compounds similar to pyrethrins derived from the flower chrysanthemum. Due to the widespread use of permethrin in agriculture, its residues contaminate the soil and the water, remain in the corps and finally they incorporate in the food chain. Moreover, permethrin is one of the main ingredients of many household or industrial insecticides, insect-repellents and it is also used in the treatment of head lice and scabies (14). Accumulating evidence supports that permethrin possesses weak estrogenic activity (15,16). Another pesticide, endrin, which is banned but is still detected in humans and animals due to its low biodegradability and its high bioaccumulation, is also documented to act as ERs agonist (17,18). Particularly important are the results of in vitro studies exploring the interference of parabens with ERs. Parabens are alkyl esters of p-hydroxybenzoic acid and are used in almost all the cosmetic products as well as foods and drugs because of their bactericidal and fungicidal properties (19). Significant number of studies suggests that parabens exhibit estrogenic activity, but the activation of ERs is significantly lower than that of estradiol (20,21). Increasing attention has been focused on the endocrine disrupting potency of phytoestrogens, which are plant-derived compounds with structural and functional similarities to natural estrogens. Phytoestrogens include isoflavones, lignans and coumestans. The main isoflavone, genistein, which is abundantly found in soy products, has been added to diet because of its favorable actions on preventing atherosclerosis, osteoporosis and even carcinogenesis (22). A growing body of studies has shown that genistein binds to ERs and exhibits estrogenic or antiestrogenic activity depending on the target tissue (23,24).
5
Nonylphenol (NP) is a compound derived from the degradation of alkyphenols ethoxylates, which are used in detergents, paints, pesticides, plastics and personal care products. High levels of NP in air, wastewater and sediment, its toxicity and its endocrine disrupting potency have recently become causes of great concern for human health. NP is reported to exhibit estrogenic activity, although that activity is considered weak enough in comparison with estradiol (25,26). Tributyltin (TBT) is a highly toxic chemical that has been extensively used as biocide in order to prevent the growth of marine organisms on the ship hulls. Although it is prohibited, TBT remains one of the most significant pollutants of the marine and aquatic environment. It is worth noting that it has been detected in human blood and liver. The impact of TBT on sex hormones balance has been long acknowledged due to the development of male characteristics (imposex) in female gastropods, but recently was documented that this effect can be suspended after the simultaneous exposure to TBT and synthetic estrogens (27). It is demonstrated that TBT may activate ERa and ERβ of adipocytes in both in vitro and in vivo experiments (28). It has been suggested that several heavy metals represent an additional group of environmental pollutants interfering with endocrine system (6). Cadmium is a metal to which human exposure is high because it is broadly used in the industrial production of batteries, pigments and electroplating. Furthermore, cadmium is detected in sedimentary rocks, marine phosphates and in atmosphere because of volcanic activity and forest fires. Cigarette smoking is an additional source of cadmium. Few in vitro studies document that cadmium binds and activates ERs (29,30). Ultra violet filters (UV filters) are chemicals widely used in cosmetics and mainly in sunscreens in order to protect the skin from the deleterious effects of sunlight. Their residues have been found in wastewater, lakes and fishes and the extent of human exposure to them is revealed by their detection in human urine samples and breast milk (31,32). Regarding the interference of
6
UV filters with ERs, increasing number of studies show their potency to act as ERs agonists (3335). Current studies suggest that EDCs may lead to substantial increase of natural estrogen concentration by interacting with enzymes or binding proteins involved in the metabolic pathways of sex hormones. Many hydroxylated metabolites of polychlorinated biphenyls (PCBs), polyhalogenated aromatic hydrocarbons (PHAHs) and BPA or its broadly used derivatives TeCBPA and TeBBPA, were shown to induce inhibition of estrogen sulfotransferase (SULT1E1), an enzyme which participates in estrogen metabolism (36). Circulating estrogens are bound to albumin and sex hormone binding globulin (SHBG), which is the major transport protein for sex steroids. Several EDCs like NP, BPA, genistein and O-hydroxybiphenyl which is used in plastic industry, may cause dose-depend displacement of estradiol from SHBG, leading to elevated levels of free estrogens (37).
DISCUSSION Elimination of orange-peel appearance is one of the main aesthetic concerns due to the consideration that the slim and flawless feminine body is absolutely desirable. The present article suggests that exposure to EDCs may indirectly contribute to the pathogenesis of cellulite. There are no scientific data that directly verify or refute the effects of EDCs on its initiation and deterioration. Cellulite results from disorders in adipose and connective tissues. Despite the existence of evidence which confirms the induction hypertrophy and hyperplasia of adipocytes by EDCs, lack of information about their effects on fibroblasts is an essential limiting factor in drawing conclusions (38). The potential contribution of EDCs to cellulite is examined due to their wide spectrum of uses. EDCs are contained in a huge variety of consumer goods like pharmaceutical pills, personal care products, detergents, food products, textiles and even children’s toys. It is certain that a
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causal relationship between EDCs and cellulite can not be established, but exposure to these environmental agents may play determinant role in triggering cellulite. It is still debatable if the prevailing concentrations of EDCs can lead to any disease. This dose response relation has arisen controversies because of the relatively low amounts of EDCs in the environment. Human exposure to EDCs, even in low concentration, is observed during critical stages of development like pregnancy and infancy. EDCs initiate affecting adipose and connective tissues early enough unlike to endogenous estrogens which start their action in puberty (6). EDCs have many modes of action and humans are simultaneously exposed to a huge number of them. It is not possible to foresee the results of their co-existence on human adipose and connective tissues because many of them may interact and cause additive effects. Moreover, EDCs may induce nongenomic responses leading to redundant, synergistic or antagonist effects (39). Also, as previously mentioned several compounds may act as ERs agonists, whereas other studies document their antagonistic activity (Table 1). ERs are also expressed in vascular endothelial and smooth muscle cells and macrophages (40). Indisputably the exact role of ERs agonists in cellulite can be elucidated only through a thorough and overall examination of their impact on each cell type. In conclusion, the present article is based on the constant interaction of humans with the environment and underlines the potential contribution of EDCs to ERs activation and possibly to the pathogenesis and perpetuation of cellulite. This perspective may stimulate the design of large scale studies in order to obtain in depth knowledge, identify unknown precipitating factors and develop effective therapies.
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ACKNOWLEDGMENTS None
CONFLICT OF INTEREST STATEMENT None
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Table 1. Agonist/Antagonist effect of endocrine disrupting chemicals by binding to estrogen receptors Endocrine
Binding
disrupting
to
chemical
estrogen receptor
Bisphenol A
Effect
Reference
ERa, ERβ
agonist
Gould et al 9, Richter et al 10
ERa, ERβ
agonist
Jobling et al 11, Harris et al 12, Takeuchi et al 13
ERβ
antagonist
Takeuchi et al 13
ERs
agonist
Go et al 15, Garey et al 16
ERa
agonist
Phthalates
Permethrin
Lemaire et al 18
Endrin ERβ
antagonist
Parabens
ERs
agonist
Byford et al 20, Routledge et al 21
Genistein
ERs
agonist
Casanova et al 23, Ju et al 24
Nonylphenol
ERs
agonist
Vivacqua et al 25, Laws et al 26
Tributyltin
ERs
agonist
Penza et al 28
Cadmium
ERa
agonist
Brama et al 29, Stoica et al 30
UV filters
ERa, ERβ
agonist
Felix et al 31, Hany et al 32, Schreurs et al 33
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Figure 1 shows the hypothesis of the present article suggesting that endocrine disrupting chemicals, which exist ubiquitously in the environment, may be key determinants in the pathogenesis of cellulite either by stimulating estrogen receptors or increasing their circulating levels due to interference with enzymes and binding proteins.
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