MicroRNAs as potential biomarkers in diseases and toxicology

Mutation Research 764–765 (2014) 46–57

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Mutation Research/Genetic Toxicology and Environmental Mutagenesis journal homepage: www.elsevier.com/locate/gentox Community address: www.elsevier.com/locate/mutres

MicroRNAs as potential biomarkers in diseases and toxicology Bénazir Siddeek a,b,f , Lilia Inoubli a,b , Nadjem Lakhdari a,b , Paul Bellon Rachel a,b , Karma Claire Fussell g , Steffen Schneider g , Claire Mauduit a,b,c,d , Mohamed Benahmed a,b,e,∗ a

Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 5, Nice, F-06204, France Université de Nice Sophia-Antipolis, UFR Médecine, Nice, F-06000, France Université Lyon 1, UFR Médecine Lyon Sud, Lyon, F-69921, France d Hospices Civils de Lyon, Hôpital Lyon Sud, laboratoire d’anatomie et de cytologie pathologiques, Pierre-Bénite, F-69495, France e Centre Hospitalier Universitaire de Nice, Pôle Digestif, Gynécologie, Obstetrique, Centre de Reproduction, Nice, F-06202, France f BASF Agro, Ecully F-69130, France g BASF SE, experimental toxicology and ecology, 67056 Ludwigshafen, Germany b c

a r t i c l e

i n f o

Article history: Received 7 January 2014 Received in revised form 20 January 2014 Accepted 20 January 2014 Available online 30 January 2014 Keywords: MicroRNAs Chemicals Circulating biomarkers

a b s t r a c t MiRNAs (microRNAs) are single-stranded non-coding RNAs of approximately 21–23 nucleotides in length whose main function is to inhibit gene expression by interfering with mRNA processes. MicroRNAs suppress gene expression by affecting mRNA (messenger RNAs) stability, targeting the mRNA for degradation, or both. In this review, we have examined how microRNA expression could be altered following exposure to chemicals and how they could represent appropriate tissue and more interestingly circulating biomarkers. Among the key questions before using the microRNA for evaluation of risk toxicity, it remains still to clarify how they could be causally involved in the adverse effects and how stable their changes are. © 2014 Published by Elsevier B.V.

1. Introduction Small RNAs of 20–30 nucleotides continue to be discovered, including some that are specific to plants or animal lineages (for reviews, see [1,2]). Various small RNAs with distinctive characteristics have been identified and can be classified into three classes based on their biogenesis mechanisms, the type of RNA protein that they are associated with and the nature of their targets: microRNAs (miRNAs), endogenous small interfering RNAs (endo-siRNAs) and Piwi-interacting RNAs (piRNAs). Endogenous siRNA are short double-stranded RNAs that contains 21–23 nucleic acids with a 19-nucleotide duplex region which is able to inhibit the gene expression of specific proteins by a mechanism called RNA interference. The piRNAs are highly enriched in the animal germline only and originate from single-stranded precursor RNAs [3]. MiRNAs are single-stranded non-coding RNAs of approximately 21–23 nucleotides in length which main function is to inhibit gene expression by interfering with messenger RNA (mRNA) processes.

∗ Corresponding author at: INSERM (National Institut of Health and Medical Research), U1065, Team 5, Bâtiment Universitaire Archimed, Centre Méditerranéen de Médecine Moléculaire (C3M), 151 route Saint-Antoine Ginestière, BP 2 3194, 06204 Nice Cedex 3, France. Tel.: +33 492 035 630; fax: +33 492 035 640. E-mail address: [email protected] (M. Benahmed). 1383-5718/$ – see front matter © 2014 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.mrgentox.2014.01.010

In animals, siRNA typically binds perfectly to its mRNA target, a perfect match to the sequence, whereas miRNA can inhibit the translation of many different mRNA sequences because its pairing is imperfect. MiRNAs suppress gene expression by affecting mRNA stability, targeting the mRNA for degradation, or both [4]. Near to 1872 miRNAs have been identified in human with the potential to regulate the expression of about two-third of human mRNAs and influence almost all genetic pathways. The possibilities of predictions for miRNA-target recognition have been developed using computer modeling [5]. A growing number of data show that microRNAs are involved in the expression of genes involved in xenobiotic exposure [6–8]. Better understanding of the non-coding RNAs is critical to determine its potential key role in the impact of environmental factors and particularly xenobiotic exposure [9] (for a review, see [10]). Since their discovery, there is a growing interest in miRNAs research allowed by the development of efficient and sensitive tools for their study. MiRNAs can be extracted from tissues and quantified easily by RT-qPCR even with low amount of input material [11]. They can also be detected by hybridization (Northern, Panomics, Nanostring, MicroArrays) ([12,13] or by Next generation sequencing [14]. Since a decade, a number of studies are pointing out the role of miRNAs in the regulation of key cellular processes and the appearance of pathologies. MicroRNAs (miRNAs) have been implicated in posttranscriptional regulation of many gene expressions

B. Siddeek et al. / Mutation Research 764–765 (2014) 46–57

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Table 1 Effects of drugs, natural and chemical compounds on miRNAs expression. Compound

Organ/Cell

Species

Altered miRNAs

References

Cigarette smoke Volatile organic compounds (formaldehyde, benzene, toluene, and xylene) Trichostatin A Sodium arsenite Arsenic trioxide Cadmium Aluminum-sulfate Aluminum-sulfate Air pollution metal-rich PM Cigarette smoke Cigarette smoke 4-(methylnitrosamino)-1-(3-pyridyl)-1butanone (NNK) (tobacco carcinogen) Hexahydro-1,3,5-trinitro-1,3,5-triazine Hexahydro-1,3,5-trinitro-1,3,5-triazine Carbon tetrachloride Dioxins Bisphenol A Wy-14, 643 Estradiol benzoate Ethanol Tamoxyfen Acetaminophen; carbon tetrachloride Iron – and aluminum – sulfate 5-fluorouracil (5-FU) (drug) Residual oil fly ash Vorinostat, myo-inositol, bexarotene, pioglitazone (cigarette smoke) 6-Mercaptopurine (immunosuppressive drug) 4-(methylnitrosamino)-1-(3-pyridyl)-1butanone Radon

Spermatozoa Lung

Human Mouse

Mir-340, mir-365, 129-3p, 634 miR-1187, miR-125a-3p, miR-125b-5p, miR-466c-5p, miR-5105, miR-3472

[68] [100]

Primary hepatocyte TK6 cell line T24 cell line

Rat

miR-379, miR-143, miR-122, miR-122, miR-143, miR-379 miR-222, miR-210, mir-19a Mir-146 Mir-146 miR-9, -128, -125b Mir-222, mir-21 Mir-294, let-7c, miR-34c, -222 Mir-218 Mir-126, Mir-34

[101] [102] [103] [95] [104] [105] [106] [107] [108] [109]

let-7, miR-15, -16, -26, -181, miR-10b miR-206, -30, -195 miR-298, -370 Mir-191 Mir-146a Let-7c Mir-29 Mir-21, mir-335,mir-153 Mir-17-92 cluster, mir-106a, mir-34 Mir-298, mir-370 Mir-9, mir-125b, mir-128 Mir-200b miR-1 and miR-133, miR-21, miR-24, and miR-29

[110] [110] [111] [112] [113] [114] [66] [115] [116] [111] [105] [117] [118] [119]

miR-195, miR-21, miR-29c and miR-34a, 146bmiR-144 and miR-451 miR-206 and miR-133b

[120]

[122]

7,12-dimethylbenz(␣)anthracene (DMBA) and N-methyl-N-nitrosourea (MNU) Acetaminophen, allyl alcohol, and ␣-naphthyl isothiocyanate 2,3,7,8-tetrachlorodibenzo-p-dioxin (environmental contaminant) 2,3,7,8-tetrachlorodibenzo-p-dioxin Doxorubicin Cyanobacterial hepatotoxin microcystin-LR Ethanol Printex 90 carbon black nanoparticles Arsenic Arsenic Acetaminophen Gentamicin 2-Amino-1-methyl-6-phenylimidazo[4,5b]pyridine (carcinogen from cooked meat) Perfluorooctane sulfonic acid Cadmium Cisplatin Folate deprivation and arsenic exposure Benzo[k]fluoranthene Thapsigargin, deoxycholic acid Fenhexamid and fludioxonil (fungicide) DDT and BPA Nonylphenol Pegylated leptin antagonist Lycopene Licorice flavonoid Quercetin Ethanol Allyl-isothiocyanate High fat diet Conjugated linoleic acid High fat diet

Human HN cells HN cells Leucocytes Lung Lung Lung

Human Rat Human Rat

Liver Neuron Hepatocytes Hepatocytes 3A placental cell Hepatocyte Testis Neurons Hepatocyte Hepatocytes Neuron Colon Heart Lung

Mouse Mouse Rat Rat Human Mouse Rat Mouse Rat

Placenta

Rat

Lung

Rat

Lung BEAS2B cell line

Human

In the liver, spleen and kidneys Liver

Mouse

hsa-miR-483-3p, hsa-miR-494, hsa-miR-2115*, hsa-miR-33b, hsa-miR-1246, hsa-miR-3202, hsa-miR-18a, hsa-miR-125b, hsa-miR-17*, and hsa-miR-886-3p miR-34a and miR-155 miR-21

Rat

miR-122

[124]

Thymus

Mouse

[125]

Embryo Heart

Zebrafish Mouse Whitefish Rat Mouse Human

miR-122 and miR-181a miR-23a, miR-18b, miR-31 miR-182 miR-27e 208b, miR-216b, miR-215, miR-34c and miR-367 let-7c, miR-9b), (miR-16a, miR-21a, miR-34a) (miR-122) Mir-21 miR-135b

Liver Lung Umbilical endothelial cell Liver Liver

Human Human Rat Mouse

Mouse Mouse

Kidney Colon

Mouse Rat

74-5p, 135a*, 466g, 1196, 466f-3p, 877, 342-3p, 195, 375, 29c, 148a, 652 Mir-21, 155 Let-7

Brain HepG2, liver Hela Lymphocyte Hepatocyte Hepatocytes Breast cancer cells Breast cancer cells Sertoli cells, testis Hypothalamus Liver Liver Liver Liver Macrophage Adipocytes Adipocytes Adipocytes

Rat Human

miR-466b, -672, and -297 Let-7

Human Human Mouse Human Human Mouse Rat Rat Mouse Mouse Mouse Mouse Mouse

Mir-222 miR-146a, miR-365, let-7f, miR-199b-5p,miR-30c-1* mir-199a-5p Mir-21, miR-125b and miR-181a Mir-21 miR-135a* and miR-199a-5p miR-10a, miR-200a, rno-miR-409-5p, miR-125a-3p Mir-21 Mir-122 miR-122 and miR-125b Mir-217 Mir-155 Mir-21 miR-103 mir-107, miR-221, mir-222 Mir-143

Mouse

[121]

[123]

[126] [127] [128] [129] [130] [128] [131] [132] [133] [134]

[135] [136] [137] [102] [138] [139] [140] [141] [142] [143] [144] [145] [146] [147] [148] [149] [150] [151]

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B. Siddeek et al. / Mutation Research 764–765 (2014) 46–57

and control of different processes such as apoptosis, DNA repair, oxidative stress response, cancer and cellular development. Those discoveries in miRNAs research open new insights in toxicology and raise the question of miRNAs regulation in response to exposure to environmental chemical toxicants or natural compounds such as alcohol, smoke, stress, hormones, medication, and diets (Table 1). This would facilitate the bio-monitoring and preventive strategies for drug development, and clinical pharmacotherapy. This review describes the current knowledge on the miRNAs expression, their potential changes in toxicological studies and circulating miRNA as potential toxicological biomarkers will be discussed.

2. MiRNA expression (Fig. 1) The stem-loop structures from which miRNAs are derived are disseminated throughout the genome, either within intronic sequences of protein-coding genes, within intronic or exonic regions of non-coding RNAs, or set between independent transcription units (inter-genic). The location of some of these intronic miRNAs is evolutionarily conserved and they are similarly coexpressed with their host genes in different animals. Here, we review the recent advances in miRNA biogenesis in animals. Particularly, we focus on the roles of miRNAs in vertebrate physiology. The majority of intronic miRNAs are transcribed from the same promoter as the host gene. However, approximately 35% of intronic miRNAs have upstream regulatory elements consistent with promoter function [15]. Pri-miRNAs are mostly transcribed by RNA polymerase II (Pol II) [16], and to a less extent by Pol III [17]. Their promoters also contain transcription start sites, CpG islands, expression sequence tags, and conserved transcription factor binding sites, enhancers and silencers [18,19]. MiRNA biogenesis is based on series of processing steps to convert the primary miRNA (pri-miRNA) transcript into the biologically active, mature miRNA (Fig. 1), [for a review see [1,20]]. Firstly, the transcribed pri-miRNA is cleaved by the RNase III-like enzyme Drosha in the nucleus [21] generating a miRNA precursor about 60–70 nt called pre-miRNA. Cleavage by Drosha requires the co-factor DGCR8 (DiGeorge critical region 8), also known as Pasha [22]. The miRNA biogenesis machinery is also subjected to regulation by feedback loops, as evidenced for the Drosha–DGCR8 complex [23,24]. Once produced, the premiRNA is translocated to the cytoplasm through the nuclear pore complex by Exportin-5. In the cytoplasm, the pre-miRNA hairpin associates with the RNase III-like enzyme Dicer that cleaves it into a double-stranded miRNA duplex comprised of the mature miRNA and the miRNA* (also known as passenger strand) [25,26]. The guide strand functions as a mature miRNA and is incorporated into an RNA-induced silencing complex (RISC). This complex contains an Argonaute (Ago) protein as a primary component that binds to the target mRNA and degrades the passenger strand. Mature miRNA guides RISC to recognize target sequences located in the 3 UTR of mRNAs leading to the inhibition of translation or degradation of mRNA [27]. MiRNA biogenesis can be regulated at each step by various mechanisms. At the transcriptional level, a number of factors like c-myc, or HMGA1 have been showed to regulate miRNAs transcription, and have been reported in databases such as Transmir [28]. Further steps, like the nuclear processing of miRNAs by Drosha can be also modulated by the transforming Growth Factor ␤ (TGF␤) signaling pathway, the Smads [29]. The c-Myc oncogenic transcription factor also transactivates drosha mRNA expression thus upregulating the Drosha protein level in addition to the transcriptional regulatation of miRNAs [30]. Tumor suppressor p53 promotes some pri-miRNA processing via interaction with p68 [31]. Furthermore, it has been shown that the p38 MAPK-MK2 signaling pathway promotes miRNA biogenesis by facilitating the nuclear

Fig. 1. MiRNA biogenesis. MicroRNA (miRNA) genes are transcribed by RNA polymerase II (Pol II) to generate the primary transcripts (pri-miRNAs). Cleavage of the pri-miRNA occurs within the nucleus by Drosha and DGCR8 complex (also known as the Microprocessor complex) which interact with helicases p68 and p72, to generate a ∼65 nucleotide pre-miRNAs. Pre-miRNA has a ∼2-nt 3 overhang, which is recognized by the nuclear export factor exportin 5. Once export through the nuclear pore complex into the cytoplasm, the RNase III Dicer supported by the proteins TRBP or PACT catalyses the second processing step to produce miRNA duplexes. Dicer, TRBP or PACT and Argonaute (AGO 1–4) mediate the processing of pre-miRNA and the assembly of the RISC (RNA-induced silencing complex). One strand of the duplex is preferentially retained by the Ago protein as the mature miRNA, whereas the other strand is degraded. The complex contains an Ago protein, GW182 and mature miRNA which is required for gene silencing, which act by specifically binding to the 3 -UTR regions of target mRNAs, causing translational repression or mRNA degradation.

localization of p68 [32]. The nuclear-cytoplasmic exportation can be regulated by steroids like estrogen and progesterone which increase Exportin-5 mRNA expression [31]. The tumor suppressor, BRCA1 (breast cancer susceptibility gene 1), associates with Microprocessor complex to accelerate processing of pri-miRNAs specifically associated with cancer [33]. Other proteins such as Esr1 (also known as estrogen receptor alpha) [34], NF90 and NF45 (nuclear factor 90 and 45) [35] associate with Drosha and inhibit also the processing of specific pri-miRNAs such as let-7 family members. Proteins regulating pri-miRNA processing by recognition of the stem-loop sequence or structure like hnRNP-A1 (heterogeneous nuclear ribonucleoprotein A1), KSRP (KH-type splicing regulatory protein) have been also been described. Lin28 (abnormal cell lineage factor 28) is an interesting protein involved in regulating multiple aspects of miRNA biogenesis. This protein can inhibit prilet-7 processing [36,37] by sequestering pri-let-7 miRNAs in the nucleoli away from the Microprocessor. Interestingly, hnRNP-A1 protein can also interact with pri-let-7a, but in this case, it negatively regulates the processing [38].

B. Siddeek et al. / Mutation Research 764–765 (2014) 46–57

The terminal loop region is a determinant of microRNA biogenesis. This region is crucial for both positive (for example, hnRNP A1) and negative (for example, Lin28) regulators to modulate miRNA levels and thereby gene regulation, reviewed in [39]. Finally, miRNA stability and degradation are dependent on different mechanisms that give to the majority of mature miRNAs, a half-life in the order of several hours to several days [40,41]. This suggests that a cis-acting element in the sequence of mature miRNA regulates specificity of degradation of miRNAs. Studies in several model systems have identified the molecular mechanisms of miRNA-regulated decay. The animal miRNAs generally lack a protective 2 -O methyl group at their 3 terminus and display template-independent nucleotide addition, mostly adenylation or uridylation that may regulate miRNA stability [42]. The XRN (5 –3 exoribonuclease) family of enzymes and hPNPaseold-35 (human polynucleotide phosphorylase protein) play various roles in miRNA stability. In the context of the present brief review aiming at identifying the role of miRNA expression in toxicology, it will be of major interest to in the future to identify how drugs/chemicals may affect this miRNA biosynthesis and degradation pathways.

3. MiRNA in toxicology (Table 1) Recently, the identification of miRNAs targets highlighted the roles of miRNA in the posttranscriptional regulation of cytochrome P450 (CYP) and nuclear receptors and considered their potential relevance and application for toxicological studies. P450s are important enzymes that catalyze the metabolism of xenobiotics including drugs, environmental chemicals, and carcinogens. The transcriptional regulation of CYPs by nuclear receptors has been well studied and the central role of miRNAs in the regulation of CYPs and nuclear receptors has been evidenced [43]. For example, CYP1A1/1A2 is regulated by miR-142-3p and miR-200a, CYP2C19 by miR-34a, CYP2D6 by let-7b and CYP2E1 by miR-10a and let7g [44]. In addition, miRNAs can modulate the action of nuclear receptors. Nuclear receptors are ligand-activated transcription factors that regulate the expression of target genes by binding to their promoters. The expression of cytochrome P450 is regulated by receptors such as pregnane X receptor (PXR), the aryl hydrocarbon receptor (AhR), and the constitutive androstane receptor (CAR). Those receptors are targeted by a number of miRNA and represent a way of P450 regulation. Indeed, mir-148a, which is abundantly expressed in the liver, targets the human PXR [45]. It was reported that miR-375 with complex regulatory effects on AhR mRNA could mediate in part the action of pollutants such as ambient particulate matter and diesel exhaust particles in the induction of asthma [45]. Also, the activation of AhR by Tranilast, an Anti-allergy Drug was shown to facilitate cell reprogramming in a miR-302-dependent way [46]. Shizu et al. suggested that phenobarbital-mediated down-regulation of miR-122 is an early and important event in the AMPK-dependent CAR activation and transactivation of its target genes [47]. Thus, microRNAs appear as key players in the regulation of genes involved in absorption, distribution, metabolism, and excretion. Peroxisome-proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors that exert in the liver a transcriptional activity. PPAR␣ was reported to be specifically regulated by miR-21 and miR-27b, in the liver [48]. Additionally, miR-10b was shown to target PPAR␣ and induce steatosis in hepatocytes [49]. Indirectly, PPAR␥ activity appears to be under the control of miR-132. Inversely, miRNA expression profiling indicated that activated PPAR␣ is a major regulator of hepatic miRNA expression and revealed that let-7C signaling cascade is critical for PPAR␣ agonist-induced liver proliferation and tumorigenesis [50].

49

Concerning AhR, its activation in TH17 cells regulates miR-132/212 cluster and induces the cells differentiation [51]. Among nuclear receptors that are regulated by miRNAs, Esr1 was reported as a target of miR-206 [52], miR-221, miR-222 [53], and miR-22 [54]. Conversely, miRNAs can also be regulated by nuclear receptors at the transcriptional level and during their maturation [55]. Some authors pointed out the potential role of these miRNAs in anti-estrogen therapies. In the mouse testis, miR-184 was shown to target nuclear receptor corepressor 2 (Ncor2) and by this way, regulates mammalian spermatogenesis [56]. Considering the wide actions of miRNAs on the expression of genes in key processes involved in detoxification, chemical metabolic activation, and in the activity nuclear receptor, miRNAs studies open new insights in the mode of action of drugs, hormones or endocrine disrupting chemicals. In this way of elucidating miRNAs function, the understanding of cell-type specificity of miRNA expression is an important step. However, very few miRNAs are exclusively found in individual tissues or cells. The miRNA expression varies from highly specific to ubiquitous and, for conserved miRNAs, is comparable between rodents and human [57]. One example of tissue specificity was found in the lung where miR-195 and miR-200c were specifically expressed in the rat lung [58]. In few research areas such as hepato-toxicity or cardiology, specific miRNAs have been identified as markers of specific tissue injury. Indeed, miR-208 is described as a myomiR since it is found at high levels in cardiac tissue. MiR-208 expression is deregulated in various cardiovascular diseases. Moreover, its expression in the cardiac tissue is described as a sensitive biomarker for cardiac injury in human [59], and inhibition studies concluded that it might be an interesting therapeutic target [60]. More often, this is a miRNAs expression profile that is linked to a specific pathology. For instance, Shapiro et al. have recently examined the role of miRNAs in renal Ischemia reperfusion injury using expression profiling. They found that samples that underwent renal injury can be distinguished from controls based on the alterations in nine miRNAs [61]. Interestingly, assessment of Doxorubicin-induced cardiomyopathy versus anthracyclins in rats indicated that miRNAs expression profile could give indications about the specific tissue response in a dose and a time dependant manner [62]. In this tissue, they represent early toxicity indicators, since their modifications are detected earlier than changes in gene expression. Thus, miRNAs can help to better understand chronic/acute toxicity mechanism, since they may be regulated earlier than genomic toxicological markers. Similarly, MCF7 breast cancer cells showed a dose- and time-dependent modification in the miRNA expression levels after a treatment with the chemotherapeutic drug 5-flourouracil. Eleven miRNAs (let-7g, miR-10b, miR-15a, miR-16, miR-21, miR-27a, miR365, miR-374b, miR-483-5p, miR-574-3p and miR-575) previously identified in the microarray to be differentially expressed after treatment were selected to analyze their responsiveness to different doses of 5-FU. Time-response data was also generated for miR-10b, miR-21, miR-483-5p, miR-574-3p and miR-575 following 12, 24, 36, 48, 60 and 72 h treatment. It was concluded that miRNAs play an important regulatory role in 5-FU induced cytotoxicity and fit in perfectly in the intricate network of 5-FU activity [63]. Furthermore, Koufaris et al. [64] examined the microRNA profile in the liver of rats exposed to genotoxic (2-acetylaminofluorene) and epigenetic (phenobarbital, diethylhexylphthalate, methapyrilene HCL, monuron, and chlorendic acid) chemical hepatocarcinogens, as well as to non-hepatocarcinogenic treatments (benzophenone, and diethylthiourea). All hepatocarcinogens affects the expression of liver mRNAs, while the hepatic microRNA profiles are associated with the mode of action of the chemical treatments and correspond to chemical carcinogenicity. The three nuclear

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B. Siddeek et al. / Mutation Research 764–765 (2014) 46–57

receptor-activating chemicals (phenobarbital, benzophenone, and diethylhexylphthalate) are characterized by the induction of the miR-200a/200b/429. In humans, a miRNAs-Environmental association study conducted by Xudong Wu identified 1842 concurrent interactions between 407 miRNAs and 497 environmental chemicals, and thus highlighted distinct miRNAs regulated genes in response to different environmental chemicals [65]. Since different drugs induce various miRNAs profiles, fitting with their cellular mode of action, the analysis of the miRNAs profile could potentially help to categorize a potentially toxic compound. MiRNAs are not only involved in the effects induced by an acute exposure, but also in chronic toxicity. In the rat testis, we recently showed that a neonatal exposure to estradiol benzoate induces germ cells death in adulthood [66]. This phenomenon is linked to increased levels of mir-29 which targets DNA methyl transferases and the anti-apoptotic protein MCL-1. The inhibition of these proteins leads to the over expression of retrotransposons, to a stimulation of apoptosis and in term to the germ cell death [66]. However, the mechanisms of imprinting and the existence of sensitive windows of exposure leading to irreversible miRNAs changes remain poorly understood and represent an interesting area for further studies. Besides the assessment of drugs on miRNAs expression at the individual level, a few studies showed that such alteration could also be observed in the next generations. For instance, the offspring of pregnant rats submitted to high fat diet presents, at the adult age, alterations in hepatic expression of insulin like growth factor-2 and key miRNAs: miR-709, miR-122, miR-192, miR-194, miR-26a, let-7a, let7b, let-7c, miR-494 and miR-483* [67]. Another example is represented by the exposure to cigarette smoke. Two of the constituents of cigarette smoke, benzo[a]pyrene and nicotine, have been shown to induce harmful phenotypes that can be transmitted to future generations. Indeed, in the multigenerational toxicity of cigarette smoke, miRNAs expression alterations (mir-340, mir-365, mir-129-3p) in the spermatozoa from human smokers and that the altered microRNAs may be at play in pathways for maintenance of healthy sperm and normal embryo development by controlling cell death/apoptosis [68]. Those studies address the potential transgenerational effects of exposure to chemicals and additional experiments should be realized to validate those effects. Indeed, this field is still a matter of debate and remains under discussion.

4. miRNA as circulating biomarkers The majority of miRNAs are intra-cellular and, as such, miRNAs are the critical mediators in the stress cellular response, disease and environmental stimuli [69]. Less is known, though, about extracellular action of miRNAs. Stable circulating miRNAs were described for the first time in 2008, from the plasma of patients with lymphoma [70]. To date, a significant number of miRNAs have been observed outside of cells, in various body fluids. Number of miRNA carriers have been also described such as ribonucleoprotein complexes, exosomes, apoptosis bodies, membrane-derived vesicles and high-density lipoproteins (Fig. 2) [71]. Exosomes are membrane vesicles of 40–100 nm in diameter corresponding to the internal vesicle of an endosomal compartment. It is initially formed by the inward budding plasma membrane into multi-vesicular bodies within endosomes. Exosomes and their miRNA content are released into the extracellular compartment on the fusion of endosomes with the plasma membrane [72–74]. Exosomes are released when endosomally-derived multi-vesicular bodies fuse with the plasma membrane [75]. Apoptotic bodies and microparticles are larger vesicles than exosomes (100–1000 nm in diameter). They represent a heterogeneous population of vesicles that are released by budding and blobbing of the plasma membrane and express

antigens specific of their parental cells [76,77]. Microparticles display a broad spectrum of bioactive substances and receptors on their surface and harbor a concentrated set of cytokines, signaling proteins, mRNAs, and microRNAs. During apoptosis, cells release larger microparticles or apoptotic bodies that also transport specific miRNAs. Lipoproteins, particularly high-density lipoprotein can also transport endogenous miRNAs and deliver them to recipient cells with possible functional targeting capabilities. This cellular export is regulated by neutral sphingomyelinase and is dependent on scavenger receptor class B type I [71]. Most of the extracellular miRNAs in blood plasma and cell culture are independent of exosomes and are bound to Argonaute 2 protein (Ago2), a part of RNA-induced silencing complex [78]. Ago2 is the main functional component of cytoplasmic miRNA ribonucleoprotein complex (miRNP). Extracellular miRNAs are in the most part byproducts of dead cells that remain in extracellular space due to the high stability of the Ago2 protein and Ago2-miRNA complex. It was also found that extracellular circulating miRNAs could be bound to other Ago proteins like Ago1. These observations raised the question as to whether circulating miRNAs may play a role, at least as potential biomarkers, in health and disease. Indeed, circulating miRNAs are abundant in blood and their levels in serum are stable, reproducible, and consistent among individuals of the same species in contrast to mRNA [79,80], which allow them to be potential non-invasive biomarkers. Several extracellular miRNAs have now revealed specific miRNA profiles in health and disease allowing them to represent a consistent signature in health and some differentiating diseases [74,81,82]. For example, several tumor-specific miRNA aberrations in serum were used as circulating biomarkers for distinguishing cancer and cancer-free diseases (Table 2). Increasing number of reports indicate that the serum miRNA expression profile can be used as a novel serum-based biomarkers potentially offering more sensitive and specific tests than those currently available for early diagnosis of cancer and other diseases. Those new approaches could improve present clinical management, including the classification of cancer, the prognosis estimation and the prediction of the therapeutic efficiency [69,79,83]. A number of circulating miRNAs were used as potential biomarkers of metabolic disorders, autoimmune, inflammatory diseases (Table 3). Interestingly, the question related to miRNA as biomarkers in health and diseases has been now extended to miRNAs as biomarkers in toxicology studies (Table 4). This question related to the role of miRNA expression and epigenetic in chemical safety was the topic of at least three recent held workshops by ILSI-HESI, US National Academy of Sciences and ECETOC [84–88]. Indeed, that the levels of specific circulating miRNA species may also be used to detect and monitor the pathological development associated with chemicals or drug-induced tissue injuries is now suggested by several investigators [43,89–92]. Using a mouse model, the level a set of plasma miRNAs has been associated with hepato-cellular injuries induced by acetaminophen overdose. More specifically mir-122 and mir-192, are both enriched in the liver tissue and exhibit doseand exposure duration-dependent changes in the plasma that are parallel to the serum amino-transferase levels and the histopathology of liver degeneration [91]. MiR-103 was also reported as an appropriate biomarker among the circulating miRNAs identified in rats with acetaminophen-induced hepato-toxicity [43]. In the same way, a study in human and mouse model suggested that circulating miR-122 can be used as a potential novel predictive and reliable blood marker for viral-, alcohol-, and chemical-induced liver injury [90]. Environmental factors in daily life such as cigarette smoking can also affect plasma miRNA profiles. Altered miRNA expression has been reported in the smoking-related diseases [93] and a study performed on smokers and non-smokers revealed that plasma miRNA profiles clearly discriminate between smokers and

Table 2 Circulating miRNAs associated to cancers. Disease

miRNA

Correlation

Ref

Disease

miRNA

Correlation

Ref

Colorectal cancer (CRC)

miR-92

Differentiation of CRC from gastric cancer, inflammatory bowel disease, and healthy controls

[152]

Gastric cancer

Discrimination of gastric cancer from healthy controls

[153]

mir-21, mir-133b

Discrimination of prostate cancer from healthy controls

[154]

mir-125b, mir-199a,mir-100, let-7 g, mir-433, mir-214 mir-10b, mir-21, mir-223, mir-338, let-7a, mir-30a-5p, mir-126 mir-452, mir-105, mir-127, mir-518-2, mir-187, mir-30a-3p, miR-196a-2 mir-18a mir-21

Breast cancer

[156]

Pancreatic cancer

mir-221 mir-141

[158] [160]

Glioblastoma

miR-141

Discrimination of prostate cancer from healthy controls

[162] [163]

Acute leukemia

mir-375, mir-141

[154]

CRC and advanced adenome

miR-92a decreased (ratio miR-638/miR-92a decreased) miR-29a and miR-92a increased

mir-15, mir-195, mir-26a, let-7i

[166]

Diffuse large B-cell lymphoma (DLBCL)

miR-155, miR-210, miR-21 increased

Set of 15 miRNAs (including for instance miR-16)

[167]

Non-small cell lung cancer (NSCLC)

miR- 128b, miR-152, miR-125b, miR-205, miR-27a, miR- 146a, miR-222, miR-23a, miR-24, miR-150

[168]

Lung cancer

mir-155, let-7a

mir-145

mir-10b, mir-34a, mir-155 92a, 21

Discrimination of breast cancer from healthy controls; correlation between miRNA levels and lymph node status Discrimination of breast cancer from healthy controls

[170]

[172]

Discrimination of glioblastoma from healthy controls

mir-128

mir-96

Mir-195, let7a

Discrimination of pancreatic cancer from healthy controls

let-7a, mir-221, mir-137, mir-372, mir-182 mir-221 and mir-222

[157]

[159] [161] [67]

Differentiation between leukemia and healthy controls

[164]

Discrimination of CRC and also advanced adenoma from healthy controls Differentiation of DLBCL from healthy controls and association of miR-21 with relapse-free survival in DLBCL Differentiation of NSCLC from healthy controls

[165]

Discrimination of lung cancer from healthy controls

[169]

[70]

[79]

B. Siddeek et al. / Mutation Research 764–765 (2014) 46–57

Prostate cancer

mir-133

[155]

[171]

[173]

[174]

51

52

B. Siddeek et al. / Mutation Research 764–765 (2014) 46–57

Fig. 2. Mechanisms of miRNA release from cells into peripheral blood circulation and transport to target cells. MP: microparticles; HDL: high-density lipoprotein; Ago2: Argonaute 2

Table 3 Circulating miRNAs associated to metabolic disorders, auto-immune and inflammatory diseases. Physiopathological status

miRNAs

Correlation

References

Pregnancy Non-small-cell lung carcinoma (NSCLC) Rheumatoid arthritis (RA)/osteoarthritis (OA)

mir-527, miR-520d-5p and miR-526a let-7f, miR-20b and miR-30e-3p

Discrimination of pregnant women from non-pregnant women Discrimination between NSCLC and healthy control

[175] [176]

miR-132 decreased

Distinction between RA or OA

[177]

mir-16 and miR-146a

Correlation with tender joint counts and 28-joint Disease Activity Score

Coronary artery disease (CAD)

miR-126, miR-17, miR-92a, miR-155, miR-145 miR-133a and miR-208a

Distinction between CAD and healthy controls

[178]

Chron disease Diabetes Alzheimer’s disease Duchenne muscular dystrophy

miR-149 miR-144 miR-137, 181c, 9, 29a/b miR-1, 133a, 206

Increased Reduced Increased

[179] [180] [181] [182]

non-smokers. This observation suggested that repeated cigarette smoking substantially alters the plasma miRNA profile [94]. Exposure to metal-rich particulate matter has been reported to modify the expression of candidate miRNAs in peripheral blood leukocytes of workers at an electric-furnace steel plant. Indeed, expression of

miRNA-222 and miRNA-21 was significantly upregulated in postexposure samples [95]. Circulating miRNAs may also represent good markers for hypertension-induced heart failure and for the response to therapeutic treatment. Indeed, in a rat model, miRNAs arrays on plasma

Table 4 MiRNA expression in seminal plasma from infertile men. Diseases

miRNAs

Correlation

References

Oligoastheno-zoospermia

miR-141, miR-29a, miR-429, miR200a miR- 34b, miR-19a, miR-16, miR-122

Upregulated in spermatozoa samples from oligoasthenozoospermic patients compared with those from normozoospermic Downregulated in supernatant sperm samples from oligoasthenozoospermic patients compared with those from normozoospermic

[183]

Astheno-zoospermia

miR-30a, miR-26a, miR-200a, miR-141, miR-29a, miR-24 miR-1973, miR-34b, miR-122

Upregulated in supernatant sperm samples from asthenozoospermic patients compared with those from normozoospermic Downregulated in supernatant sperm samples from asthenozoospermic patients compared with those from normozoospermic

Infertility

miR-574-5p, miR-297, miR-122, miR-1275, miR-373, miR-185 and miR-193b miR-100, miR-512-3p, miR-16, miR-19b, miR-23b and miR-26a

Upregulated in the semen of infertile males with semen abnormalities

Non obstructive azoospermia

miR-19b and let-7a

[184]

Downregulated in the semen of infertile males with semen abnormalities Upregulated in supernatant sperm from idiopathic infertile males with non obstructive azoospermia compared with fertile controls

[185]

B. Siddeek et al. / Mutation Research 764–765 (2014) 46–57

highlighted modifications in miR-16, miR-20b, miR-93, miR-106b, miR-223, and miR-423-5p. A time course study showed that those changes are correlated to disease progression [96]. In kidney diseases, a number of studies have highlighted the sensitivity of miRNAs detection in plasma and urine (for review [97]). In injury induced by renal ischemia reperfusion or streptozotocin induced diabetes in mice, miR-10a and miR-30d concentrations in plasma and urine are positively correlated with the degree of kidney injury [98]. In humans, urinary and plasma miR-21 are associated with severe acute kidney injury [99]. Together, there are now many studies establishing a potential link between the level of circulating miRNA and clinical diagnosis or prognosis in many pathologies or injuries. The use of circulating miRNAs in body fluids as potential toxicological biomarkers, and the link between miRNA-related pharmaco-genomics and adverse drug reactions will be a matter of future investigations [43].

5. Conclusions MiRNAs are highly conserved between human and animal models and can regulate biological pathways by repressing target proteins. Chemicals can affect those pathways by inducing their down or up-regulation. Also, miRNA profiling in response to toxic compounds can provide toxicant-specific profiles in specific organs. Given their specificity to tested compounds, the time and dose dependency of their modifications, the sensitivity and simplicity of their detection in various tissues, miRNAs appear like promising tools in toxicological studies. Interestingly, circulating miRNAs could be accessible through non-invasive protocols and stable. Circulating miRNAs thus represent ideal candidates in toxicological studies, and may be used as biomarkers of chemical exposure for safety assessment. However, with regard to the involvement of miRNA expression in the effects of exposure to chemicals, there are at least two main observations that should be taken into account. Firstly, while there are a growing number of reports showing altered miRNAs profile following exposure to drugs/chemicals, the mechanisms leading to the pathological phenotype remain poorly understood. One of the major limitations of numerous studies analyzing the miRNAs expression changes in experimental models after exposure to chemicals is that these changes, generally, are viewed associated rather than causal to the adverse apical endpoints. One of the appropriate approaches to establish a causal link between miRNA expression and the adverse effects could be the following; identify first the adverse effect and then try to delineate and dissect the supporting miRNA expression changes. Recently, by using such an approach, alterations in mir-29 family members that induced adult germ cell death process leading to infertility were identified following neonatal exposure to the xenoestrogen estradiol benzoate [66]. Secondly, a number of studies have highlighted the dose and time dependency of miRNAs profile after exposure to chemical compounds. Furthermore, studies have showed that exposure can lead to long term changes, and possibly irreversible. The irreversibility of miRNA expression changes is likely occurring when the exposure takes place during critical developmental periods i.e. the in utero and perinatal periods that are specifically sensitive to chemicals. Those observations are to be viewed in the context of the concept of Developmental Origin of Health and Diseases (also termed the Barker’s hypothesis). In this context, low-dose effects have received considerable attention from the scientific and regulatory communities. Analysis of miRNAs seems to be an appropriate approach in risk assessment at low doses, and long term effects induced by EDCs. Based on the increasing amounts of accumulating data on miRNA expression alterations following exposure to chemicals and the fact that circulating miRNAs appear as very

53

interesting biomarkers, the possibility that miRNAs measurement could be included in toxicological studies is open. While the field of epigenetic (including miRNA but also methylation and chromatin remodeling) is a rapidly growing field in both understanding of these mechanisms in health and diseases as well as in terms of availability of tools, some key questions remain still to be clarified: (i) are miRNA expression changes causes or consequences of the adverse effects? (ii) Are they stable and irreversible? (86).

Conflict of interest None.

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