{"paper_id":"827ae19e-fbdb-45b7-8743-7a9b4b6ebddf","body_text":"Front. Biosci. (Landmark Ed) 2026; 31(1): 42777\nhttps://doi.org/10.31083/FBL42777\nCopyright: © 2026 The Author(s). Published by IMR Press.\nThis is an open access article under the CC BY 4.0 license .\nPublisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nReview\nEpigenetic Mechanisms of Reproductive Dysfunction Induced by\nEndocrine-Disrupting Chemicals: Evidence From Molecular Studies\nSeonhwa Hwang1,2,†\n , Hyun Bon Kang 1,†\n , Dae Hyun Kim 3,*, Min Hi Park 1,2,*\n1College of Pharmacy, Kyungsung University, 48434 Busan, Republic of Korea\n2Brain Busan 21 Plus Research Project Group, Kyungsung University, 48434 Busan, Republic of Korea\n3Department of Food Science & Technology, College of Natural Resources and Life Science, Pusan National University, 50463 Miryang, Republic of\nKorea\n*Correspondence: dhkim74@pusan.ac.kr (Dae Hyun Kim); parkmh@ks.ac.kr (Min Hi Park)\n†These authors contributed equally.\nAcademic Editors: Y ongmei Xi and Alexander Shpakov\nSubmitted: 30 May 2025 Revised: 25 July 2025 Accepted: 31 July 2025 Published: 16 January 2026\nAbstract\nEndocrine-disrupting chemicals (EDCs), including bisphenol A (BPA), phthalates, organochlorine pesticides, and heavy metal ions,\npose serious threats to reproductive health by interfering with hormonal balance and molecular signaling pathways. Recent research\nhad expanded our understanding of these compounds has beyond their traditional role in hormone receptor interference. EDCs can\ntrigger lasting epigenetic changes, including abnormal DNA methylation, histone modifications, RNA methylation, and altered regulation\nof non-coding RNA, which can impair reproductive functions such as gametogenesis, folliculogenesis, steroidogenesis, and embryo\nimplantation. Importantly, EDC-mediated epigenetic alterations have been linked to various reproductive disorders, including polycystic\novary syndrome (PCOS), endometriosis, reduced ovarian reserve, and impaired spermatogenesis. For example, BPA exposure alters\nDNA methylation in estrogen signaling and aromatase gene expression, whereas phthalates disrupt histone acetylation and methylation\nin hormone synthesis pathways. Similarly, pesticides and heavy metal ions may influence microRNA expression and histone structure,\nfurther disrupting endocrine-regulated gene networks. These alterations may occur during sensitive developmental windows and can\nlead to long-term or transgenerational effects on reproductive health. Understanding how EDCs exert their toxicity through epigenetic\nmechanisms is essential for early detection of exposure, identification of molecular biomarkers, and development of targeted therapies\nto reduce reproductive risks. Here, we discuss the emerging molecular evidence that provides a comprehensive overview of how EDCs\nimpair reproductive health through epigenetic pathways, thereby offering a framework for future research and translational applications.\nKeywords: reproductive dysfunction; endocrine-disrupting chemicals (EDCs); histone modification; DNA methylation; RNA methyla-\ntion; non-coding RNA (ncRNA)\n1. Introduction\nOver the past few decades, increasing evidence has\ndrawn attention to the detrimental effects of environ-\nmental pollutants on reproductive health. Among these,\nendocrine-disrupting chemicals (EDCs), such as bisphe-\nnol A (BPA), phthalates, organochlorine pesticides such as\ndichlorodiphenyltrichloroethane (DDT), and heavy metal\nions such as lead ions (Pb 2+) and cadmium ions (Cd 2+),\nhave gained particular attention because of their widespread\nuse in industrial, agricultural, and consumer products. This\nleads to chronic, low-level exposure in the general popu-\nlation through ingestion, inhalation, and dermal absorption\n[1–7].\nAlthough earlier studies have primarily focused on\nhormonal disruptions mediated by receptor binding, such as\nestrogenic or anti-androgenic actions [ 2,8], EDCs also act\nthrough epigenetic pathways. Epigenetic modifications, in-\ncluding DNA methylation, histone modifications, and non-\ncoding RNA (ncRNA) expression, play pivotal roles in\nregulating gene activity without altering the nucleotide se-\nquences [ 9–12]. These epigenetic processes are essential\nfor maintaining normal reproductive functions, such as ga-\nmetogenesis, folliculogenesis, ovulation, and steroid hor-\nmone biosynthesis [ 11,13]. Consequently, when EDCs in-\nterfere with these highly coordinated regulatory systems,\nit can lead to a cascade of reproductive dysfunctions, in-\ncluding infertility, hormonal imbalances, and developmen-\ntal abnormalities in the reproductive tract.\nEDC exposure during critical developmental periods\ncauses abnormal epigenetic reprogramming in reproduc-\ntive tissues. For instance, BPA exposure hypermethylates\nEstrogen receptor 1 (ESR1) and Cytochrome P450 fam-\nily 19 subfamily A member 1 (CYP19A1), reduces histone\nacetylation (Histone H3 lysine 9 acetylation (H3K9ac)),\nand upregulates repressive markers such as histone H3 ly-\nsine 27 trimethylation (H3K27me3), ultimately impairing\novarian and testicular function [ 14–18]. Phthalates such as\ndi(2-ethylhexyl) phthalate (DEHP) and its active metabo-\nlite mono(2-ethylhexyl) phthalate (MEHP) disrupt histone-\nmodifying enzyme and DNA methyltransferase (DNMT)\nactivity, reducing the transcription of essential steroido-\n\ngenic genes such as steroidogenic acute regulatory ( STAR)\nand cholesterol side-chain cleavage enzyme ( CYP11A1)\n[19–22]. Pesticides such as DDT and chlorpyrifos disrupt\nthe expression of microRNAs (miRNA), such as miR-21\nand miR-137, and induce abnormal DNA methylation at\nhormone receptor gene promoters, thereby impairing repro-\nductive hormone signaling and development [ 23–26]. In\naddition, heavy metal ions, including Pb 2+ and Cd2+, pro-\nmote both global hypomethylation and site-specific hyper-\nmethylation of reproductive gene promoters, along with al-\ntered histone modification patterns, such as H3K9me2 and\nH3K27me3 [27–29].\nRecognizing the epigenetic basis of EDC-induced re-\nproductive toxicity is essential for advancing scientific un-\nderstanding and clinical practice. First, epigenetic alter-\nations are promising biomarkers for the early detection of\nchemical exposure and reproductive risk, often before vis-\nible symptoms appear. Second, elucidating these molec-\nular mechanisms provides insights into how even short-\nterm environmental exposure can result in enduring or even\ntransgenerational reproductive abnormalities owing to the\nstable inheritance of epigenetic marks. Third, mechanis-\ntic knowledge can inform the design of targeted therapeu-\ntic interventions, such as epigenetic modulators or antioxi-\ndants, and support evidence-based public health regulations\naimed at minimizing human exposure to harmful EDCs.\nThese considerations emphasize the importance of multi-\ndisciplinary research integrating toxicology, molecular bi-\nology, epidemiology, and policy.\nThis review aimed to clarify how epigenetic mecha-\nnisms contribute to the reproductive toxicity of EDCs. We\npresent an integrative analysis of recent molecular studies\ninvolving DNA and RNA methylation, histone modifica-\ntions, and ncRNA dysregulation, focusing on their func-\ntional impacts on the male and female reproductive sys-\ntems. By emphasizing on the key molecular targets and\npathways, we also outline future directions for mechanistic\nresearch, biomarker discovery, and regulatory action. Al-\nthough EDCs differ in structure and origin, they ultimately\nconverge on shared molecular pathways that mediate their\nreproductive toxicity. At the cellular level, they affect re-\nproductive tissues, including granulosa cells, Leydig cells,\nSertoli cells, and oocytes, by interfering with essential pro-\ncesses, such as steroid hormone synthesis, gametogenesis,\nfollicular maturation, and embryo implantation.\nAt the epigenetic level, EDCs alter the activity and ex-\npression of enzymes such as DNMT1, DNMT3a, histone\nacetyltransferases (HA Ts), histone deacetylases (HDACs),\nand histone methyltransferases, such as enhancer of zeste\nhomolog 2 (EZH2) and G9a. These disruptions lead\nto abnormal DNA methylation (such as at ESR1 and\nCYP19A1), altered histone modification patterns (such as\nincreased H3K27me3 and decreased H3K9ac), and changes\nin miRNA expression (such as miR-21 and miR-146a), ul-\ntimately silencing genes critical for hormonal balance and\nreproductive cell viability. Functionally, these molecular\nchanges result in decreased estradiol and testosterone pro-\nduction, anovulation, impaired spermatogenesis, reduced\noocyte quality, and increased risk of infertility or miscar-\nriage. Understanding these converging epigenetic path-\nways is essential for developing targeted therapies and iden-\ntifying early biomarkers of reproductive toxicity.\n2. Epigenetic Mechanisms in Reproductive\nPhysiology\nEpigenetic mechanisms are essential processes that\nregulate gene expression patterns without altering the un-\nderlying DNA sequence [30,31]. The key epigenetic mech-\nanisms include histone modifications, DNA methylation,\nRNA methylation, and non-coding RNAs (ncRNAs) such\nas microRNAs (miRNAs) (Fig. 1) [31–33].\n2.1 Types and Functional Roles of Histone Modifications\nHistone acetylation involves HA T-mediated acetyl\ngroup addition to lysine residues on histone tails, which\nneutralizes the positive charge on lysine, thereby reduc-\ning interactions between histones and DNA. Therefore, the\nchromatin becomes less compact, creating an open and\ntranscriptionally active state that promotes gene expression\n[34,35].\nHistone deacetylation is mediated by histone deacety-\nlases (HDACs), which remove acetyl groups from his-\ntone tails to restore the positive charge on lysine residues,\nstrengthening the interaction between histones and DNA.\nThe resulting tighter chromatin structure represses gene\ntranscription by reducing the accessibility of transcription\nfactors to the DNA [ 36,37].\nHistone methylation is a complex process that mainly\noccurs at the lysine and arginine residues. The effect of\nmethylation depends on both the specific modified residues,\nsuch as H3K4, H3K9, H3K27, and H3K36, and methy-\nlation degree (mono-, di-, or tri-methylation). For exam-\nple, trimethylation at H3K4 (H3K4me3) is typically asso-\nciated with active transcription, whereas H3K27me3 and\nH3K9me3 are associated with gene repression. These mod-\nifications are tightly controlled by specific histone methyl-\ntransferases and demethylases that modulate gene expres-\nsion during gametogenesis, embryogenesis, and hormone-\nresponsive processes in reproduction [ 38–40].\nHistone phosphorylation involves adding phosphate\ngroups to the serine, threonine, or tyrosine residues on hi-\nstones. This modification plays a crucial role in regulating\nchromatin dynamics during various biological processes.\nFor example, H3 phosphorylation at serine 10 (H3S10ph)\nand serine 28 (H3S28ph) is closely linked to chromosome\ncondensation during mitosis and meiosis, ensuring proper\nchromosome alignment and segregation [ 41,42].\nHistone ubiquitination typically occurs on lysine\nresidues such as H2AK119 and H2BK120 [ 43]. This mod-\nification influences chromatin configuration and gene ex-\n2\n\n\nFig. 1. Epigenetic mechanisms involved in reproductive physiology. Histone modifications, DNA methylation, RNA methylation,\nand non-coding RNAs (ncRNAs) represent essential epigenetic mechanisms. Four prevalent histone modifications include acetylation\n(Ac), methylation (Me), phosphorylation (P), and ubiquitination (Ub). Additionally, histone SUMOylation involves the covalent at-\ntachment of small ubiquitin-like modifier (SUMO) proteins to specific histone residues. DNA methylation primarily occurs at cytosine\nresidues within cytosine–phosphate–guanine (CpG) dinucleotide regions, commonly referred to as CpG islands. RNA methylation is a\nreversible epigenetic modification that is tightly regulated by specialized enzymes known as “writers”, “erasers”, and “readers”. Among\nvarious ncRNAs, miRNAs regulate gene expression at the post-transcriptional level by binding complementary messenger RNA (mRNA)\nsequences, resulting in mRNA degradation or translation suppression. HA Ts, histone acetyltransferases; HDACs, histone deacetylases;\nDNMT, DNA methyltransferase; METTL3, methyltransferase-like 3; METTL14, methyltransferase-like 14; WTAP , Wilms tumor 1-\nassociated protein; FTO, fat mass and obesity-associated protein; ALKBH5, AlkB homolog 5; YTHDC1, YTH domain containing 1.\npression by modulating transcriptional activation, DNA re-\npair, and histone turnover. H2B mono-ubiquitination is as-\nsociated with active transcription, whereas H2A ubiquitina-\ntion is often linked to transcriptional repression and DNA\ndamage response [30,44].\nHistone SUMOylation involves the attachment of\nsmall ubiquitin-like modifier (SUMO) proteins to histone\nresidues. This modification typically represses gene ex-\npression by altering chromatin structure, affecting tran-\nscription factor interactions, and promoting the recruitment\nof repressive protein complexes involved in transcriptional\nsilencing and DNA repair [ 45–48].\n2.2 DNA Methylation: Mechanisms and Regulatory\nFunctions\nDNA methylation is an epigenetic modification that\nprimarily occurs at cytosine residues within cytosine–\nphosphate–guanine (CpG) dinucleotides, known as CpG\nislands, which are typically located in gene promoter re-\ngions. This process involves the covalent addition of\nmethyl groups by DNMTs, primarily DNMT1, DNMT3a,\nand DNMT3b. DNMT1 is mainly responsible for maintain-\ning DNA methylation patterns during replication, thereby\nensuring that these patterns are epigenetically inherited.\nDNMT3a and DNMT3b are involved in establishing new\nmethylation patterns ( de novo methylation) during devel-\nopment and cellular differentiation [ 49,50].\nDNA methylation generally leads to transcriptional\nrepression by preventing transcription factors from bind-\ning to DNA and facilitating methyl-CpG binding domain\n(MBD) protein recruitment. These proteins in turn recruit\nhistone-modifying enzymes that further enhance gene si-\nlencing. However, in some cases, DNA methylation can\nactivate gene expression depending on the specific genomic\ncontext and the involvement of certain transcription factors\nthat are sensitive to alterations in methylation [ 51].\n2.3 RNA Methylation and Its Emerging Epigenetic Roles\nRNA methylation is an important epigenetic modifi-\ncation that primarily affects mRNA expression. The most\ncommon and widely studied form of RNA methylation is\nN6-methyladenosine (m6A), where a methyl group is added\n3\n\nto the N-6 position of adenosine. This process is care-\nfully controlled by specialized enzymes known as “writ-\ners”, “erasers”, and “readers”.\nWriters are enzymes, such as methyltransferase-like\n3 (METTL3), methyltransferase-like 14 (METTL14), and\nthe Wilms tumor 1-associated protein (WTAP), which\nadd methyl groups to RNA and play crucial roles in\nRNA modification. METTL3 acts as the main catalytic\nunit of the methyltransferase complex, transferring methyl\ngroups from S-adenosylmethionine (SAM) to adenosine\nresidues in RNA. METTL14 provides structural support\nto METTL3, stabilizing the complex and improving its\nefficiency. WTAP regulates this process by guiding the\nMETTL3–METTL14 complex to specific RNA targets and\nensuring that it is correctly positioned within the cell [ 52,\n53].\nIn contrast, erasers such as fat mass and obesity-\nassociated protein (FTO) and AlkB homolog 5 (ALKBH5)\nremove these methyl groups, effectively reversing RNA\nmethylation. FTO was originally linked to obesity but\nlater found to demethylate m6A residues in RNA, impact-\ning RNA stability, translation, and alternative splicing [54].\nALKBH5 specifically removes methyl groups from m6A\nresidues in nuclear RNA, influencing RNA export from the\nnucleus and affecting overall RNA molecule lifespan and\nfunction. This makes ALKBH5 a key player in regulating\nRNA metabolism and gene expression [ 52,55].\nReaders are specialized proteins that recognize\nand bind to methylated RNA, affecting important post-\ntranscriptional processes, such as RNA stability, splic-\ning, export from the nucleus, localization within the cell,\nand translation. The most well-known readers belong to\nthe YT521-B homology (YTH) family, which includes\nYTHDF1, YTHDF2, and YTHDF3. YTHDF1 promotes\ntranslation by interacting with translation initiation factors.\nYTHDF2 accelerates m6A-tagged RNA breakdown by di-\nrecting it to processing bodies (P-bodies) for degradation.\nYTHDF3 interacts with YTHDF1 and YTHDF2 to coor-\ndinate both methylated RNA translation and degradation.\nAdditionally, YTHDC1 is a nuclear reader that influences\nalternative splicing by helping splicing factors interact with\nmethylated pre-mRNAs, thereby fine-tuning gene expres-\nsion [52,56].\nIn addition to m6A, other RNA methylations occur at\ndifferent sites and nucleotide positions. For instance, m1A\naffects RNA structure, stability, and translation by disrupt-\ning standard base pairing [ 57]. 5-methylcytosine (m5C),\nproduced by RNA methyltransferases such as NSUN fam-\nily proteins and DNMT2, contributes to RNA stability,\nprocessing, and nuclear export [ 13]. N7-methylguanosine\n(m7G), found at the 5 ′ cap of mRNA, increases RNA sta-\nbility and translation efficiency [ 53]. Meanwhile, 2 ′-O-\nmethylation (Nm) is common in transfer RNA (tRNA), ri-\nbosomal RNA (rRNA), and small nuclear RNA (snRNA),\nsupporting RNA stability and function [ 58].\n2.4 Non-Coding RNAs as Epigenetic Regulators\nncRNAs are transcribed from DNAs that are not trans-\nlated into proteins. Instead of functioning as protein syn-\nthesis templates, they play an essential regulatory role in\ngene expression and cellular processes. Among the various\nncRNAs, miRNAs, long ncRNAs (lncRNAs), and piwi-\ninteracting RNAs (piRNAs) are particularly important ow-\ning to their broad functional impacts [ 59].\nmiRNAs are short (approximately 22 nucleotides),\nsingle-stranded ncRNAs that regulate gene expression at\nthe post-transcriptional level. They bind to complementary\nsequences in target mRNAs, leading to mRNA degradation\nor translation inhibition. miRNAs are involved in various\nbiological processes, including cell proliferation, differen-\ntiation, apoptosis, and metabolism [ 60]. lncRNAs, which\nare typically >200 nucleotides, regulate gene expression\nthrough several mechanisms, including chromatin remod-\neling, transcriptional regulation, RNA splicing, and serving\nas molecular scaffolds. They also recruit other epigenetic\nregulators, such as DNMT and histone modifiers, thereby\ninfluencing chromatin structure and transcriptional activ-\nity [ 61]. PiRNAs are small ncRNAs (26–31 nucleotides)\nprimarily expressed in germ cells [ 33]. They are involved\nin silencing transposable elements, preserving genome in-\ntegrity, and regulating germ cell development. Their in-\nteraction with Piwi proteins is essential for maintaining\ngermline genome stability [ 33,62].\nTogether, these different ncRNAs form a complex\nand highly sophisticated regulatory network that modu-\nlates gene expression at both transcriptional and post-\ntranscriptional levels, significantly influencing cellular\nfunctions and physiological processes.\n3. General Mechanisms of Reproductive\nDysfunction\nReproductive dysfunction refers to any condition that\nimpairs fertility or reproductive health. The hypothalamic–\npituitary–gonadal (HPG) axis plays a central role in reg-\nulating reproductive functions, including gonadotropin se-\ncretion, steroidogenesis, and gametogenesis. The HPG axis\nfunctions through a finely tuned balance of hormonal sig-\nnaling.\nGonadotropin-releasing hormone (GnRH), secreted\nby the hypothalamus, stimulates luteinizing hormone (LH)\nand follicle-stimulating hormone (FSH) release from the pi-\ntuitary gland. In males, LH primarily acts on Leydig cells\nto promote testosterone production, whereas in females, it\nstimulates theca cells to produce androgens. FSH acts on\nSertoli cells in males to support spermatogenesis and on\ngranulosa cells in females to promote follicular develop-\nment and estrogen production [ 63,64].\nAt the cellular level, reproductive dysfunction results\nfrom impaired gametogenesis, abnormal follicular devel-\nopment, disrupted embryo implantation, and compromised\nembryonic growth. For instance, Leydig cell dysfunction\n4\n\n\ncan reduce testosterone production, which negatively af-\nfects sperm development and libido [ 65]. In females, dis-\nrupted follicular growth can impair ovulation and reduce\nendometrial receptivity, thereby decreasing the chances of\nsuccessful implantation and pregnancy.\n3.1 Epigenetic and Molecular Pathways in Male\nReproductive Dysfunction\nMale reproductive dysfunction can result from ge-\nnetic defects, hormonal imbalances, anatomical abnormal-\nities, lifestyle factors, and environmental exposures [ 66].\nGenetic conditions such as Klinefelter syndrome disrupt\ntesticular function, whereas hormonal imbalances within\nthe HPG axis impair gonadotropin production and release.\nStructural abnormalities, including varicocele and the con-\ngenital absence of vas deferens, interfere with sperm pro-\nduction and transport. Lifestyle factors such as obesity, ex-\ncess alcohol consumption, smoking, and chronic stress sig-\nnificantly reduce fertility [ 67,68]. Furthermore, exposure\nto EDCs, such as phthalates and BPA, exacerbates repro-\nductive dysfunction by disrupting hormonal signaling and\nincreasing oxidative stress [ 69–71].\nSpermatogenesis is a complex process involving the\nmitotic proliferation, meiotic division, and post-meiotic dif-\nferentiation of germ cells [ 72]. Spermatogonial stem cells\nundergo mitosis to produce spermatocytes, which subse-\nquently undergo meiosis to generate haploid spermatids.\nThese spermatids mature into spermatozoa through a pro-\ncess called spermiogenesis, which involves chromatin con-\ndensation, acrosome and flagellum formation, and cyto-\nplasmic reduction. Oxidative stress caused by increased\nreactive oxygen species (ROS) production owing to en-\nvironmental toxins, smoking, and poor dietary habits can\nseverely impair sperm quality [ 73,74]. ROS-induced dam-\nage, such as lipid peroxidation, mitochondrial dysfunction,\nand DNA fragmentation, reduces the sperm fertilization po-\ntential and embryo viability. Elevated oxidative stress in-\ncreases sperm apoptosis and decreases sperm motility.\nEpigenetic regulation plays a key role in regulating\ngene expression during spermatogenesis. Aberrant DNA\nmethylation, such as androgen receptor ( AR) gene hyper-\nmethylation, disrupts testosterone signaling and sperm pro-\nduction [75]. Studies have demonstrated that AR promoter\nhypermethylation is linked to reduced AR expression in in-\nfertile males, which is correlated with low testosterone lev-\nels and poor sperm quality [ 76,77]. Histone modifications\nsignificantly affect chromatin structure and gene expres-\nsion. Abnormal histone methylation patterns, such as in-\ncreased H3K9 methylation and decreased H3K4 methyla-\ntion, have been associated with male infertility by silencing\ngenes critical for spermatogenesis [ 78]. Furthermore, re-\nduced histone H4 acetylation is associated with decreased\nsperm motility and poor semen quality [ 79].\nCollectively, these findings highlight that epigenetic\ndysregulation is a key mechanism underlying male repro-\nductive dysfunction and provides potential targets for diag-\nnostic biomarkers and therapeutic interventions.\n3.2 Epigenetic and Molecular Pathways in Female\nReproductive Dysfunction\nFemale reproductive dysfunction encompasses vari-\nous disorders affecting ovarian function, hormone produc-\ntion, and fertility. Clinical manifestations include infer-\ntility, ovulatory dysfunction, decreased ovarian reserve,\nmenstrual irregularities, and gynecological disorders such\nas polycystic ovary syndrome (PCOS) and endometrio-\nsis. Female reproductive dysfunction arises from various\ncauses, including genetic predisposition, hormonal imbal-\nances, structural abnormalities of the reproductive tract,\nlifestyle factors, and environmental exposures [ 80,81].\nDisruptions in the hypothalamic–pituitary–ovarian\n(HPO) axis due to genetic or hormonal factors can lead to\nirregular ovulation and impaired hormone production [ 82].\nStructural abnormalities such as uterine fibroids and fal-\nlopian tube obstructions interfere with embryo implanta-\ntion and increase miscarriage risk. Lifestyle factors, includ-\ning obesity, smoking, poor diet, and chronic stress, signif-\nicantly reduce ovarian reserve and increase infertility risk\n[68]. Furthermore, exposure to EDCs and environmen-\ntal toxins exacerbates reproductive dysfunction by inducing\noxidative stress and causing hormonal dysregulation [ 83].\nPCOS is characterized by hyperandrogenism, insulin\nresistance, and disrupted follicular development [ 84]. Ele-\nvated androgen levels suppress normal follicular develop-\nment, whereas insulin resistance promotes excess andro-\ngen production by ovarian theca cells, further exacerbating\nanovulation and infertility. Endometriosis involves ectopic\ngrowth of endometrial tissue, leading to chronic inflamma-\ntion, pelvic pain, and reduced fertility [85]. Increased estro-\ngen production and elevated inflammatory cytokine levels\nin endometriosis contribute to adhesion formation, ovarian\ndysfunction, and implantation failure [ 86].\nOxidative stress caused by elevated ROS levels in the\novarian follicles and endometrial tissue significantly im-\npairs oocyte quality, embryo viability, and endometrial re-\nceptivity [87]. Elevated ROS levels also disrupt embryonic\ndevelopment, luteal phase function, and progesterone pro-\nduction, thereby reducing implantation success rates and in-\ncreasing miscarriage risk.\nEpigenetic modifications, including DNA methyla-\ntion and histone modifications, play crucial roles in regulat-\ning ovarian function and reproductive hormone signaling.\nThe hypermethylation of specific genes, such as estrogen\nreceptor alpha ( ESR1), has been linked to reduced ovarian\nresponsiveness to gonadotropins [ 88]. Alterations in his-\ntone acetylation and methylation impair ovarian steroido-\ngenesis and folliculogenesis. Additionally, miRNA, partic-\nularly miR-200 and miR-21, expression is dysregulated in\nreproductive dysfunction, which negatively affects ovarian\nsteroidogenesis, follicular maturation, and overall fertility.\n5\n\nFig. 2. Mechanisms of reproductive dysfunction induced by endocrine-disrupting chemicals (EDCs). Gonadotropin-releasing hor-\nmone (GnRH), released by the hypothalamus, stimulates the anterior pituitary to secrete luteinizing hormone (LH) and follicle-stimulating\nhormone (FSH). In males, LH acts on Leydig cells to promote testosterone synthesis, while FSH supports spermatogenesis through Ser-\ntoli cell regulation. In females, LH and FSH coordinate androgen synthesis in theca cells, follicular maturation, and estrogen production\nin granulosa cells. Reactive oxygen species (ROS), generated in response to EDCs, contribute to oxidative stress through mechanisms\nsuch as lipid peroxidation, mitochondrial dysfunction, and DNA fragmentation, ultimately exacerbating reproductive dysfunction. The\nupper left panel depicts the steroidogenic pathway in Leydig cells, while the upper right panel illustrates steroidogenesis in theca and\ngranulosa cells. EDC exposure modulates the expression of key steroidogenic enzymes, impairing hormone biosynthesis. Blue and\nred arrows indicate upregulated and downregulated expression of enzymes involved in steroid hormone synthesis, respectively. DEHP ,\ndi(2-ethylhexyl) phthalate; MEHP , metabolite mono(2-ethylhexyl) phthalate; StAR, steroidogenic acute regulatory; CYP11A, choles-\nterol side-chain cleavage enzyme; HSD3B, hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1; DHT, dihy-\ndrotestosterone; DBP , dibutyl phthalate; BBP , Benzyl butyl phthalate.\nFor example, miR-21 overexpression impairs ovarian gran-\nulosa cell function, whereas abnormal miR-200 levels have\nbeen associated with PCOS pathogenesis [ 89,90].\nThese findings emphasize the critical role of epige-\nnetic dysregulation in female reproductive dysfunction and\nhighlight potential diagnostic biomarkers and therapeutic\ntargets for improving reproductive health.\n4. Endocrine Disruptors and Reproductive\nDisorders\nEndocrine disruptors interfere with normal hormonal\nfunctions by mimicking, blocking, or altering hormone sig-\nnaling pathways (Fig. 2) [ 91]. Both human epidemiolog-\nical studies and animal research have consistently linked\nexposure to EDCs with impaired sperm production, com-\npromised ovarian function, abnormal gonadal develop-\nment, and reproductive disorders such as endometriosis and\nPCOS [92–96]. Among the EDCs, BPA and phthalates have\nbeen extensively studied because of their widespread pres-\nence and established reproductive toxicity.\n4.1 Epigenetic Effects of Bisphenol A (BP A) on\nReproductive Function\nPrevious studies have examined the effects of en-\ndocrine disruptors on reproductive health, with BPA be-\ning one of the most extensively studied compounds. BPA\nsignificantly affects reproductive function through epige-\nnetic mechanisms, as demonstrated by the consistent find-\nings of numerous animal and human studies [14]. Exposure\nto BPA during the prenatal and neonatal periods markedly\nchanges DNA methylation patterns, histone modifications,\nand miRNA expression, which play crucial roles in regulat-\ning ovarian follicle development, steroidogenesis, and the\nreproductive cycle [11].\nAmong these epigenetic mechanisms, DNA methyla-\ntion is strongly associated with the effects of BPA on ovar-\nian gene expression. Animal studies have revealed that\nBPA exposure hypermethylates the genes essential for ovar-\nian steroidogenesis, such as ESR1, aromatase ( CYP19A1),\nand luteinizing hormone receptor ( LHR), thereby down-\nregulating their expression, which impairs ovarian func-\ntion and reduces reproductive capacity [ 15,16]. In addi-\ntion, BPA alters histone acetylation and methylation pat-\n6\n\n\nterns at the promoters of critical reproductive genes. For\ninstance, in mouse models, BPA exposure decreased H3K9\nacetylation and increased H3K27 trimethylation, modifica-\ntions that typically repress transcription and significantly\ndisrupt the expression of genes necessary for normal ovar-\nian development and function [ 17,18]. These histone al-\nterations are mediated by the BPA-induced dysregulation\nof chromatin-modifying enzymes. BPA reduces HA T ac-\ntivity and increases HDAC expression, leading to global\nhistone hypoacetylation and the transcriptional repression\nof reproduction-related genes. Moreover, females with\nendometriosis exhibit distinct epigenetic profiles, includ-\ning altered miRNA expression patterns linked to elevated\nserum and urinary BPA levels [ 97]. Epigenetic reprogram-\nming is associated with increased disease severity and a\nhigh risk of recurrence.\nBPA disrupts reproductive health by altering miRNA\nexpression. In animal models, exposure to BPA during crit-\nical developmental periods has been associated with the\naltered expression of key miRNAs, including miR-146a,\nmiR-21, and miR-200 family members, as well as ovar-\nian cell proliferation, apoptosis, steroidogenesis, and in-\nflammatory signaling regulators [ 98–101]. For instance,\nmiR-21 upregulation suppresses phosphatase and tensin\nhomolog (PTEN), a negative regulator of the PI3K/AKT\npathway, thereby promoting granulosa cell survival and\npotentially contributing to abnormal follicular persistence\n[102]. Likewise, miR-146a targets interleukin-1 receptor-\nassociated kinase 1 (IRAK1) and TNF receptor-associated\nfactor 6 (TRAF6), which are key components of the NF-\nκB signaling pathway, and modifies the ovarian inflamma-\ntory environment [ 103]. The miR-200 family is involved\nin epithelial-to-mesenchymal transition (EMT) via zinc fin-\nger E-box binding homeobox 1 (ZEB1) and ZEB2 regula-\ntion, and its dysregulation may impair follicular remodeling\nand oocyte maturation. These molecular changes directly\ncontribute to impaired follicular development, accelerated\novarian aging, and diminished reproductive potential.\nEpidemiological studies in humans have corroborated\nmolecular findings observed in animal models. Clinical\nstudies have identified significant changes in DNA methy-\nlation patterns of genes related to steroidogenesis and hor-\nmone signaling in women with higher urinary BPA concen-\ntrations, which correlate with reproductive disorders such\nas PCOS, endometriosis, and infertility [ 104]. For exam-\nple, elevated BPA levels in females with PCOS have been\nassociated with CYP19A1 and ESR1 hypermethylation, cor-\nrelating with elevated androgen levels and insulin resis-\ntance [105]. Additionally, females with endometriosis dis-\nplay distinct epigenetic profiles, including altered miRNA\nexpression patterns linked to elevated serum and urinary\nBPA levels, which influence disease severity and recur-\nrence [106]. Beyond BPA, growing attention has been paid\nto its structural analogs and derivatives such as bisphe-\nnol S (BPS) and bisphenol F (BPF), which are commonly\nused as BPA substitutes in plastics and consumer products.\nEmerging evidence suggests that BPS and BPF may ex-\nert endocrine-disrupting and epigenetic effects similar to or\neven more potent than those of BPA [ 107]. Studies have\nshown that BPS exposure alters the methylation of genes\ninvolved in steroidogenesis and increases oxidative stress\nin ovarian tissues [ 108,109]. BPF is associated with dis-\nrupted histone acetylation patterns and altered reproductive\nmiRNA expression [110]. Although marketed as safe alter-\nnatives, these compounds appear to share similar epigenetic\ninterferences, raising concerns about their reproductive tox-\nicity and necessitating further investigation.\nThese findings clearly indicate that the reproductive\ntoxicity of BPA is driven primarily by its impact on the\nepigenetic landscape of reproductive tissues. BPA disrupts\nhormonal signaling and regulates genes critical for repro-\nductive function by inducing changes in DNA methyla-\ntion, histone modifications, and non-coding RNA expres-\nsion. Taken together, these epigenetic alterations provide\nstrong mechanistic evidence linking EDC exposure to re-\nproductive dysfunction.\n4.2 Phthalate-Induced Epigenetic Modifications in\nReproductive Tissues\nPhthalates, commonly used as plasticizers in daily\nproducts, are increasingly linked to reproductive health\nthrough epigenetic mechanisms. Among the most common\nphthalates, diethylhexyl phthalate (DEHP) induces signifi-\ncant changes in DNA methylation and histone modification,\nthereby disrupting the transcriptional regulation of genes in-\nvolved in steroidogenesis and spermatogenesis [ 4].\nDEHP exposure leads to the epigenetic dysregula-\ntion of reproductive tissues. Animal studies have demon-\nstrated that exposure to DEHP increases H3 acetylation\nat the promoters of reproductive genes, leading to abnor-\nmal activation [ 19]. Simultaneously, DEHP reduces DNA\nmethylation at key steroidogenic genes, such as steroido-\ngenic factor-1 ( SF-1) and CYP17A1, which are essential\nfor testosterone biosynthesis [ 20,21]. Hypomethylation\ndisrupts the hormonal balance required for proper testicu-\nlar function. Simultaneously, DEHP increases H3 acety-\nlation (H3K9ac) and H3K4 trimethylation (H3K4me3) at\nthese gene loci, while decreasing repressive markers such\nas H3K9me2 and H3K27me3 [ 111–114]. These chro-\nmatin changes are mediated by altered expression of epige-\nnetic enzymes, including downregulation of DNMT3a and\nHDACs and upregulation of HA Ts and histone methyltrans-\nferases (HMTs), such as mixed-lineage leukemia protein\n1 (MLL1). This imbalance creates a transcriptionally ac-\ntive chromatin state, leading to aberrant expression of re-\nproductive genes. This impairs hormone synthesis and re-\nduces testosterone production and sperm quality, which has\nbeen consistently observed in animal models [ 113]. Fur-\nthermore, these chromatin alterations appear to be long last-\ning and may have transgenerational consequences [ 115].\n7\n\nMEHP , a biologically active DEHP metabolite, ex-\nerts strong epigenetic effects. Studies using MA-10 mouse\nLeydig cells have shown that MEHP significantly disrupts\nthe expression of key steroidogenic proteins, particularly\nSTAR protein [ 22]. This effect is driven by both histone\nand DNA modifications in the star gene promoter, result-\ning in transcriptional repression and impaired Leydig cell\nfunction. Furthermore, MEHP increases repressive his-\ntone markers such as H3K27 trimethylation (H3K27me3)\nand decreases activating markers such as H3K9 acetyla-\ntion (H3K9ac), thereby promoting a condensed chromatin\nstructure [114,116]. It also downregulates coactivator pro-\nteins, such as CBP/p300, and reduces the activity of ten-\neleven translocation methylcytosine dioxygenase (TET) en-\nzymes, contributing to stable gene silencing. These epige-\nnetic changes are not limited to star and other steroidogenic\ngenes, including Cyp11a1 and Hsd3b1, indicating broad\nsuppression of the steroid biosynthesis cascade. Impor-\ntantly, the epigenetic effects of MEHP persist even after\nexposure ends, raising concerns about long-term and po-\ntentially heritable reproductive dysfunction [ 117].\nPhthalate-induced epigenetic disruption has been\nshown to negatively affect female reproductive health. An-\nimal studies have shown that exposure to DEHP and MEHP\nresults in marked alterations in histone acetylation and\nmethylation in the promoters of key ovarian steroidogenic\ngenes, such as CYP19A1 and ESR1. These changes im-\npair follicular development and disrupt the ovulatory cycle\n[118,119]. Moreover, MEHP exposure in endometrial cell\ncultures increases the secretion of inflammatory cytokines,\nparticularly tumor necrosis factor-alpha (TNF- α), suggest-\ning that epigenetic regulation contributes to inflammatory\nreproductive conditions such as endometriosis [ 120].\nHuman clinical studies have supported these findings\nin animal models. Research has consistently linked ele-\nvated urinary levels of phthalate metabolites to menstrual ir-\nregularities, reduced ovarian reserve, premature ovarian ag-\ning, a high risk of preterm birth, and other adverse reproduc-\ntive outcomes [ 121,122]. These clinical findings provide\nmolecular evidence that phthalates interfere with reproduc-\ntive function through epigenetic dysregulation, underscor-\ning their relevance as a public health concern. Taken to-\ngether, phthalate-induced epigenetic modifications disrupt\nthe hormonal balance and transcriptional regulation in re-\nproductive tissues, providing a mechanistic explanation for\ntheir roles in both male and female reproductive dysfunc-\ntions.\n4.3 Epigenetic Mechanisms of Pesticide-Associated\nReproductive Disfunction\nPesticides, including DDT and chlorpyrifos, are po-\ntent endocrine disruptors, with growing evidence that their\nreproductive toxicity is largely mediated through epige-\nnetic mechanisms [ 123]. Epidemiological and experimen-\ntal studies have consistently shown that pesticide exposure\nnegatively affects reproductive health in both males and\nfemales by altering DNA methylation, modifying histone\nstructure, and disrupting ncRNA expression [ 23,124,125].\nThe epigenetic effects of prenatal and develop-\nmental exposure to DDT and its persistent metabolite\ndichlorodiphenyldichloroethylene (DDE) have been exten-\nsively studied. Research shows that DDT exposure can\nlead to abnormal DNA methylation of genes critical for re-\nproductive development and hormone regulation [ 23–25].\nFor example, both DDT and DDE have been associated\nwith hypomethylation at the promoter regions of estrogen-\nresponsive genes such as ESR1, which disrupts estrogen\nsignaling pathways essential for reproductive organ forma-\ntion and fertility. Furthermore, transgenerational studies\nhave found that maternal exposure to DDT alters the methy-\nlation patterns of key reproductive genes, including insulin-\nlike growth factor 2 ( IGF2), which persists across multiple\ngenerations [24,26]. These epigenetic changes reduce fer-\ntility, delay sexual maturation, and increase the incidence\nof undescended testes in male offspring.\nSimilarly, chlorpyrifos, a widely used organophos-\nphate pesticide, exerts reproductive toxicity through com-\nprehensive epigenetic modifications. Exposure to chlor-\npyrifos alter miRNA expression profiles, which may dis-\nrupt critical reproductive signaling pathways. For example,\nstudies on zebrafish embryos have shown that organophos-\nphate compounds can upregulate the expression of miR-\n137 and miR-141, resulting in developmental abnormalities\n[126]. Although direct evidence of chlorpyrifos-induced\nmiRNA alterations in mammalian reproductive tissues re-\nmains limited, the neurotoxic and reproductive effects con-\nsistently observed in animal models suggest that miRNA\ndysregulation may play a central role in chlorpyrifos toxi-\ncity. Recent animal studies have demonstrated that chlor-\npyrifos exposure leads to abnormal DNA methylation pat-\nterns in genes regulating the HPG axis, such as GnRH1,\nESR1, and AR [127]. In particular, GnRH1 promoter hy-\npomethylation is associated with early onset of puberty and\ndisrupted reproductive hormone signaling [ 128]. In addi-\ntion, chlorpyrifos alters histone modification states in re-\nproductive tissues. In animal models, decreased histone\nH3K9 acetylation (H3K9ac) and H4 acetylation (H4ac)\nhave been observed, leading to the transcriptional repres-\nsion of genes involved in steroidogenesis and gametogen-\nesis [ 129]. These chromatin changes appear to be medi-\nated by the dysregulation of epigenetic enzymes such as\nDNMT1 and HDAC1, which are downregulated following\nchlorpyrifos exposure. The resulting imbalance in the chro-\nmatin remodeling machinery may contribute to the long-\nterm suppression of reproductive gene expression, with po-\ntential long-term consequences for fertility.\nThe findings of clinical studies align closely with an-\nimal study findings, further strengthening the link between\npesticide exposure and epigenetic changes in reproductive\ntissues [16]. Epidemiological studies have reported abnor-\n8\n\n\nmal DNA methylation patterns at key loci, such as ESR1\nand AR genes, in individuals with past pesticide exposure\n[130]. For instance, ESR1 promoter hypomethylation dys-\nregulates estrogen signaling, which may impair endome-\ntrial receptivity and ovulation. Likewise, AR hypermethy-\nlation can weaken androgen signaling, contributing to re-\nduced spermatogenesis and impaired Leydig cell function\nin males [ 131,132]. These epigenetic modifications corre-\nlate with a range of reproductive issues, including reduced\nsperm concentration and motility, disrupted menstrual cy-\ncles, anovulation, and increased incidence of infertility and\nmiscarriage. Moreover, these methylation changes may\npersist even after the end of exposure, indicating potential\nlong-term or transgenerational effects. In occupational co-\nhorts, a high pesticide burden has also been linked to altered\nmethylation of imprinted genes such as IGF2 and H19,\nwhich play critical roles in embryonic growth and placen-\ntal development, suggesting possible implications on preg-\nnancy outcomes and offspring health [ 133,134]. Taken to-\ngether, these findings support a mechanistic model in which\npesticide-induced epigenetic modifications, such as DNA\nhypomethylation, histone alterations, and miRNA dysreg-\nulation, directly contribute to endocrine disruption and im-\npaired reproductive capacity.\n4.4 Heavy Metal Ions as Epigenetic Modifiers of Fertility\nDivalent heavy metal ions such as Pb 2+ and Cd 2+\nare widely recognized as potent endocrine disruptors due\nto their environmental persistence and strong reproductive\ntoxicity [5–7]. It is the ionic forms, rather than the elemen-\ntal metals or their poorly soluble salts, that are primarily\nresponsible for these toxic effects. Although they are not\nclassified as toxins in the classical toxicological sense, these\nheavy metal ions function as environmental contaminants\nthat exert harmful biological effects through multiple path-\nways, including oxidative stress, hormonal disruption, and\nepigenetic alterations. Extensive research has consistently\ndemonstrated the harmful effects of heavy metal exposure\non male and female reproductive health [ 135].\nIn males, exposure to Pb 2+ and Cd 2+ has been\nstrongly associated with impaired spermatogenesis, char-\nacterized by reduced sperm count, poor sperm motility, and\nabnormal sperm morphology [ 136,137]. These disruptions\nare primarily attributed to damage to the seminiferous ep-\nithelium and dysfunction of the blood–testis barrier, as ob-\nserved in rodent models. In particular, Cd 2+ induces necro-\nsis of Sertoli and germ cells, whereas Pb 2+ tends to affect\nLeydig cells and the HPG axis. Animal studies have shown\nthat exposure to these heavy metal ions impairs testicular\nfunction by downregulating the expression of key enzymes\nsuch as STAR, CYP11A1, and 17β-hydroxysteroid dehydro-\ngenase (HSD17B3) [7,138,139]. It is also important to note\nthat lead can exist in multiple oxidation states. Although\nPb2+ is the biologically active and more stable form, lead\ncan also form compounds in the +4 oxidation state. These\nPb(IV) species are strong oxidants and are typically reduced\nto Pb 2+ in biological systems [ 140]. This chemical com-\nplexity demonstrates the importance of clearly identifying\nthe ionic species when evaluating the toxicity of lead com-\npounds.\nClinical studies support these findings, showing that\nelevated blood levels of Pb2+ and Cd2+ are associated with\nreduced testosterone production, increased oxidative stress,\nand compromised sperm DNA integrity in exposed indi-\nviduals [ 141]. Additionally, these metals increase testicu-\nlar oxidative stress by elevating ROS and depleting antiox-\nidant enzymes, such as superoxide dismutase (SOD) and\nglutathione peroxidase (GPx), resulting in lipid peroxida-\ntion and mitochondrial dysfunction in germ cells. Such ox-\nidative damage contributes to DNA fragmentation in sperm,\nchromatin condensation defects, and reduced fertilization\npotential.\nIn females, heavy metal ions exposure is strongly\nassociated with ovarian dysfunction, disrupted follicular\ndevelopment, and diminished reproductive capacity [ 142,\n143]. Cd 2+ accumulates in ovarian tissue owing to its long\nbiological half-life and ability to mimic essential divalent\ncations, such as Ca and Zn, thereby interfering with cel-\nlular signaling and enzyme activity. Experimental studies\nhave shown that Cd 2+ disrupts ovarian steroidogenesis by\ndownregulating the expression and activity of key enzymes\ninvolved in estrogen and progesterone synthesis, including\ncytochrome P450 side-chain cleavage enzyme ( CYP11A1),\naromatase (CYP19A1), and 3 β-hydroxysteroid dehydroge-\nnase ( HSD3B1). These molecular changes decrease the\nlevels of circulating estradiol and progesterone, disrupt-\ning the HPO axis and impairing ovulation. Cd 2+ also in-\nduces oxidative stress within ovarian follicles by increas-\ning ROS, which damages granulosa cells and oocytes and\npromotes apoptosis and atresia. Epidemiological studies\nhave demonstrated that elevated Cd2+ levels are associated\nwith menstrual irregularities, reduced ovarian reserve, in-\ncreased infertility rates, and poor pregnancy outcomes such\nas preterm birth and reduced fetal growth [ 144]. Further-\nmore, a high Cd 2+ burden reduces fertility outcomes, par-\nticularly in women undergoing assisted reproductive tech-\nnology (ART), in whom lower oocyte quality and fertiliza-\ntion rates have been observed. During pregnancy, Cd 2+\ncan cross the placental barrier, contributing to impaired pla-\ncental development and adverse outcomes, such as preterm\nbirth, low birth weight, and intrauterine growth restriction.\nAt the molecular level, heavy metals contribute to re-\nproductive toxicity, primarily through epigenetic dysregu-\nlation. Pb 2+, Cd 2+, and soluble ionic forms of mercury\n(such as HgCl 2) and nickel (such as NiSO 4 or NiCl2) alter\nDNA methylation and histone modification profiles, par-\nticularly at promoters of genes essential for hormonal sig-\nnaling, gametogenesis, and oxidative defense. In contrast,\narsenic trioxide (As2O3) does not dissociate in solution but\nacts as a precursor to toxic trivalent arsenic compounds and\n9\n\norganoarsenicals, and should be evaluated separately in tox-\nicological contexts. DNA methylation changes are among\nthe most widely documented epigenetic effects of heavy\nmetal exposure. Pb 2+ and Cd2+ induce global hypomethy-\nlation, compromising genomic stability, while simultane-\nously promoting hypermethylation at specific CpG-rich\npromoters. For example, aberrant methylation of follicle-\nstimulating hormone receptor (FSHR), LHR, ESR1, and AR\nhas been reported in animal models and human tissues,\nleading to decreased hormonal sensitivity and disrupted re-\nproductive function [27,28].\nSimultaneously, heavy metal exposure disrupts his-\ntone modifications, further contributing to epigenetic dys-\nregulation. Cd 2+, for example, has been associated with\nreduced H3K9 acetylation and increased H3K27 trimethy-\nlation at the promoter regions of steroidogenic genes such\nas CYP11A1, STAR, and HSD17B3, as well as antioxidant\ngenes such as GPX4 and SOD2 [29]. These changes pro-\nmote chromatin condensation and transcriptional repres-\nsion, ultimately impairing the expression of genes criti-\ncal for reproductive functions. Beyond Cd 2+ and Pb 2+,\nother heavy metals also exhibit distinct epigenetic signa-\ntures in reproductive tissues. For instance, As causes global\nhypomethylation and gene-specific hypermethylation (e.g.,\np16, p53), along with inhibition of HA T activity, disrupt-\ning oocyte maturation and endometrial receptivity [ 145].\nHg, particularly methylmercury (MeHg), decreases DNMT\nexpression and alters histone marks (such as H3K9me2\nand H4K20me3), impairing spermatogenesis and inducing\ngerm cell apoptosis [ 146]. Ni 2+, typically as NiSO or\nNiCl2, also exerts notable epigenetic effects. Ni exposure\ninduces global DNA hypomethylation and gene-specific\nhypermethylation at loci involved in gonadal development\nand hormone synthesis [ 147]. It enhances repressive his-\ntone marks such as H3K9me2 and H3K27me3 via the up-\nregulation of methyltransferases such as G9a and EZH2,\nleading to chromatin condensation and transcriptional si-\nlencing. These effects are associated with disrupted sper-\nmatogenesis and follicular viability in experimental models\n[148,149].\nThese findings suggest that heavy metal ion-induced\nreproductive toxicity is driven by epigenetic dysregulation.\nA deep understanding of these molecular alterations could\nprovide essential insights into the mechanisms of heavy-\nmetal-induced reproductive dysfunction and guide the de-\nvelopment of targeted prevention and treatment strategies.\nCollectively, these epigenetic alterations illustrate\nhow heavy metals act as endocrine disruptors by reprogram-\nming the epigenome of the reproductive tissues. Heavy\nmetal ions contribute to long-term reproductive dysfunction\nand transgenerational health effects through mechanisms\ninvolving aberrant DNA methylation, histone modification,\nand oxidative stress-linked epigenetic remodeling.\n5. Conclusion\nEDCs pose a significant threat to reproductive health\nby interfering with hormonal regulation and inducing sta-\nble epigenetic changes that alter gene expression profiles\ncritical for gametogenesis, steroidogenesis, and follicular\ndevelopment. This review highlights the multifaceted epi-\ngenetic mechanisms, including DNA methylation, histone\nmodifications, and ncRNA regulation, through which var-\nious EDCs such as BPA, phthalates, pesticides, and heavy\nmetal ions impair reproductive functions in both sexes.\nAccumulating evidence indicates that these epigenetic\nalterations are not only persistent but may also exert trans-\ngenerational effects, raising public health concerns regard-\ning long-term reproductive consequences. However, gaps\nremain in our understanding of compound-specific epige-\nnetic signatures, dose–response relationships, sex-specific\neffects, and reversibility of these modifications.\nFuture studies should prioritize the identification of\nepigenetic biomarkers for the early detection of EDC expo-\nsure and susceptibility as well as development of targeted\nepigenetic therapies. Additionally, integrative approaches\ncombining epigenomics, transcriptomics, and single-cell\nanalysis are essential for elucidating the tissue- and cell-\ntype-specific effects of EDCs. A deep understanding of\nthese mechanisms will guide risk assessment, public poli-\ncies, and therapeutic intervention strategies for mitigating\nEDC-induced reproductive dysfunction.\nAuthor Contributions\nDHK and MHP conceived and designed the study. SH\nand HBK conducted the literature search, analyzed the data,\nand prepared the figure visualizations. SH, HBK, and MHP\nwrote the manuscript. DHK and MHP reviewed and edited\nthe manuscript. All authors contributed to editorial changes\nin the manuscript. All authors read and approved the final\nmanuscript. All authors have participated sufficiently in the\nwork and agreed to be accountable for all aspects of the\nwork.\nEthics Approval and Consent to Participate\nNot applicable.\nAcknowledgment\nNot applicable.\nFunding\nThis research was supported by the Regional Innova-\ntion System & Education (RISE) program through the In-\nstitute for Regional Innovation System & Education in Bu-\nsan Metropolitan City, funded by the Ministry of Education\n(MOE) and the Busan Metropolitan City, Republic of Ko-\nrea (2025-RISE-02-005-000).\n10\n\n\nConflict of Interest\nThe authors declare no conflict of interest.\nDeclaration of AI and AI-Assisted\nTechnologies in the Writing Process\nDuring the preparation of this work, the authors used\nChatGPT to check spell and grammar. After using this tool,\nthe authors reviewed and edited the content as needed and\ntakes full responsibility for the content of the publication.\nReferences\n[1] Schug TT, Janesick A, Blumberg B, Heindel JJ. Endocrine dis-\nrupting chemicals and disease susceptibility. The Journal of\nSteroid Biochemistry and Molecular Biology. 2011; 127: 204–\n215. https://doi.org/10.1016/j.jsbmb.2011.08.007.\n[2] Gore AC. Introduction to endocrine-disrupting chemicals.\nEndocrine-disrupting chemicals: from basic research to clini-\ncal practice (pp. 3–8). Humana Press: Totowa, NJ. 2007. https:\n//doi.org/10.1007/1-59745-107-X_1 .\n[3] Bertram MG, Gore AC, Tyler CR, Brodin T. Endocrine-\ndisrupting chemicals. Current Biology: CB. 2022; 32: R727–\nR730. https://doi.org/10.1016/j.cub.2022.05.063.\n[4] Chen J, Wu S, Wen S, Shen L, Peng J, Y an C, et al. The Mecha-\nnism of Environmental Endocrine Disruptors (DEHP) Induces\nEpigenetic Transgenerational Inheritance of Cryptorchidism.\nPLoS ONE. 2015; 10: e0126403. https://doi.org/10.1371/jour\nnal.pone.0126403.\n[5] Thompson J, Bannigan J. Cadmium: toxic effects on the repro-\nductive system and the embryo. Reproductive Toxicology. 2008;\n25: 304–315. https://doi.org/10.1016/j.reprotox.2008.02.001.\n[6] Zhang Z, Wang Q, Gao X, Tang X, Xu H, Wang W,et al. Repro-\nductive toxicity of cadmium stress in male animals. Toxicology.\n2024; 504: 153787. https://doi.org/10.1016/j.tox.2024.153787.\n[7] Pinon-Lataillade G, Thoreux-Manlay A, Coffigny H, Masse\nR, Soufir JC. Reproductive toxicity of chronic lead ex-\nposure in male and female mice. Human & Experimen-\ntal Toxicology. 1995; 14: 872–878. https://doi.org/10.1177/\n096032719501401103.\n[8] Kahn LG, Philippat C, Nakayama SF, Slama R, Trasande L.\nEndocrine-disrupting chemicals: implications for human health.\nThe Lancet. Diabetes & Endocrinology. 2020; 8: 703–718.\nhttps://doi.org/10.1016/S2213-8587(20)30129-7 .\n[9] Fromme H, Küchler T, Otto T, Pilz K, Müller J, Wenzel A. Oc-\ncurrence of phthalates and bisphenol A and F in the environment.\nWater Research. 2002; 36: 1429–1438. https://doi.org/10.1016/\ns0043-1354(01)00367-0 .\n[10] Tapia-Orozco N, Santiago-Toledo G, Barrón V , Espinosa-\nGarcía AM, García-García JA, García-Arrazola R. Environmen-\ntal epigenomics: Current approaches to assess epigenetic effects\nof endocrine disrupting compounds (EDC’s) on human health.\nEnvironmental Toxicology and Pharmacology. 2017; 51: 94–\n99. https://doi.org/10.1016/j.etap.2017.02.004.\n[11] Santangeli S, Maradonna F, Olivotto I, Piccinetti CC, Gioac-\nchini G, Carnevali O. Effects of BPA on female reproductive\nfunction: The involvement of epigenetic mechanism. General\nand Comparative Endocrinology. 2017; 245: 122–126. https:\n//doi.org/10.1016/j.ygcen.2016.08.010.\n[12] Hiam D, Simar D, Laker R, Altıntaş A, Gibson-Helm M,\nFletcher E, et al . Epigenetic reprogramming of immune cells\nin women with PCOS impact genes controlling reproductive\nfunction. The Journal of Clinical Endocrinology & Metabolism.\n2019; 104: 6155–6170. https://doi.org/10.1210/jc.2019-01015.\n[13] Bohnsack KE, Höbartner C, Bohnsack MT. Eukaryotic 5-\nmethylcytosine (m 5C) RNA Methyltransferases: Mechanisms,\nCellular Functions, and Links to Disease. Genes. 2019; 10: 102.\nhttps://doi.org/10.3390/genes10020102.\n[14] Doherty LF, Bromer JG, Zhou Y , Aldad TS, Taylor HS. In utero\nexposure to diethylstilbestrol (DES) or bisphenol-A (BPA) in-\ncreases EZH2 expression in the mammary gland: an epigenetic\nmechanism linking endocrine disruptors to breast cancer. Hor-\nmones & Cancer. 2010; 1: 146–155. https://doi.org/10.1007/\ns12672-010-0015-9 .\n[15] Palak E, Lebiedzinska W, Lupu O, Pulawska K, Anisimowicz S,\nMieczkowska AN, et al. Molecular insights underlying the ad-\nverse effects of bisphenol A on gonadal somatic cells’ steroido-\ngenic activity. Reproductive Biology. 2023; 23: 100766. https:\n//doi.org/10.1016/j.repbio.2023.100766.\n[16] Bhandari RK, Taylor JA, Sommerfeld-Sager J, Tillitt DE, Ricke\nW A, V om Saal FS. Estrogen receptor 1 expression and methyla-\ntion of Esr1 promoter in mouse fetal prostate mesenchymal cells\ninduced by gestational exposure to bisphenol A or ethinylestra-\ndiol. Environmental Epigenetics. 2019; 5: dvz012. https://doi.or\ng/10.1093/eep/dvz012.\n[17] Liu B, Zhou S, Y ang C, Chen P , Chen P , Xi D, et al. Bisphenol\nA deteriorates egg quality through HDAC7 suppression. Onco-\ntarget. 2017; 8: 92359–92365. https://doi.org/10.18632/oncota\nrget.21308.\n[18] D’Cruz SC, Hao C, Labussiere M, Mustieles V , Freire C, Legoff\nL, et al. Genome-wide distribution of histone trimethylation re-\nveals a global impact of bisphenol A on telomeric binding pro-\nteins and histone acetyltransferase factors: a pilot study with\nhuman and in vitro data. Clinical Epigenetics. 2022; 14: 186.\nhttps://doi.org/10.1186/s13148-022-01408-2 .\n[19] Tian Y , Guo J, Hua L, Jiang Y , Ge W, Zhang X, et al . Mech-\nanisms of imbalanced testicular homeostasis in infancy due\nto aberrant histone acetylation in undifferentiated spermatogo-\nnia under different concentrations of Di(2-ethylhexyl) phtha-\nlate (DEHP) exposure. Environmental Pollution. 2024; 347:\n123742. https://doi.org/10.1016/j.envpol.2024.123742.\n[20] Y ang L, Liu S, Song P , Liu Z, Peng Z, Kong D, et al . DEHP-\nmediated oxidative stress leads to impaired testosterone synthe-\nsis in Leydig cells through the cAMP/PKA/SF-1/StAR pathway.\nEnvironmental Pollution. 2025; 366: 125503. https://doi.org/10.\n1016/j.envpol.2024.125503.\n[21] Sekaran S, Jagadeesan A. In utero exposure to phthalate down-\nregulates critical genes in Leydig cells of F1 male progeny.\nJournal of Cellular Biochemistry. 2015; 116: 1466–1477. https:\n//doi.org/10.1002/jcb.25108.\n[22] Traore K, More P , Adla A, Dogbey G, Papadopoulos V , Zirkin\nB. MEHP induces alteration of mitochondrial function and in-\nhibition of steroid biosynthesis in MA-10 mouse tumor Leydig\ncells. Toxicology. 2021; 463: 152985. https://doi.org/10.1016/j.\ntox.2021.152985.\n[23] Ben Maamar M, Nilsson E, Sadler-Riggleman I, Beck D, Mc-\nCarrey JR, Skinner MK. Developmental origins of transgenera-\ntional sperm DNA methylation epimutations following ancestral\nDDT exposure. Developmental Biology. 2019; 445: 280–293.\nhttps://doi.org/10.1016/j.ydbio.2018.11.016.\n[24] Wu HC, Cohn BA, Cirillo PM, Santella RM, Terry MB. DDT\nexposure during pregnancy and DNA methylation alterations in\nfemale offspring in the Child Health and Development Study.\nReproductive Toxicology. 2020; 92: 138–147. https://doi.org/\n10.1016/j.reprotox.2019.02.010.\n[25] Tran CM, Lee H, Lee B, Ra JS, Kim KT. Effects of the chorion\non the developmental toxicity of organophosphate esters in ze-\nbrafish embryos. Journal of Hazardous Materials. 2021; 401:\n123389. https://doi.org/10.1016/j.jhazmat.2020.123389.\n[26] Song Y , Wu N, Wang S, Gao M, Song P , Lou J,et al. Transgen-\nerational impaired male fertility with an Igf2 epigenetic defect in\nthe rat are induced by the endocrine disruptor p,p’-DDE. Human\n11\n\nReproduction. 2014; 29: 2512–2521. https://doi.org/10.1093/hu\nmrep/deu208.\n[27] Li X, Lu Z, Du X, Y e Y , Zhu J, Li Y , et al . Prenatal cad-\nmium exposure has inter-generational adverse effects on Sertoli\ncells through the follicle-stimulating hormone receptor pathway.\nReproduction. 2023; 166: 271–284. https://doi.org/10.1530/RE\nP-23-0070 .\n[28] Nuli M, Kumar JP , Korni R, Putta S. Cadmium Toxicity: Un-\nveiling the Threat to Human Health. Indian Journal of Pharma-\nceutical Sciences. 2024; 86.\n[29] Rzymski P , Tomczyk K, Rzymski P , Poniedziałek B, Opala T,\nWilczak M. Impact of heavy metals on the female reproductive\nsystem. Annals of Agricultural and Environmental Medicine.\n2015; 22: 259–264. https://doi.org/10.5604/12321966.1152077.\n[30] Al Aboud NM, Tupper C, Jialal I. Genetics, Epigenetic Mecha-\nnism. StatPearls: Treasure Island (FL). 2018.\n[31] Acharjee S, Chauhan S, Pal R, Tomar RS. Mechanisms of DNA\nmethylation and histone modifications. Progress in Molecular\nBiology and Translational Science. 2023; 197: 51–92. https://\ndoi.org/10.1016/bs.pmbts.2023.01.001.\n[32] Bure IV , Nemtsova MV , Kuznetsova EB. Histone Modifications\nand Non-Coding RNAs: Mutual Epigenetic Regulation and Role\nin Pathogenesis. International Journal of Molecular Sciences.\n2022; 23: 5801. https://doi.org/10.3390/ijms23105801.\n[33] Wei JW, Huang K, Y ang C, Kang CS. Non-coding RNAs as reg-\nulators in epigenetics (Review). Oncology Reports. 2017; 37:\n3–9. https://doi.org/10.3892/or.2016.5236.\n[34] Turner BM. Histone acetylation and an epigenetic code. BioEs-\nsays: News and Reviews in Molecular, Cellular and Develop-\nmental Biology. 2000; 22: 836–845. https://doi.org/10.1002/\n1521-1878(200009)22:9<836::AID-BIES9>3.0.CO;2-X .\n[35] Sterner DE, Berger SL. Acetylation of histones\nand transcription-related factors. Microbiology and\nMolecular Biology Reviews. 2000; 64: 435–459.\nhttps://doi.org/10.1128/MMBR.64.2.435-459.2000.\n[36] Adcock IM, Ito K, Barnes PJ. Histone deacetylation: an impor-\ntant mechanism in inflammatory lung diseases. COPD. 2005; 2:\n445–455. https://doi.org/10.1080/15412550500346683.\n[37] Zhang G, Pradhan S. Mammalian epigenetic mechanisms.\nIUBMB Life. 2014; 66: 240–256. https://doi.org/10.1002/iub.\n1264.\n[38] Villeneuve LM, Natarajan R. Epigenetic mechanisms. Contribu-\ntions to Nephrology. 2011; 170: 57–65. https://doi.org/10.1159/\n000324944.\n[39] Lennartsson A, Ekwall K. Histone modification patterns and\nepigenetic codes. Biochimica et Biophysica Acta. 2009; 1790:\n863–868. https://doi.org/10.1016/j.bbagen.2008.12.006.\n[40] Dean W. DNA methylation and demethylation: a pathway to\ngametogenesis and development. Molecular Reproduction and\nDevelopment. 2014; 81: 113–125. https://doi.org/10.1002/mrd.\n22280.\n[41] Loury R, Sassone-Corsi P . Histone phosphorylation: how to\nproceed. Methods. 2003; 31: 40–48. https://doi.org/10.1016/\ns1046-2023(03)00086-0 .\n[42] Rossetto D, Avvakumov N, Côté J. Histone phosphorylation:\na chromatin modification involved in diverse nuclear events.\nEpigenetics. 2012; 7: 1098–1108. https://doi.org/10.4161/epi.\n21975.\n[43] Davie JR, Sattarifard H, Sudhakar SRN, Roberts CT, Bea-\ncon TH, Muker I, et al . Basic Epigenetic Mechanisms. Sub-\ncellular Biochemistry. 2025; 108: 1–49. https://doi.org/10.1007/\n978-3-031-75980-2_1 .\n[44] Gong F, Miller KM. Histone methylation and the DNA damage\nresponse. Mutation Research. Reviews in Mutation Research.\n2019; 780: 37–47. https://doi.org/10.1016/j.mrrev.2017.09.003.\n[45] V ertegaal ACO. Signalling mechanisms and cellular functions\nof SUMO. Nature Reviews. Molecular Cell Biology. 2022; 23:\n715–731. https://doi.org/10.1038/s41580-022-00500-y .\n[46] Shiio Y , Eisenman RN. Histone sumoylation is associated with\ntranscriptional repression. Proceedings of the National Academy\nof Sciences of the United States of America. 2003; 100: 13225–\n13230. https://doi.org/10.1073/pnas.1735528100.\n[47] Y ang SH, Sharrocks AD. SUMO promotes HDAC-mediated\ntranscriptional repression. Molecular Cell. 2004; 13: 611–617.\nhttps://doi.org/10.1016/s1097-2765(04)00060-7 .\n[48] Rosonina E, Akhter A, Dou Y , Babu J, Sri Theivakadadcham\nVS. Regulation of transcription factors by sumoylation. Tran-\nscription. 2017; 8: 220–231. https://doi.org/10.1080/21541264.\n2017.1311829.\n[49] Moore LD, Le T, Fan G. DNA methylation and its basic func-\ntion. Neuropsychopharmacology. 2013; 38: 23–38. https://doi.\norg/10.1038/npp.2012.112.\n[50] Bird A. DNA methylation patterns and epigenetic memory.\nGenes & Development. 2002; 16: 6–21. https://doi.org/10.1101/\ngad.947102.\n[51] Hashimoto H, V ertino PM, Cheng X. Molecular coupling of\nDNA methylation and histone methylation. Epigenomics. 2010;\n2: 657–669. https://doi.org/10.2217/epi.10.44.\n[52] Zaccara S, Ries RJ, Jaffrey SR. Reading, writ-\ning and erasing mRNA methylation. Nature Re-\nviews. Molecular Cell Biology. 2019; 20: 608–624.\nhttps://doi.org/10.1038/s41580-019-0168-5 .\n[53] Wang MK, Gao CC, Y ang YG. Emerging Roles of RNA Methy-\nlation in Development. Accounts of Chemical Research. 2023;\n56: 3417–3427. https://doi.org/10.1021/acs.accounts.3c00448.\n[54] Strick A, von Hagen F, Gundert L, Klümper N, Tolkach Y ,\nSchmidt D, et al. The N6‐methyladenosine (m6A) erasers alky-\nlation repair homologue 5 (ALKBH5) and fat mass and obe-\nsity‐associated protein (FTO) are prognostic biomarkers in pa-\ntients with clear cell renal carcinoma. BJU international. 2020;\n125: 617-624. https://doi.org/10.1111/bju.15019.\n[55] Gao Z, Zha X, Li M, Xia X, Wang S. Insights into the m 6A\ndemethylases FTO and ALKBH5: structural, biological func-\ntion, and inhibitor development. Cell & Bioscience. 2024; 14:\n108. https://doi.org/10.1186/s13578-024-01286-6 .\n[56] Liu N, Pan T. RNA epigenetics. Translational Research: the\nJournal of Laboratory and Clinical Medicine. 2015; 165: 28–\n35. https://doi.org/10.1016/j.trsl.2014.04.003.\n[57] Jin H, Huo C, Zhou T, Xie S. m 1A RNA Modification in Gene\nExpression Regulation. Genes. 2022; 13: 910. https://doi.org/\n10.3390/genes13050910.\n[58] Monaco PL, Marcel V , Diaz JJ, Catez F. 2’-O-Methylation of Ri-\nbosomal RNA: Towards an Epitranscriptomic Control of Trans-\nlation? Biomolecules. 2018; 8: 106. https://doi.org/10.3390/bi\nom8040106.\n[59] Costa FF. Non-coding RNAs, epigenetics and complexity. Gene.\n2008; 410: 9–17. https://doi.org/10.1016/j.gene.2007.12.008.\n[60] Chuang JC, Jones PA. Epigenetics and microRNAs. Pediatric\nResearch. 2007; 61: 24R–29R. https://doi.org/10.1203/pdr.0b\n013e3180457684.\n[61] Wang C, Wang L, Ding Y , Lu X, Zhang G, Y ang J, et al .\nLncRNA Structural Characteristics in Epigenetic Regulation.\nInternational Journal of Molecular Sciences. 2017; 18: 2659.\nhttps://doi.org/10.3390/ijms18122659.\n[62] Peng JC, Lin H. Beyond transposons: the epigenetic and somatic\nfunctions of the Piwi-piRNA mechanism. Current Opinion in\nCell Biology. 2013; 25: 190–194. https://doi.org/10.1016/j.ce\nb.2013.01.010.\n[63] Ramaswamy S, Weinbauer GF. Endocrine control of spermato-\ngenesis: Role of FSH and LH/ testosterone. Spermatogene-\nsis. 2015; 4: e996025. https://doi.org/10.1080/21565562.2014.\n996025.\n12\n\n\n[64] Christensen A, Bentley GE, Cabrera R, Ortega HH, Perfito N,\nWu TJ, et al. Hormonal regulation of female reproduction. Hor-\nmone and Metabolic Research. 2012; 44: 587–591. https://doi.\norg/10.1055/s-0032-1306301 .\n[65] Joensen UN, Jørgensen N, Rajpert-De Meyts E, Skakkebaek NE.\nTesticular dysgenesis syndrome and Leydig cell function. Basic\n& Clinical Pharmacology & Toxicology. 2008; 102: 155–161.\nhttps://doi.org/10.1111/j.1742-7843.2007.00197.x.\n[66] Skakkebaek NE, Rajpert-De Meyts E, Buck Louis GM, Toppari\nJ, Andersson AM, Eisenberg ML, et al. Male Reproductive Dis-\norders and Fertility Trends: Influences of Environment and Ge-\nnetic Susceptibility. Physiological Reviews. 2016; 96: 55–97.\nhttps://doi.org/10.1152/physrev.00017.2015.\n[67] Durairajanayagam D. Lifestyle causes of male infertility. Arab\nJournal of Urology. 2018; 16: 10–20. https://doi.org/10.1016/j.\naju.2017.12.004.\n[68] Bala R, Singh V , Rajender S, Singh K. Environment, Lifestyle,\nand Female Infertility. Reproductive Sciences. 2021; 28: 617–\n638. https://doi.org/10.1007/s43032-020-00279-3 .\n[69] Ghosh A, Tripathy A, Ghosh D. Impact of endocrine disrupting\nchemicals (EDCs) on reproductive health of human. In Proceed-\nings of the zoological society (V ol. 75, No. 1, pp. 16–30). 2022.\n[70] Amir S, Shah STA, Mamoulakis C, Docea AO, Kalantzi OI,\nZachariou A, et al . Endocrine Disruptors Acting on Estrogen\nand Androgen Pathways Cause Reproductive Disorders through\nMultiple Mechanisms: A Review. International Journal of En-\nvironmental Research and Public Health. 2021; 18: 1464. https:\n//doi.org/10.3390/ijerph18041464.\n[71] Pan J, Liu P , Y u X, Zhang Z, Liu J. The adverse role of endocrine\ndisrupting chemicals in the reproductive system. Frontiers in En-\ndocrinology. 2024; 14: 1324993. https://doi.org/10.3389/fendo.\n2023.1324993.\n[72] de Kretser DM, Loveland KL, Meinhardt A, Simorangkir D,\nWreford N. Spermatogenesis. Human Reproduction. 1998; 13:\n1–8. https://doi.org/10.1093/humrep/13.suppl_1.1.\n[73] Liu B, Wu SD, Shen LJ, Zhao TX, Wei Y , Tang XL, et al .\nSpermatogenesis dysfunction induced by PM 2.5 from automo-\nbile exhaust via the ROS-mediated MAPK signaling pathway.\nEcotoxicology and Environmental Safety. 2019; 167: 161–168.\nhttps://doi.org/10.1016/j.ecoenv.2018.09.118.\n[74] Guerriero G, Trocchia S, Abdel-Gawad FK, Ciarcia G. Roles of\nreactive oxygen species in the spermatogenesis regulation. Fron-\ntiers in Endocrinology. 2014; 5: 56. https://doi.org/10.3389/fend\no.2014.00056.\n[75] Rotondo JC, Lanzillotti C, Mazziotta C, Tognon M, Martini F.\nEpigenetics of Male Infertility: The Role of DNA Methylation.\nFrontiers in Cell and Developmental Biology. 2021; 9: 689624.\nhttps://doi.org/10.3389/fcell.2021.689624.\n[76] Hornig NC, Rodens P , Dörr H, Hubner NC, Kulle AE, Schweik-\nert HU, et al . Epigenetic Repression of Androgen Receptor\nTranscription in Mutation-Negative Androgen Insensitivity Syn-\ndrome (AIS Type II). The Journal of Clinical Endocrinology and\nMetabolism. 2018; 103: 4617–4627. https://doi.org/10.1210/jc\n.2018-00052.\n[77] Ferlin A, Vinanzi C, Garolla A, Selice R, Zuccarello D, Caz-\nzadore C, et al . Male infertility and androgen receptor gene\nmutations: clinical features and identification of seven novel\nmutations. Clinical Endocrinology. 2006; 65: 606–610. https:\n//doi.org/10.1111/j.1365-2265.2006.02635.x.\n[78] Rajender S, Avery K, Agarwal A. Epigenetics, spermatogenesis\nand male infertility. Mutation Research. 2011; 727: 62–71. http\ns://doi.org/10.1016/j.mrrev.2011.04.002.\n[79] Wu L, Wei Y , Li H, Li W, Gu C, Sun J, et al. The ubiquitination\nand acetylation of histones are associated with male reproductive\ndisorders induced by chronic exposure to arsenite. Toxicology\nand Applied Pharmacology. 2020; 408: 115253. https://doi.org/\n10.1016/j.taap.2020.115253.\n[80] Roy A, Matzuk MM. Reproductive tract function and dysfunc-\ntion in women. Nature Reviews. Endocrinology. 2011; 7: 517–\n525. https://doi.org/10.1038/nrendo.2011.79.\n[81] Kumar S, Sharma A, Kshetrimayum C. Environmental & occu-\npational exposure & female reproductive dysfunction. The In-\ndian Journal of Medical Research. 2019; 150: 532–545. https:\n//doi.org/10.4103/ijmr.IJMR_1652_17.\n[82] Mikhael S, Punjala-Patel A, Gavrilova-Jordan L. Hypothalamic-\nPituitary-Ovarian Axis Disorders Impacting Female Fertility.\nBiomedicines. 2019; 7: 5. https://doi.org/10.3390/biomedicines\n7010005.\n[83] Meli R, Monnolo A, Annunziata C, Pirozzi C, Ferrante MC.\nOxidative Stress and BPA Toxicity: An Antioxidant Approach\nfor Male and Female Reproductive Dysfunction. Antioxidants.\n2020; 9: 405. https://doi.org/10.3390/antiox9050405.\n[84] Zeng X, Xie YJ, Liu YT, Long SL, Mo ZC. Polycystic ovar-\nian syndrome: Correlation between hyperandrogenism, insulin\nresistance and obesity. Clinica Chimica Acta. 2020; 502: 214–\n221. https://doi.org/10.1016/j.cca.2019.11.003.\n[85] Evans MB, Decherney AH. Fertility and Endometriosis. Clinical\nObstetrics and Gynecology. 2017; 60: 497–502. https://doi.org/\n10.1097/GRF.0000000000000295.\n[86] Miller JE, Ahn SH, Monsanto SP , Khalaj K, Koti M, Tayade\nC. Implications of immune dysfunction on endometriosis asso-\nciated infertility. Oncotarget. 2017; 8: 7138–7147. https://doi.or\ng/10.18632/oncotarget.12577.\n[87] Sugino N. Reactive oxygen species in ovarian physiology. Re-\nproductive Medicine and Biology. 2005; 4: 31–44. https://doi.\norg/10.1007/BF03016135.\n[88] Rod A, Jarzabek K, Wolczynski S, Benhaim A, Reznik Y ,\nDenoual-Ziad C, et al . ESR1 and FSHR gene polymorphisms\ninfluence ovarian response to FSH in poor responder women\nwith normal FSH levels. Endocrinology & Metabolic Syndrome.\n2014; 3: 1000141. https://doi.org/10.4172/2161-1017.1000141.\n[89] Aldakheel FM, Abuderman AA, Alduraywish SA, Xiao Y , Guo\nWW. MicroRNA-21 inhibits ovarian granulosa cell prolifera-\ntion by targeting SNHG7 in premature ovarian failure with poly-\ncystic ovary syndrome. Journal of Reproductive Immunology.\n2021; 146: 103328. https://doi.org/10.1016/j.jri.2021.103328.\n[90] Rashid G, Khan NA, Elsori D, Y ouness RA, Hassan H, Siwan\nD, et al . miRNA expression in PCOS: unveiling a paradigm\nshift toward biomarker discovery. Archives of Gynecology\nand Obstetrics. 2024; 309: 1707–1723. https://doi.org/10.1007/\ns00404-024-07379-4 .\n[91] Guarnotta V , Amodei R, Frasca F, Aversa A, Giordano C. Impact\nof Chemical Endocrine Disruptors and Hormone Modulators on\nthe Endocrine System. International Journal of Molecular Sci-\nences. 2022; 23: 5710. https://doi.org/10.3390/ijms23105710.\n[92] Ananthasubramanian P , Ananth S, Kumaraguru S, Barathi S,\nSantosh W, V asantharekha R. Associated effects of endocrine\ndisrupting chemicals (EDCs) on neuroendocrine axes and neu-\nrotransmitter profile in polycystic ovarian syndrome condition.\nProceedings of the Zoological Society. 2021; 74: 378–386.\nhttps://doi.org/10.1007/s12595-021-00411-4 .\n[93] Wen X, Xiong Y , Qu X, Jin L, Zhou C, Zhang M, et al. The risk\nof endometriosis after exposure to endocrine-disrupting chemi-\ncals: a meta-analysis of 30 epidemiology studies. Gynecologi-\ncal Endocrinology. 2019; 35: 645–650. https://doi.org/10.1080/\n09513590.2019.1590546.\n[94] Craig ZR, Wang W, Flaws JA. Endocrine-disrupting chemicals\nin ovarian function: effects on steroidogenesis, metabolism and\nnuclear receptor signaling. Reproduction (Cambridge, England).\n2011; 142: 633–646. https://doi.org/10.1530/REP-11-0136 .\n[95] Cannarella R, Gül M, Rambhatla A, Agarwal A. Tempo-\nral decline of sperm concentration: role of endocrine dis-\n13\n\nruptors. Endocrine. 2023; 79: 1–16. https://doi.org/10.1007/\ns12020-022-03136-2 .\n[96] Wang C, Y ang L, Wang S, Zhang Z, Y u Y , Wang M, et al .\nThe classic EDCs, phthalate esters and organochlorines, in rela-\ntion to abnormal sperm quality: a systematic review with meta-\nanalysis. Scientific Reports. 2016; 6: 19982. https://doi.org/10.\n1038/srep19982.\n[97] Chou WC, Lee PH, Tan YY , Lin HC, Y ang CW, Chen KH,\net al . An integrative transcriptomic analysis reveals bisphenol\nA exposure-induced dysregulation of microRNA expression in\nhuman endometrial cells. Toxicology in Vitro: an International\nJournal Published in Association with BIBRA. 2017; 41: 133–\n142. https://doi.org/10.1016/j.tiv.2017.02.012.\n[98] Avissar-Whiting M, V eiga KR, Uhl KM, Maccani MA, Gagne\nLA, Moen EL, et al. Bisphenol A exposure leads to specific mi-\ncroRNA alterations in placental cells. Reproductive Toxicology.\n2010; 29: 401–406. https://doi.org/10.1016/j.reprotox.2010.04.\n004.\n[99] Gao GZ, Zhao Y , Li HX, Li W. Bisphenol A-elicited miR-146a-\n5p impairs murine testicular steroidogenesis through negative\nregulation of Mta3 signaling. Biochemical and Biophysical Re-\nsearch Communications. 2018; 501: 478–485. https://doi.org/\n10.1016/j.bbrc.2018.05.017.\n[100] Zama AM, Uzumcu M. Fetal and neonatal exposure to the\nendocrine disruptor methoxychlor causes epigenetic alterations\nin adult ovarian genes. Endocrinology. 2009; 150: 4681–4691.\nhttps://doi.org/10.1210/en.2009-0499.\n[101] Liu J, Lin Y , Peng C, Jiang C, Li J, Wang W, et al . Bisphe-\nnol F induced hyperglycemia via activation of oxidative stress-\nresponsive miR-200 family in the pancreas. Ecotoxicology and\nEnvironmental Safety. 2023; 255: 114769. https://doi.org/10.\n1016/j.ecoenv.2023.114769.\n[102] Yin N, Luo C, Wei L, Y ang G, Bo L, Mao C. The mech-\nanisms of MicroRNA 21 in premature ovarian insufficiency\nmice with mesenchymal stem cells transplantation: The in-\nvolved molecular and immunological mechanisms. Journal\nof Ovarian Research. 2024; 17: 75. https://doi.org/10.1186/\ns13048-024-01390-8 .\n[103] Chen X, Xie M, Liu D, Shi K. Downregulation of microRNA\n146a inhibits ovarian granulosa cell apoptosis by simultaneously\ntargeting interleukin 1 receptor associated kinase and tumor\nnecrosis factor receptor associated factor 6. Molecular Medicine\nReports. 2015; 12: 5155–5162. https://doi.org/10.3892/mmr.\n2015.4036.\n[104] Navarro-Lafuente F, Adoamnei E, Arense-Gonzalo JJ, Prieto-\nSánchez MT, Sánchez-Ferrer ML, Parrado A, et al . Maternal\nurinary concentrations of bisphenol A during pregnancy are as-\nsociated with global DNA methylation in cord blood of new-\nborns in the “NELA” birth cohort. The Science of the Total En-\nvironment. 2022; 838: 156540. https://doi.org/10.1016/j.scitot\nenv.2022.156540.\n[105] Prabhu NB, Adiga D, Kabekkodu SP , Bhat SK, Satyamoorthy\nK, Rai PS. Bisphenol A exposure modulates reproductive and\nendocrine system, mitochondrial function and cellular senes-\ncence in female adult rats: A hallmarks of polycystic ovarian\nsyndrome phenotype. Environmental Toxicology and Pharma-\ncology. 2022; 96: 104010. https://doi.org/10.1016/j.etap.2022.\n104010.\n[106] Chandrakanth A, Firdous S, V asantharekha R, Santosh W,\nSeetharaman B. Exploring the Effects of Endocrine-Disrupting\nChemicals and miRNA Expression in the Pathogenesis of En-\ndometriosis by Unveiling the Pathways: a Systematic Review.\nReproductive Sciences. 2024; 31: 932–941. https://doi.org/10.\n1007/s43032-023-01412-8 .\n[107] Edaes FS, de Souza CB. BPS and BPF are as Car-\ncinogenic as BPA and are Not Viable Alternatives for its\nReplacement. Endocrine, Metabolic & Immune Disorders\nDrug Targets. 2022; 22: 927–934. https://doi.org/10.2174/\n1871530322666220316141032.\n[108] Gao Z, He W, Liu Y , Gao Y , Fan W, Luo Y , et al . Peri-\nnatal bisphenol S exposure exacerbates the oxidative bur-\nden and apoptosis in neonatal ovaries by suppressing the\nmTOR/autophagy axis. Environmental Pollution. 2024; 349:\n123939. https://doi.org/10.1016/j.envpol.2024.123939.\n[109] Hao L, Ru S, Qin J, Wang W, Zhang J, Wei S, et al. Transgen-\nerational effects of parental bisphenol S exposure on zebrafish\n(Danio rerio) reproduction. Food and Chemical Toxicology.\n2022; 165: 113142. https://doi.org/10.1016/j.fct.2022.113142.\n[110] Nguyen M, Sabry R, Davis OS, Favetta LA. Effects of BPA,\nBPS, and BPF on Oxidative Stress and Antioxidant Enzyme Ex-\npression in Bovine Oocytes and Spermatozoa. Genes. 2022; 13:\n142. https://doi.org/10.3390/genes13010142.\n[111] Zhang X, Guo N, Jin H, Liu R, Zhang Z, Cheng C, et al .\nBisphenol A drives di(2-ethylhexyl) phthalate promoting thy-\nroid tumorigenesis via regulating HDAC6/PTEN and c-MYC\nsignaling. Journal of Hazardous Materials. 2022; 425: 127911.\nhttps://doi.org/10.1016/j.jhazmat.2021.127911.\n[112] Li MH, Wang JJ, Feng YQ, Liu X, Y an ZH, Zhang XJ, et al .\nH3K4me3 as a target of di(2-ethylhexyl) phthalate (DEHP) im-\npairing primordial follicle assembly. Chemosphere. 2023; 310:\n136811. https://doi.org/10.1016/j.chemosphere.2022.136811.\n[113] Liu C, Qian P , Y ang L, Zhang L, Chen C, He M, et al .\nPubertal exposure to di-(2-ethylhexyl)-phthalate inhibits G9a-\nmediated histone methylation during spermatogenesis in mice.\nArchives of Toxicology. 2016; 90: 955–969. https://doi.org/10.\n1007/s00204-015-1529-2 .\n[114] Lu Z, Zhang C, Han C, An Q, Cheng Y , Chen Y , et al . Plas-\nticizer Bis(2-ethylhexyl) Phthalate Causes Meiosis Defects and\nDecreases Fertilization Ability of Mouse Oocytes in Vivo. Jour-\nnal of Agricultural and Food Chemistry. 2019; 67: 3459–3468.\nhttps://doi.org/10.1021/acs.jafc.9b00121.\n[115] Stenz L, Escoffier J, Rahban R, Nef S, Paoloni-Giacobino A.\nTesticular Dysgenesis Syndrome and Long-Lasting Epigenetic\nSilencing of Mouse Sperm Genes Involved in the Reproductive\nSystem after Prenatal Exposure to DEHP . PLoS ONE. 2017; 12:\ne0170441. https://doi.org/10.1371/journal.pone.0170441.\n[116] Zhang L, Y ang R, Xu G, Wang L, Chen W, Tan Y , et al . Pa-\nternal DEHP Exposure Triggers Reproductive Toxicity in Off-\nspring via Epigenetic Modification of H3K27me3. Toxics. 2025;\n13: 172. https://doi.org/10.3390/toxics13030172.\n[117] Sant KE, Dolinoy DC, Jilek JL, Shay BJ, Harris C. Mono-2-\nethylhexyl phthalate (MEHP) alters histiotrophic nutrition path-\nways and epigenetic processes in the developing conceptus. The\nJournal of Nutritional Biochemistry. 2016; 27: 211–218. https:\n//doi.org/10.1016/j.jnutbio.2015.09.008.\n[118] Martínez-Razo LD, Martínez-Ibarra A, Vázquez-Martínez ER,\nCerbón M. The impact of Di-(2-ethylhexyl) Phthalate and\nMono(2-ethylhexyl) Phthalate in placental development, func-\ntion, and pathophysiology. Environment International. 2021;\n146: 106228. https://doi.org/10.1016/j.envint.2020.106228.\n[119] Li L, Liu JC, Lai FN, Liu HQ, Zhang XF, Dyce PW, et al .\nDi (2-ethylhexyl) Phthalate Exposure Impairs Growth of Antral\nFollicle in Mice. PLoS ONE. 2016; 11: e0148350. https://doi.or\ng/10.1371/journal.pone.0148350.\n[120] Kim HG, Lim YS, Hwang S, Kim HY , Moon Y , Song YJ,\net al . Di-(2-ethylhexyl) Phthalate Triggers Proliferation, Mi-\ngration, Stemness, and Epithelial-Mesenchymal Transition in\nHuman Endometrial and Endometriotic Epithelial Cells via the\nTransforming Growth Factor-β/Smad Signaling Pathway. Inter-\nnational Journal of Molecular Sciences. 2022; 23: 3938. https:\n//doi.org/10.3390/ijms23073938.\n[121] Messerlian C, Souter I, Gaskins AJ, Williams PL, Ford JB,\n14\n\n\nChiu YH, et al . Urinary phthalate metabolites and ovarian re-\nserve among women seeking infertility care. Human Reproduc-\ntion (Oxford, England). 2016; 31: 75–83. https://doi.org/10.\n1093/humrep/dev292.\n[122] Cao M, Pan W, Shen X, Li C, Zhou J, Liu J. Urinary lev-\nels of phthalate metabolites in women associated with risk of\npremature ovarian failure and reproductive hormones. Chemo-\nsphere. 2020; 242: 125206. https://doi.org/10.1016/j.chemosph\nere.2019.125206.\n[123] Collotta M, Bertazzi PA, Bollati V . Epigenetics and pesti-\ncides. Toxicology. 2013; 307: 35–41. https://doi.org/10.1016/\nj.tox.2013.01.017.\n[124] Han X, Huang Q. Environmental pollutants exposure and male\nreproductive toxicity: The role of epigenetic modifications. Tox-\nicology. 2021; 456: 152780. https://doi.org/10.1016/j.tox.2021.\n152780.\n[125] Biswas S, Ghosh S, Das S, Maitra S. Female reproduction:\nat the crossroads of endocrine disruptors and epigenetics. Pro-\nceedings of the Zoological Society. 2021; 74: 532–545. https:\n//doi.org/10.1007/s12595-021-00403-4 .\n[126] Tran CM, Kim KT. miR-137 and miR-141 regulate tail defects\nin zebrafish embryos caused by triphenyl phosphate (TPHP).\nEnvironmental Pollution (Barking, Essex: 1987). 2020; 262:\n114286. https://doi.org/10.1016/j.envpol.2020.114286.\n[127] Gore AC. Environmental toxicant effects on neuroendocrine\nfunction. Endocrine. 2001; 14: 235–246. https://doi.org/10.\n1385/ENDO:14:2:235.\n[128] Lahimer M, Djekkoun N, Tricotteaux-Zarqaoui S, Corona A,\nLafosse I, Ali HB, et al . Impact of Perinatal Coexposure to\nChlorpyrifos and a High-Fat Diet on Kisspeptin and GnRHR\nPresence and Reproductive Organs. Toxics. 2023; 11: 789.https:\n//doi.org/10.3390/toxics11090789.\n[129] Abd-Elhakim YM, El Sharkawy NI, El Bohy KM, Hassan\nMA, Gharib HSA, El-Metwally AE, et al . Iprodione and/or\nchlorpyrifos exposure induced testicular toxicity in adult rats\nby suppression of steroidogenic genes and SIRT1/TERT/PGC-\n1α pathway. Environmental Science and Pollution Research In-\nternational. 2021; 28: 56491–56506. https://doi.org/10.1007/\ns11356-021-14339-x .\n[130] Gaudet MM, Campan M, Figueroa JD, Y ang XR, Lissowska J,\nPeplonska B, et al. DNA hypermethylation of ESR1 and PGR in\nbreast cancer: pathologic and epidemiologic associations. Can-\ncer Epidemiology, Biomarkers & Prevention: a Publication of\nthe American Association for Cancer Research, Cosponsored by\nthe American Society of Preventive Oncology. 2009; 18: 3036–\n3043. https://doi.org/10.1158/1055-9965.EPI-09-0678 .\n[131] Xu Q, Lin HY , Y eh SD, Y u IC, Wang RS, Chen YT, et al. In-\nfertility with defective spermatogenesis and steroidogenesis in\nmale mice lacking androgen receptor in Leydig cells. Endocrine.\n2007; 32: 96–106. https://doi.org/10.1007/s12020-007-9015-0 .\n[132] O’Hara L, Smith LB. Androgen receptor roles in spermato-\ngenesis and infertility. Best Practice & Research. Clinical En-\ndocrinology & Metabolism. 2015; 29: 595–605. https://doi.org/\n10.1016/j.beem.2015.04.006.\n[133] Argyraki M, Damdimopoulou P , Chatzimeletiou K, Grimbizis\nGF, Tarlatzis BC, Syrrou M, et al . In-utero stress and mode\nof conception: impact on regulation of imprinted genes, fetal\ndevelopment and future health. Human Reproduction Update.\n2019; 25: 777–801. https://doi.org/10.1093/humupd/dmz025.\n[134] LaRocca J, Binder AM, McElrath TF, Michels KB. The impact\nof first trimester phthalate and phenol exposure on IGF2/H19 ge-\nnomic imprinting and birth outcomes. Environmental Research.\n2014; 133: 396–406. https://doi.org/10.1016/j.envres.2014.04.\n032.\n[135] Leoni G, Bogliolo L, Deiana G, Berlinguer F, Rosati I, Pin-\ntus PP , et al . Influence of cadmium exposure on in vitro ovine\ngamete dysfunction. Reproductive Toxicology. 2002; 16: 371–\n377. https://doi.org/10.1016/s0890-6238(02)00040-0 .\n[136] Telisman S, Colak B, Pizent A, Jurasović J, Cvitković P . Re-\nproductive toxicity of low-level lead exposure in men. Environ-\nmental Research. 2007; 105: 256–266. https://doi.org/10.1016/\nj.envres.2007.05.011.\n[137] Aoyagi T, Ishikawa H, Miyaji K, Hayakawa K, Hata M. Cad-\nmium‐induced testicular damage in a rat model of subchronic\nintoxication. Reproductive Medicine and Biology. 2002; 1: 59-\n63. https://doi.org/10.1046/j.1445-5781.2002.00010.x.\n[138] Hari Priya P , Reddy PS. Effect of restraint stress on\nlead‐induced male reproductive toxicity in rats. Journal of Ex-\nperimental Zoology Part A: Ecological Genetics and Physiol-\nogy. 2012; 317: 455–465. https://doi.org/10.1002/jez.1738.\n[139] Niewenhuis RJ. Effects of cadmium upon regenerated testicu-\nlar vessels in the rat. Biology of Reproduction. 1980; 23: 171–\n179. https://doi.org/10.1095/biolreprod23.1.171.\n[140] Ahamed T, Brown SP , Salehi M. Investigate the role of biofilm\nand water chemistry on lead deposition onto and release from\npolyethylene: An implication for potable water pipes. Journal\nof Hazardous Materials. 2020; 400: 123253. https://doi.org/10.\n1016/j.jhazmat.2020.123253.\n[141] Kumar S, Sharma A. Cadmium toxicity: effects on human\nreproduction and fertility. Reviews on Environmental Health.\n2019; 34: 327–338. https://doi.org/10.1515/reveh-2019-0016 .\n[142] Massányi P , Lukác N, Uhrín V , Toman R, Pivko J, Rafay J, et\nal. Female reproductive toxicology of cadmium. Acta Biologica\nHungarica. 2007; 58: 287–299. https://doi.org/10.1556/ABiol.\n58.2007.3.5.\n[143] Cheng Y , Zhang J, Wu T, Jiang X, Jia H, Qing S, et al . Re-\nproductive toxicity of acute Cd exposure in mouse: Resulting\nin oocyte defects and decreased female fertility. Toxicology and\nApplied Pharmacology. 2019; 379: 114684. https://doi.org/10.\n1016/j.taap.2019.114684.\n[144] Pollack AZ, Ranasinghe S, Sjaarda LA, Mumford SL. Cad-\nmium and Reproductive Health in Women: A Systematic Re-\nview of the Epidemiologic Evidence. Current Environmental\nHealth Reports. 2014; 1: 172–184. https://doi.org/10.1007/\ns40572-014-0013-0 .\n[145] Chanda S, Dasgupta UB, Guhamazumder D, Gupta M, Chaud-\nhuri U, Lahiri S, et al . DNA hypermethylation of promoter of\ngene p53 and p16 in arsenic-exposed people with and with-\nout malignancy. Toxicological Sciences. 2006; 89: 431–437.\nhttps://doi.org/10.1093/toxsci/kfj030.\n[146] Ke T, Tinkov AA, Skalny A V , Santamaria A, Rocha JBT, Bow-\nman AB, et al. Epigenetics and Methylmercury-Induced Neuro-\ntoxicity, Evidence from Experimental Studies. Toxics. 2023; 11:\n72. https://doi.org/10.3390/toxics11010072.\n[147] Deobagkar D. DNA methylation and toxicogenomics. Toxicol-\nogy and Epigenetics. 2012; 25–50.\n[148] Y ang Y , Zuo Z, Y ang Z, Yin H, Wei L, Fang J, et al . Nickel\nchloride induces spermatogenesis disorder by testicular dam-\nage and hypothalamic-pituitary-testis axis disruption in mice.\nEcotoxicology and Environmental Safety. 2021; 225: 112718.\nhttps://doi.org/10.1016/j.ecoenv.2021.112718.\n[149] Lukac N, Forgacs Z, Duranova H, Jambor T, Zemanova J, Mas-\nsanyi P ,et al. In vitro assessment of the impact of nickel on the\nviability and steroidogenesis in the human adrenocortical carci-\nnoma (NCI-H295R) cell line. Physiological Research. 2020; 69:\n871–883. https://doi.org/10.33549/physiolres.934452.\n15","source_license":"CC-BY-4.0","license_restricted":false}