Epigenetic Mechanisms of Reproductive Dysfunction Induced by Endocrine-Disrupting Chemicals: Evidence From Molecular Studies

Endocrine-disrupting chemicals (EDCs), including bisphenol A (BPA), phthalates, organochlorine pesticides, and heavy metal ions, pose serious threats to reproductive health by interfering with hormonal balance and molecular signaling pathways. Recent research had expanded our understanding of these compounds has beyond their traditional role in hormone receptor interference. EDCs can trigger lasting epigenetic changes, including abnormal DNA methylation, histone modifications, RNA methylation, and altered regulation of non-coding RNA, which can impair reproductive functions such as gametogenesis, folliculogenesis, steroidogenesis, and embryo implantation. Importantly, EDC-mediated epigenetic alterations have been linked to various reproductive disorders, including polycystic ovary syndrome (PCOS), endometriosis, reduced ovarian reserve, and impaired spermatogenesis. For example, BPA exposure alters DNA methylation in estrogen signaling and aromatase gene expression, whereas phthalates disrupt histone acetylation and methylation in hormone synthesis pathways. Similarly, pesticides and heavy metal ions may influence microRNA expression and histone structure, further disrupting endocrine-regulated gene networks. These alterations may occur during sensitive developmental windows and can lead to long-term or transgenerational effects on reproductive health. Understanding how EDCs exert their toxicity through epigenetic mechanisms is essential for early detection of exposure, identification of molecular biomarkers, and development of targeted therapies to reduce reproductive risks. Here, we discuss the emerging molecular evidence that provides a comprehensive overview of how EDCs impair reproductive health through epigenetic pathways, thereby offering a framework for future research and translational applications.

reproductive dysfunction; endocrine-disrupting chemicals (EDCs); histone modification; DNA methylation; RNA methyla- tion; non-coding RNA (ncRNA) 1. Introduction Over the past few decades, increasing evidence has drawn attention to the detrimental effects of environ- mental pollutants on reproductive health. Among these, endocrine-disrupting chemicals (EDCs), such as bisphe- nol A (BPA), phthalates, organochlorine pesticides such as dichlorodiphenyltrichloroethane (DDT), and heavy metal ions such as lead ions (Pb 2+) and cadmium ions (Cd 2+), have gained particular attention because of their widespread use in industrial, agricultural, and consumer products. This leads to chronic, low-level exposure in the general popu- lation through ingestion, inhalation, and dermal absorption [1–7]. Although earlier studies have primarily focused on hormonal disruptions mediated by receptor binding, such as estrogenic or anti-androgenic actions [ 2,8], EDCs also act through epigenetic pathways. Epigenetic modifications, in- cluding DNA methylation, histone modifications, and non- coding RNA (ncRNA) expression, play pivotal roles in regulating gene activity without altering the nucleotide se- quences [ 9–12]. These epigenetic processes are essential for maintaining normal reproductive functions, such as ga- metogenesis, folliculogenesis, ovulation, and steroid hor- mone biosynthesis [ 11,13]. Consequently, when EDCs in- terfere with these highly coordinated regulatory systems, it can lead to a cascade of reproductive dysfunctions, in- cluding infertility, hormonal imbalances, and developmen- tal abnormalities in the reproductive tract. EDC exposure during critical developmental periods causes abnormal epigenetic reprogramming in reproduc- tive tissues. For instance, BPA exposure hypermethylates Estrogen receptor 1 (ESR1) and Cytochrome P450 fam- ily 19 subfamily A member 1 (CYP19A1), reduces histone acetylation (Histone H3 lysine 9 acetylation (H3K9ac)), and upregulates repressive markers such as histone H3 ly- sine 27 trimethylation (H3K27me3), ultimately impairing ovarian and testicular function [ 14–18]. Phthalates such as di(2-ethylhexyl) phthalate (DEHP) and its active metabo- lite mono(2-ethylhexyl) phthalate (MEHP) disrupt histone- modifying enzyme and DNA methyltransferase (DNMT) activity, reducing the transcription of essential steroido- genic genes such as steroidogenic acute regulatory ( STAR) and cholesterol side-chain cleavage enzyme ( CYP11A1) [19–22]. Pesticides such as DDT and chlorpyrifos disrupt the expression of microRNAs (miRNA), such as miR-21 and miR-137, and induce abnormal DNA methylation at hormone receptor gene promoters, thereby impairing repro- ductive hormone signaling and development [ 23–26]. In addition, heavy metal ions, including Pb 2+ and Cd2+, pro- mote both global hypomethylation and site-specific hyper- methylation of reproductive gene promoters, along with al- tered histone modification patterns, such as H3K9me2 and H3K27me3 [27–29]. Recognizing the epigenetic basis of EDC-induced re- productive toxicity is essential for advancing scientific un- derstanding and clinical practice. First, epigenetic alter- ations are promising biomarkers for the early detection of chemical exposure and reproductive risk, often before vis- ible symptoms appear. Second, elucidating these molec- ular mechanisms provides insights into how even short- term environmental exposure can result in enduring or even transgenerational reproductive abnormalities owing to the stable inheritance of epigenetic marks. Third, mechanis- tic knowledge can inform the design of targeted therapeu- tic interventions, such as epigenetic modulators or antioxi- dants, and support evidence-based public health regulations aimed at minimizing human exposure to harmful EDCs. These considerations emphasize the importance of multi- disciplinary research integrating toxicology, molecular bi- ology, epidemiology, and policy. This review aimed to clarify how epigenetic mecha- nisms contribute to the reproductive toxicity of EDCs. We present an integrative analysis of recent molecular studies involving DNA and RNA methylation, histone modifica- tions, and ncRNA dysregulation, focusing on their func- tional impacts on the male and female reproductive sys- tems. By emphasizing on the key molecular targets and pathways, we also outline future directions for mechanistic research, biomarker discovery, and regulatory action. Al- though EDCs differ in structure and origin, they ultimately converge on shared molecular pathways that mediate their reproductive toxicity. At the cellular level, they affect re- productive tissues, including granulosa cells, Leydig cells, Sertoli cells, and oocytes, by interfering with essential pro- cesses, such as steroid hormone synthesis, gametogenesis, follicular maturation, and embryo implantation. At the epigenetic level, EDCs alter the activity and ex- pression of enzymes such as DNMT1, DNMT3a, histone acetyltransferases (HA Ts), histone deacetylases (HDACs), and histone methyltransferases, such as enhancer of zeste homolog 2 (EZH2) and G9a. These disruptions lead to abnormal DNA methylation (such as at ESR1 and CYP19A1), altered histone modification patterns (such as increased H3K27me3 and decreased H3K9ac), and changes in miRNA expression (such as miR-21 and miR-146a), ul- timately silencing genes critical for hormonal balance and reproductive cell viability. Functionally, these molecular changes result in decreased estradiol and testosterone pro- duction, anovulation, impaired spermatogenesis, reduced oocyte quality, and increased risk of infertility or miscar- riage. Understanding these converging epigenetic path- ways is essential for developing targeted therapies and iden- tifying early biomarkers of reproductive toxicity. 2. Epigenetic Mechanisms in Reproductive Physiology Epigenetic mechanisms are essential processes that regulate gene expression patterns without altering the un- derlying DNA sequence [30,31]. The key epigenetic mech- anisms include histone modifications, DNA methylation, RNA methylation, and non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) (Fig. 1) [31–33]. 2.1 Types and Functional Roles of Histone Modifications Histone acetylation involves HA T-mediated acetyl group addition to lysine residues on histone tails, which neutralizes the positive charge on lysine, thereby reduc- ing interactions between histones and DNA. Therefore, the chromatin becomes less compact, creating an open and transcriptionally active state that promotes gene expression [34,35]. Histone deacetylation is mediated by histone deacety- lases (HDACs), which remove acetyl groups from his- tone tails to restore the positive charge on lysine residues, strengthening the interaction between histones and DNA. The resulting tighter chromatin structure represses gene transcription by reducing the accessibility of transcription factors to the DNA [ 36,37]. Histone methylation is a complex process that mainly occurs at the lysine and arginine residues. The effect of methylation depends on both the specific modified residues, such as H3K4, H3K9, H3K27, and H3K36, and methy- lation degree (mono-, di-, or tri-methylation). For exam- ple, trimethylation at H3K4 (H3K4me3) is typically asso- ciated with active transcription, whereas H3K27me3 and H3K9me3 are associated with gene repression. These mod- ifications are tightly controlled by specific histone methyl- transferases and demethylases that modulate gene expres- sion during gametogenesis, embryogenesis, and hormone- responsive processes in reproduction [ 38–40]. Histone phosphorylation involves adding phosphate groups to the serine, threonine, or tyrosine residues on hi- stones. This modification plays a crucial role in regulating chromatin dynamics during various biological processes. For example, H3 phosphorylation at serine 10 (H3S10ph) and serine 28 (H3S28ph) is closely linked to chromosome condensation during mitosis and meiosis, ensuring proper chromosome alignment and segregation [ 41,42]. Histone ubiquitination typically occurs on lysine residues such as H2AK119 and H2BK120 [ 43]. This mod- ification influences chromatin configuration and gene ex- 2 Fig. 1. Epigenetic mechanisms involved in reproductive physiology. Histone modifications, DNA methylation, RNA methylation, and non-coding RNAs (ncRNAs) represent essential epigenetic mechanisms. Four prevalent histone modifications include acetylation (Ac), methylation (Me), phosphorylation (P), and ubiquitination (Ub). Additionally, histone SUMOylation involves the covalent at- tachment of small ubiquitin-like modifier (SUMO) proteins to specific histone residues. DNA methylation primarily occurs at cytosine residues within cytosine–phosphate–guanine (CpG) dinucleotide regions, commonly referred to as CpG islands. RNA methylation is a reversible epigenetic modification that is tightly regulated by specialized enzymes known as “writers”, “erasers”, and “readers”. Among various ncRNAs, miRNAs regulate gene expression at the post-transcriptional level by binding complementary messenger RNA (mRNA) sequences, resulting in mRNA degradation or translation suppression. HA Ts, histone acetyltransferases; HDACs, histone deacetylases; DNMT, DNA methyltransferase; METTL3, methyltransferase-like 3; METTL14, methyltransferase-like 14; WTAP , Wilms tumor 1- associated protein; FTO, fat mass and obesity-associated protein; ALKBH5, AlkB homolog 5; YTHDC1, YTH domain containing 1. pression by modulating transcriptional activation, DNA re- pair, and histone turnover. H2B mono-ubiquitination is as- sociated with active transcription, whereas H2A ubiquitina- tion is often linked to transcriptional repression and DNA damage response [30,44]. Histone SUMOylation involves the attachment of small ubiquitin-like modifier (SUMO) proteins to histone residues. This modification typically represses gene ex- pression by altering chromatin structure, affecting tran- scription factor interactions, and promoting the recruitment of repressive protein complexes involved in transcriptional silencing and DNA repair [ 45–48]. 2.2 DNA Methylation: Mechanisms and Regulatory Functions DNA methylation is an epigenetic modification that primarily occurs at cytosine residues within cytosine– phosphate–guanine (CpG) dinucleotides, known as CpG islands, which are typically located in gene promoter re- gions. This process involves the covalent addition of methyl groups by DNMTs, primarily DNMT1, DNMT3a, and DNMT3b. DNMT1 is mainly responsible for maintain- ing DNA methylation patterns during replication, thereby ensuring that these patterns are epigenetically inherited. DNMT3a and DNMT3b are involved in establishing new methylation patterns ( de novo methylation) during devel- opment and cellular differentiation [ 49,50]. DNA methylation generally leads to transcriptional repression by preventing transcription factors from bind- ing to DNA and facilitating methyl-CpG binding domain (MBD) protein recruitment. These proteins in turn recruit histone-modifying enzymes that further enhance gene si- lencing. However, in some cases, DNA methylation can activate gene expression depending on the specific genomic context and the involvement of certain transcription factors that are sensitive to alterations in methylation [ 51]. 2.3 RNA Methylation and Its Emerging Epigenetic Roles RNA methylation is an important epigenetic modifi- cation that primarily affects mRNA expression. The most common and widely studied form of RNA methylation is N6-methyladenosine (m6A), where a methyl group is added 3 to the N-6 position of adenosine. This process is care- fully controlled by specialized enzymes known as “writ- ers”, “erasers”, and “readers”. Writers are enzymes, such as methyltransferase-like 3 (METTL3), methyltransferase-like 14 (METTL14), and the Wilms tumor 1-associated protein (WTAP), which add methyl groups to RNA and play crucial roles in RNA modification. METTL3 acts as the main catalytic unit of the methyltransferase complex, transferring methyl groups from S-adenosylmethionine (SAM) to adenosine residues in RNA. METTL14 provides structural support to METTL3, stabilizing the complex and improving its efficiency. WTAP regulates this process by guiding the METTL3–METTL14 complex to specific RNA targets and ensuring that it is correctly positioned within the cell [ 52, 53]. In contrast, erasers such as fat mass and obesity- associated protein (FTO) and AlkB homolog 5 (ALKBH5) remove these methyl groups, effectively reversing RNA methylation. FTO was originally linked to obesity but later found to demethylate m6A residues in RNA, impact- ing RNA stability, translation, and alternative splicing [54]. ALKBH5 specifically removes methyl groups from m6A residues in nuclear RNA, influencing RNA export from the nucleus and affecting overall RNA molecule lifespan and function. This makes ALKBH5 a key player in regulating RNA metabolism and gene expression [ 52,55]. Readers are specialized proteins that recognize and bind to methylated RNA, affecting important post- transcriptional processes, such as RNA stability, splic- ing, export from the nucleus, localization within the cell, and translation. The most well-known readers belong to the YT521-B homology (YTH) family, which includes YTHDF1, YTHDF2, and YTHDF3. YTHDF1 promotes translation by interacting with translation initiation factors. YTHDF2 accelerates m6A-tagged RNA breakdown by di- recting it to processing bodies (P-bodies) for degradation. YTHDF3 interacts with YTHDF1 and YTHDF2 to coor- dinate both methylated RNA translation and degradation. Additionally, YTHDC1 is a nuclear reader that influences alternative splicing by helping splicing factors interact with methylated pre-mRNAs, thereby fine-tuning gene expres- sion [52,56]. In addition to m6A, other RNA methylations occur at different sites and nucleotide positions. For instance, m1A affects RNA structure, stability, and translation by disrupt- ing standard base pairing [ 57]. 5-methylcytosine (m5C), produced by RNA methyltransferases such as NSUN fam- ily proteins and DNMT2, contributes to RNA stability, processing, and nuclear export [ 13]. N7-methylguanosine (m7G), found at the 5 ′ cap of mRNA, increases RNA sta- bility and translation efficiency [ 53]. Meanwhile, 2 ′-O- methylation (Nm) is common in transfer RNA (tRNA), ri- bosomal RNA (rRNA), and small nuclear RNA (snRNA), supporting RNA stability and function [ 58]. 2.4 Non-Coding RNAs as Epigenetic Regulators ncRNAs are transcribed from DNAs that are not trans- lated into proteins. Instead of functioning as protein syn- thesis templates, they play an essential regulatory role in gene expression and cellular processes. Among the various ncRNAs, miRNAs, long ncRNAs (lncRNAs), and piwi- interacting RNAs (piRNAs) are particularly important ow- ing to their broad functional impacts [ 59]. miRNAs are short (approximately 22 nucleotides), single-stranded ncRNAs that regulate gene expression at the post-transcriptional level. They bind to complementary sequences in target mRNAs, leading to mRNA degradation or translation inhibition. miRNAs are involved in various biological processes, including cell proliferation, differen- tiation, apoptosis, and metabolism [ 60]. lncRNAs, which are typically >200 nucleotides, regulate gene expression through several mechanisms, including chromatin remod- eling, transcriptional regulation, RNA splicing, and serving as molecular scaffolds. They also recruit other epigenetic regulators, such as DNMT and histone modifiers, thereby influencing chromatin structure and transcriptional activ- ity [ 61]. PiRNAs are small ncRNAs (26–31 nucleotides) primarily expressed in germ cells [ 33]. They are involved in silencing transposable elements, preserving genome in- tegrity, and regulating germ cell development. Their in- teraction with Piwi proteins is essential for maintaining germline genome stability [ 33,62]. Together, these different ncRNAs form a complex and highly sophisticated regulatory network that modu- lates gene expression at both transcriptional and post- transcriptional levels, significantly influencing cellular functions and physiological processes. 3. General Mechanisms of Reproductive Dysfunction Reproductive dysfunction refers to any condition that impairs fertility or reproductive health. The hypothalamic– pituitary–gonadal (HPG) axis plays a central role in reg- ulating reproductive functions, including gonadotropin se- cretion, steroidogenesis, and gametogenesis. The HPG axis functions through a finely tuned balance of hormonal sig- naling. Gonadotropin-releasing hormone (GnRH), secreted by the hypothalamus, stimulates luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release from the pi- tuitary gland. In males, LH primarily acts on Leydig cells to promote testosterone production, whereas in females, it stimulates theca cells to produce androgens. FSH acts on Sertoli cells in males to support spermatogenesis and on granulosa cells in females to promote follicular develop- ment and estrogen production [ 63,64]. At the cellular level, reproductive dysfunction results from impaired gametogenesis, abnormal follicular devel- opment, disrupted embryo implantation, and compromised embryonic growth. For instance, Leydig cell dysfunction 4 can reduce testosterone production, which negatively af- fects sperm development and libido [ 65]. In females, dis- rupted follicular growth can impair ovulation and reduce endometrial receptivity, thereby decreasing the chances of successful implantation and pregnancy. 3.1 Epigenetic and Molecular Pathways in Male Reproductive Dysfunction Male reproductive dysfunction can result from ge- netic defects, hormonal imbalances, anatomical abnormal- ities, lifestyle factors, and environmental exposures [ 66]. Genetic conditions such as Klinefelter syndrome disrupt testicular function, whereas hormonal imbalances within the HPG axis impair gonadotropin production and release. Structural abnormalities, including varicocele and the con- genital absence of vas deferens, interfere with sperm pro- duction and transport. Lifestyle factors such as obesity, ex- cess alcohol consumption, smoking, and chronic stress sig- nificantly reduce fertility [ 67,68]. Furthermore, exposure to EDCs, such as phthalates and BPA, exacerbates repro- ductive dysfunction by disrupting hormonal signaling and increasing oxidative stress [ 69–71]. Spermatogenesis is a complex process involving the mitotic proliferation, meiotic division, and post-meiotic dif- ferentiation of germ cells [ 72]. Spermatogonial stem cells undergo mitosis to produce spermatocytes, which subse- quently undergo meiosis to generate haploid spermatids. These spermatids mature into spermatozoa through a pro- cess called spermiogenesis, which involves chromatin con- densation, acrosome and flagellum formation, and cyto- plasmic reduction. Oxidative stress caused by increased reactive oxygen species (ROS) production owing to en- vironmental toxins, smoking, and poor dietary habits can severely impair sperm quality [ 73,74]. ROS-induced dam- age, such as lipid peroxidation, mitochondrial dysfunction, and DNA fragmentation, reduces the sperm fertilization po- tential and embryo viability. Elevated oxidative stress in- creases sperm apoptosis and decreases sperm motility. Epigenetic regulation plays a key role in regulating gene expression during spermatogenesis. Aberrant DNA methylation, such as androgen receptor ( AR) gene hyper- methylation, disrupts testosterone signaling and sperm pro- duction [75]. Studies have demonstrated that AR promoter hypermethylation is linked to reduced AR expression in in- fertile males, which is correlated with low testosterone lev- els and poor sperm quality [ 76,77]. Histone modifications significantly affect chromatin structure and gene expres- sion. Abnormal histone methylation patterns, such as in- creased H3K9 methylation and decreased H3K4 methyla- tion, have been associated with male infertility by silencing genes critical for spermatogenesis [ 78]. Furthermore, re- duced histone H4 acetylation is associated with decreased sperm motility and poor semen quality [ 79]. Collectively, these findings highlight that epigenetic dysregulation is a key mechanism underlying male repro- ductive dysfunction and provides potential targets for diag- nostic biomarkers and therapeutic interventions. 3.2 Epigenetic and Molecular Pathways in Female Reproductive Dysfunction Female reproductive dysfunction encompasses vari- ous disorders affecting ovarian function, hormone produc- tion, and fertility. Clinical manifestations include infer- tility, ovulatory dysfunction, decreased ovarian reserve, menstrual irregularities, and gynecological disorders such as polycystic ovary syndrome (PCOS) and endometrio- sis. Female reproductive dysfunction arises from various causes, including genetic predisposition, hormonal imbal- ances, structural abnormalities of the reproductive tract, lifestyle factors, and environmental exposures [ 80,81]. Disruptions in the hypothalamic–pituitary–ovarian (HPO) axis due to genetic or hormonal factors can lead to irregular ovulation and impaired hormone production [ 82]. Structural abnormalities such as uterine fibroids and fal- lopian tube obstructions interfere with embryo implanta- tion and increase miscarriage risk. Lifestyle factors, includ- ing obesity, smoking, poor diet, and chronic stress, signif- icantly reduce ovarian reserve and increase infertility risk [68]. Furthermore, exposure to EDCs and environmen- tal toxins exacerbates reproductive dysfunction by inducing oxidative stress and causing hormonal dysregulation [ 83]. PCOS is characterized by hyperandrogenism, insulin resistance, and disrupted follicular development [ 84]. Ele- vated androgen levels suppress normal follicular develop- ment, whereas insulin resistance promotes excess andro- gen production by ovarian theca cells, further exacerbating anovulation and infertility. Endometriosis involves ectopic growth of endometrial tissue, leading to chronic inflamma- tion, pelvic pain, and reduced fertility [85]. Increased estro- gen production and elevated inflammatory cytokine levels in endometriosis contribute to adhesion formation, ovarian dysfunction, and implantation failure [ 86]. Oxidative stress caused by elevated ROS levels in the ovarian follicles and endometrial tissue significantly im- pairs oocyte quality, embryo viability, and endometrial re- ceptivity [87]. Elevated ROS levels also disrupt embryonic development, luteal phase function, and progesterone pro- duction, thereby reducing implantation success rates and in- creasing miscarriage risk. Epigenetic modifications, including DNA methyla- tion and histone modifications, play crucial roles in regulat- ing ovarian function and reproductive hormone signaling. The hypermethylation of specific genes, such as estrogen receptor alpha ( ESR1), has been linked to reduced ovarian responsiveness to gonadotropins [ 88]. Alterations in his- tone acetylation and methylation impair ovarian steroido- genesis and folliculogenesis. Additionally, miRNA, partic- ularly miR-200 and miR-21, expression is dysregulated in reproductive dysfunction, which negatively affects ovarian steroidogenesis, follicular maturation, and overall fertility. 5 Fig. 2. Mechanisms of reproductive dysfunction induced by endocrine-disrupting chemicals (EDCs). Gonadotropin-releasing hor- mone (GnRH), released by the hypothalamus, stimulates the anterior pituitary to secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In males, LH acts on Leydig cells to promote testosterone synthesis, while FSH supports spermatogenesis through Ser- toli cell regulation. In females, LH and FSH coordinate androgen synthesis in theca cells, follicular maturation, and estrogen production in granulosa cells. Reactive oxygen species (ROS), generated in response to EDCs, contribute to oxidative stress through mechanisms such as lipid peroxidation, mitochondrial dysfunction, and DNA fragmentation, ultimately exacerbating reproductive dysfunction. The upper left panel depicts the steroidogenic pathway in Leydig cells, while the upper right panel illustrates steroidogenesis in theca and granulosa cells. EDC exposure modulates the expression of key steroidogenic enzymes, impairing hormone biosynthesis. Blue and red arrows indicate upregulated and downregulated expression of enzymes involved in steroid hormone synthesis, respectively. DEHP , di(2-ethylhexyl) phthalate; MEHP , metabolite mono(2-ethylhexyl) phthalate; StAR, steroidogenic acute regulatory; CYP11A, choles- terol side-chain cleavage enzyme; HSD3B, hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1; DHT, dihy- drotestosterone; DBP , dibutyl phthalate; BBP , Benzyl butyl phthalate. For example, miR-21 overexpression impairs ovarian gran- ulosa cell function, whereas abnormal miR-200 levels have been associated with PCOS pathogenesis [ 89,90]. These findings emphasize the critical role of epige- netic dysregulation in female reproductive dysfunction and highlight potential diagnostic biomarkers and therapeutic targets for improving reproductive health. 4. Endocrine Disruptors and Reproductive Disorders Endocrine disruptors interfere with normal hormonal functions by mimicking, blocking, or altering hormone sig- naling pathways (Fig. 2) [ 91]. Both human epidemiolog- ical studies and animal research have consistently linked exposure to EDCs with impaired sperm production, com- promised ovarian function, abnormal gonadal develop- ment, and reproductive disorders such as endometriosis and PCOS [92–96]. Among the EDCs, BPA and phthalates have been extensively studied because of their widespread pres- ence and established reproductive toxicity. 4.1 Epigenetic Effects of Bisphenol A (BP A) on Reproductive Function Previous studies have examined the effects of en- docrine disruptors on reproductive health, with BPA be- ing one of the most extensively studied compounds. BPA significantly affects reproductive function through epige- netic mechanisms, as demonstrated by the consistent find- ings of numerous animal and human studies [14]. Exposure to BPA during the prenatal and neonatal periods markedly changes DNA methylation patterns, histone modifications, and miRNA expression, which play crucial roles in regulat- ing ovarian follicle development, steroidogenesis, and the reproductive cycle [11]. Among these epigenetic mechanisms, DNA methyla- tion is strongly associated with the effects of BPA on ovar- ian gene expression. Animal studies have revealed that BPA exposure hypermethylates the genes essential for ovar- ian steroidogenesis, such as ESR1, aromatase ( CYP19A1), and luteinizing hormone receptor ( LHR), thereby down- regulating their expression, which impairs ovarian func- tion and reduces reproductive capacity [ 15,16]. In addi- tion, BPA alters histone acetylation and methylation pat- 6 terns at the promoters of critical reproductive genes. For instance, in mouse models, BPA exposure decreased H3K9 acetylation and increased H3K27 trimethylation, modifica- tions that typically repress transcription and significantly disrupt the expression of genes necessary for normal ovar- ian development and function [ 17,18]. These histone al- terations are mediated by the BPA-induced dysregulation of chromatin-modifying enzymes. BPA reduces HA T ac- tivity and increases HDAC expression, leading to global histone hypoacetylation and the transcriptional repression of reproduction-related genes. Moreover, females with endometriosis exhibit distinct epigenetic profiles, includ- ing altered miRNA expression patterns linked to elevated serum and urinary BPA levels [ 97]. Epigenetic reprogram- ming is associated with increased disease severity and a high risk of recurrence. BPA disrupts reproductive health by altering miRNA expression. In animal models, exposure to BPA during crit- ical developmental periods has been associated with the altered expression of key miRNAs, including miR-146a, miR-21, and miR-200 family members, as well as ovar- ian cell proliferation, apoptosis, steroidogenesis, and in- flammatory signaling regulators [ 98–101]. For instance, miR-21 upregulation suppresses phosphatase and tensin homolog (PTEN), a negative regulator of the PI3K/AKT pathway, thereby promoting granulosa cell survival and potentially contributing to abnormal follicular persistence [102]. Likewise, miR-146a targets interleukin-1 receptor- associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6), which are key components of the NF- κB signaling pathway, and modifies the ovarian inflamma- tory environment [ 103]. The miR-200 family is involved in epithelial-to-mesenchymal transition (EMT) via zinc fin- ger E-box binding homeobox 1 (ZEB1) and ZEB2 regula- tion, and its dysregulation may impair follicular remodeling and oocyte maturation. These molecular changes directly contribute to impaired follicular development, accelerated ovarian aging, and diminished reproductive potential. Epidemiological studies in humans have corroborated molecular findings observed in animal models. Clinical studies have identified significant changes in DNA methy- lation patterns of genes related to steroidogenesis and hor- mone signaling in women with higher urinary BPA concen- trations, which correlate with reproductive disorders such as PCOS, endometriosis, and infertility [ 104]. For exam- ple, elevated BPA levels in females with PCOS have been associated with CYP19A1 and ESR1 hypermethylation, cor- relating with elevated androgen levels and insulin resis- tance [105]. Additionally, females with endometriosis dis- play distinct epigenetic profiles, including altered miRNA expression patterns linked to elevated serum and urinary BPA levels, which influence disease severity and recur- rence [106]. Beyond BPA, growing attention has been paid to its structural analogs and derivatives such as bisphe- nol S (BPS) and bisphenol F (BPF), which are commonly used as BPA substitutes in plastics and consumer products. Emerging evidence suggests that BPS and BPF may ex- ert endocrine-disrupting and epigenetic effects similar to or even more potent than those of BPA [ 107]. Studies have shown that BPS exposure alters the methylation of genes involved in steroidogenesis and increases oxidative stress in ovarian tissues [ 108,109]. BPF is associated with dis- rupted histone acetylation patterns and altered reproductive miRNA expression [110]. Although marketed as safe alter- natives, these compounds appear to share similar epigenetic interferences, raising concerns about their reproductive tox- icity and necessitating further investigation. These findings clearly indicate that the reproductive toxicity of BPA is driven primarily by its impact on the epigenetic landscape of reproductive tissues. BPA disrupts hormonal signaling and regulates genes critical for repro- ductive function by inducing changes in DNA methyla- tion, histone modifications, and non-coding RNA expres- sion. Taken together, these epigenetic alterations provide strong mechanistic evidence linking EDC exposure to re- productive dysfunction. 4.2 Phthalate-Induced Epigenetic Modifications in Reproductive Tissues Phthalates, commonly used as plasticizers in daily products, are increasingly linked to reproductive health through epigenetic mechanisms. Among the most common phthalates, diethylhexyl phthalate (DEHP) induces signifi- cant changes in DNA methylation and histone modification, thereby disrupting the transcriptional regulation of genes in- volved in steroidogenesis and spermatogenesis [ 4]. DEHP exposure leads to the epigenetic dysregula- tion of reproductive tissues. Animal studies have demon- strated that exposure to DEHP increases H3 acetylation at the promoters of reproductive genes, leading to abnor- mal activation [ 19]. Simultaneously, DEHP reduces DNA methylation at key steroidogenic genes, such as steroido- genic factor-1 ( SF-1) and CYP17A1, which are essential for testosterone biosynthesis [ 20,21]. Hypomethylation disrupts the hormonal balance required for proper testicu- lar function. Simultaneously, DEHP increases H3 acety- lation (H3K9ac) and H3K4 trimethylation (H3K4me3) at these gene loci, while decreasing repressive markers such as H3K9me2 and H3K27me3 [ 111–114]. These chro- matin changes are mediated by altered expression of epige- netic enzymes, including downregulation of DNMT3a and HDACs and upregulation of HA Ts and histone methyltrans- ferases (HMTs), such as mixed-lineage leukemia protein 1 (MLL1). This imbalance creates a transcriptionally ac- tive chromatin state, leading to aberrant expression of re- productive genes. This impairs hormone synthesis and re- duces testosterone production and sperm quality, which has been consistently observed in animal models [ 113]. Fur- thermore, these chromatin alterations appear to be long last- ing and may have transgenerational consequences [ 115]. 7 MEHP , a biologically active DEHP metabolite, ex- erts strong epigenetic effects. Studies using MA-10 mouse Leydig cells have shown that MEHP significantly disrupts the expression of key steroidogenic proteins, particularly STAR protein [ 22]. This effect is driven by both histone and DNA modifications in the star gene promoter, result- ing in transcriptional repression and impaired Leydig cell function. Furthermore, MEHP increases repressive his- tone markers such as H3K27 trimethylation (H3K27me3) and decreases activating markers such as H3K9 acetyla- tion (H3K9ac), thereby promoting a condensed chromatin structure [114,116]. It also downregulates coactivator pro- teins, such as CBP/p300, and reduces the activity of ten- eleven translocation methylcytosine dioxygenase (TET) en- zymes, contributing to stable gene silencing. These epige- netic changes are not limited to star and other steroidogenic genes, including Cyp11a1 and Hsd3b1, indicating broad suppression of the steroid biosynthesis cascade. Impor- tantly, the epigenetic effects of MEHP persist even after exposure ends, raising concerns about long-term and po- tentially heritable reproductive dysfunction [ 117]. Phthalate-induced epigenetic disruption has been shown to negatively affect female reproductive health. An- imal studies have shown that exposure to DEHP and MEHP

in marked alterations in histone acetylation and methylation in the promoters of key ovarian steroidogenic genes, such as CYP19A1 and ESR1. These changes im- pair follicular development and disrupt the ovulatory cycle [118,119]. Moreover, MEHP exposure in endometrial cell cultures increases the secretion of inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF- α), suggest- ing that epigenetic regulation contributes to inflammatory reproductive conditions such as endometriosis [ 120]. Human clinical studies have supported these findings in animal models. Research has consistently linked ele- vated urinary levels of phthalate metabolites to menstrual ir- regularities, reduced ovarian reserve, premature ovarian ag- ing, a high risk of preterm birth, and other adverse reproduc- tive outcomes [ 121,122]. These clinical findings provide molecular evidence that phthalates interfere with reproduc- tive function through epigenetic dysregulation, underscor- ing their relevance as a public health concern. Taken to- gether, phthalate-induced epigenetic modifications disrupt the hormonal balance and transcriptional regulation in re- productive tissues, providing a mechanistic explanation for their roles in both male and female reproductive dysfunc- tions. 4.3 Epigenetic Mechanisms of Pesticide-Associated Reproductive Disfunction Pesticides, including DDT and chlorpyrifos, are po- tent endocrine disruptors, with growing evidence that their reproductive toxicity is largely mediated through epige- netic mechanisms [ 123]. Epidemiological and experimen- tal studies have consistently shown that pesticide exposure negatively affects reproductive health in both males and females by altering DNA methylation, modifying histone structure, and disrupting ncRNA expression [ 23,124,125]. The epigenetic effects of prenatal and develop- mental exposure to DDT and its persistent metabolite dichlorodiphenyldichloroethylene (DDE) have been exten- sively studied. Research shows that DDT exposure can lead to abnormal DNA methylation of genes critical for re- productive development and hormone regulation [ 23–25]. For example, both DDT and DDE have been associated with hypomethylation at the promoter regions of estrogen- responsive genes such as ESR1, which disrupts estrogen signaling pathways essential for reproductive organ forma- tion and fertility. Furthermore, transgenerational studies have found that maternal exposure to DDT alters the methy- lation patterns of key reproductive genes, including insulin- like growth factor 2 ( IGF2), which persists across multiple generations [24,26]. These epigenetic changes reduce fer- tility, delay sexual maturation, and increase the incidence of undescended testes in male offspring. Similarly, chlorpyrifos, a widely used organophos- phate pesticide, exerts reproductive toxicity through com- prehensive epigenetic modifications. Exposure to chlor- pyrifos alter miRNA expression profiles, which may dis- rupt critical reproductive signaling pathways. For example, studies on zebrafish embryos have shown that organophos- phate compounds can upregulate the expression of miR- 137 and miR-141, resulting in developmental abnormalities [126]. Although direct evidence of chlorpyrifos-induced miRNA alterations in mammalian reproductive tissues re- mains limited, the neurotoxic and reproductive effects con- sistently observed in animal models suggest that miRNA dysregulation may play a central role in chlorpyrifos toxi- city. Recent animal studies have demonstrated that chlor- pyrifos exposure leads to abnormal DNA methylation pat- terns in genes regulating the HPG axis, such as GnRH1, ESR1, and AR [127]. In particular, GnRH1 promoter hy- pomethylation is associated with early onset of puberty and disrupted reproductive hormone signaling [ 128]. In addi- tion, chlorpyrifos alters histone modification states in re- productive tissues. In animal models, decreased histone H3K9 acetylation (H3K9ac) and H4 acetylation (H4ac) have been observed, leading to the transcriptional repres- sion of genes involved in steroidogenesis and gametogen- esis [ 129]. These chromatin changes appear to be medi- ated by the dysregulation of epigenetic enzymes such as DNMT1 and HDAC1, which are downregulated following chlorpyrifos exposure. The resulting imbalance in the chro- matin remodeling machinery may contribute to the long- term suppression of reproductive gene expression, with po- tential long-term consequences for fertility. The findings of clinical studies align closely with an- imal study findings, further strengthening the link between pesticide exposure and epigenetic changes in reproductive tissues [16]. Epidemiological studies have reported abnor- 8 mal DNA methylation patterns at key loci, such as ESR1 and AR genes, in individuals with past pesticide exposure [130]. For instance, ESR1 promoter hypomethylation dys- regulates estrogen signaling, which may impair endome- trial receptivity and ovulation. Likewise, AR hypermethy- lation can weaken androgen signaling, contributing to re- duced spermatogenesis and impaired Leydig cell function in males [ 131,132]. These epigenetic modifications corre- late with a range of reproductive issues, including reduced sperm concentration and motility, disrupted menstrual cy- cles, anovulation, and increased incidence of infertility and miscarriage. Moreover, these methylation changes may persist even after the end of exposure, indicating potential long-term or transgenerational effects. In occupational co- horts, a high pesticide burden has also been linked to altered methylation of imprinted genes such as IGF2 and H19, which play critical roles in embryonic growth and placen- tal development, suggesting possible implications on preg- nancy outcomes and offspring health [ 133,134]. Taken to- gether, these findings support a mechanistic model in which pesticide-induced epigenetic modifications, such as DNA hypomethylation, histone alterations, and miRNA dysreg- ulation, directly contribute to endocrine disruption and im- paired reproductive capacity. 4.4 Heavy Metal Ions as Epigenetic Modifiers of Fertility Divalent heavy metal ions such as Pb 2+ and Cd 2+ are widely recognized as potent endocrine disruptors due to their environmental persistence and strong reproductive toxicity [5–7]. It is the ionic forms, rather than the elemen- tal metals or their poorly soluble salts, that are primarily responsible for these toxic effects. Although they are not classified as toxins in the classical toxicological sense, these heavy metal ions function as environmental contaminants that exert harmful biological effects through multiple path- ways, including oxidative stress, hormonal disruption, and epigenetic alterations. Extensive research has consistently demonstrated the harmful effects of heavy metal exposure on male and female reproductive health [ 135]. In males, exposure to Pb 2+ and Cd 2+ has been strongly associated with impaired spermatogenesis, char- acterized by reduced sperm count, poor sperm motility, and abnormal sperm morphology [ 136,137]. These disruptions are primarily attributed to damage to the seminiferous ep- ithelium and dysfunction of the blood–testis barrier, as ob- served in rodent models. In particular, Cd 2+ induces necro- sis of Sertoli and germ cells, whereas Pb 2+ tends to affect Leydig cells and the HPG axis. Animal studies have shown that exposure to these heavy metal ions impairs testicular function by downregulating the expression of key enzymes such as STAR, CYP11A1, and 17β-hydroxysteroid dehydro- genase (HSD17B3) [7,138,139]. It is also important to note that lead can exist in multiple oxidation states. Although Pb2+ is the biologically active and more stable form, lead can also form compounds in the +4 oxidation state. These Pb(IV) species are strong oxidants and are typically reduced to Pb 2+ in biological systems [ 140]. This chemical com- plexity demonstrates the importance of clearly identifying the ionic species when evaluating the toxicity of lead com- pounds. Clinical studies support these findings, showing that elevated blood levels of Pb2+ and Cd2+ are associated with reduced testosterone production, increased oxidative stress, and compromised sperm DNA integrity in exposed indi- viduals [ 141]. Additionally, these metals increase testicu- lar oxidative stress by elevating ROS and depleting antiox- idant enzymes, such as superoxide dismutase (SOD) and glutathione peroxidase (GPx), resulting in lipid peroxida- tion and mitochondrial dysfunction in germ cells. Such ox- idative damage contributes to DNA fragmentation in sperm, chromatin condensation defects, and reduced fertilization potential. In females, heavy metal ions exposure is strongly associated with ovarian dysfunction, disrupted follicular development, and diminished reproductive capacity [ 142, 143]. Cd 2+ accumulates in ovarian tissue owing to its long biological half-life and ability to mimic essential divalent cations, such as Ca and Zn, thereby interfering with cel- lular signaling and enzyme activity. Experimental studies have shown that Cd 2+ disrupts ovarian steroidogenesis by downregulating the expression and activity of key enzymes involved in estrogen and progesterone synthesis, including cytochrome P450 side-chain cleavage enzyme ( CYP11A1), aromatase (CYP19A1), and 3 β-hydroxysteroid dehydroge- nase ( HSD3B1). These molecular changes decrease the levels of circulating estradiol and progesterone, disrupt- ing the HPO axis and impairing ovulation. Cd 2+ also in- duces oxidative stress within ovarian follicles by increas- ing ROS, which damages granulosa cells and oocytes and promotes apoptosis and atresia. Epidemiological studies have demonstrated that elevated Cd2+ levels are associated with menstrual irregularities, reduced ovarian reserve, in- creased infertility rates, and poor pregnancy outcomes such as preterm birth and reduced fetal growth [ 144]. Further- more, a high Cd 2+ burden reduces fertility outcomes, par- ticularly in women undergoing assisted reproductive tech- nology (ART), in whom lower oocyte quality and fertiliza- tion rates have been observed. During pregnancy, Cd 2+ can cross the placental barrier, contributing to impaired pla- cental development and adverse outcomes, such as preterm birth, low birth weight, and intrauterine growth restriction. At the molecular level, heavy metals contribute to re- productive toxicity, primarily through epigenetic dysregu- lation. Pb 2+, Cd 2+, and soluble ionic forms of mercury (such as HgCl 2) and nickel (such as NiSO 4 or NiCl2) alter DNA methylation and histone modification profiles, par- ticularly at promoters of genes essential for hormonal sig- naling, gametogenesis, and oxidative defense. In contrast, arsenic trioxide (As2O3) does not dissociate in solution but acts as a precursor to toxic trivalent arsenic compounds and 9 organoarsenicals, and should be evaluated separately in tox- icological contexts. DNA methylation changes are among the most widely documented epigenetic effects of heavy metal exposure. Pb 2+ and Cd2+ induce global hypomethy- lation, compromising genomic stability, while simultane- ously promoting hypermethylation at specific CpG-rich promoters. For example, aberrant methylation of follicle- stimulating hormone receptor (FSHR), LHR, ESR1, and AR has been reported in animal models and human tissues, leading to decreased hormonal sensitivity and disrupted re- productive function [27,28]. Simultaneously, heavy metal exposure disrupts his- tone modifications, further contributing to epigenetic dys- regulation. Cd 2+, for example, has been associated with reduced H3K9 acetylation and increased H3K27 trimethy- lation at the promoter regions of steroidogenic genes such as CYP11A1, STAR, and HSD17B3, as well as antioxidant genes such as GPX4 and SOD2 [29]. These changes pro- mote chromatin condensation and transcriptional repres- sion, ultimately impairing the expression of genes criti- cal for reproductive functions. Beyond Cd 2+ and Pb 2+, other heavy metals also exhibit distinct epigenetic signa- tures in reproductive tissues. For instance, As causes global hypomethylation and gene-specific hypermethylation (e.g., p16, p53), along with inhibition of HA T activity, disrupt- ing oocyte maturation and endometrial receptivity [ 145]. Hg, particularly methylmercury (MeHg), decreases DNMT expression and alters histone marks (such as H3K9me2 and H4K20me3), impairing spermatogenesis and inducing germ cell apoptosis [ 146]. Ni 2+, typically as NiSO or NiCl2, also exerts notable epigenetic effects. Ni exposure induces global DNA hypomethylation and gene-specific hypermethylation at loci involved in gonadal development and hormone synthesis [ 147]. It enhances repressive his- tone marks such as H3K9me2 and H3K27me3 via the up- regulation of methyltransferases such as G9a and EZH2, leading to chromatin condensation and transcriptional si- lencing. These effects are associated with disrupted sper- matogenesis and follicular viability in experimental models [148,149]. These findings suggest that heavy metal ion-induced reproductive toxicity is driven by epigenetic dysregulation. A deep understanding of these molecular alterations could provide essential insights into the mechanisms of heavy- metal-induced reproductive dysfunction and guide the de- velopment of targeted prevention and treatment strategies. Collectively, these epigenetic alterations illustrate how heavy metals act as endocrine disruptors by reprogram- ming the epigenome of the reproductive tissues. Heavy metal ions contribute to long-term reproductive dysfunction and transgenerational health effects through mechanisms involving aberrant DNA methylation, histone modification, and oxidative stress-linked epigenetic remodeling. 5. Conclusion EDCs pose a significant threat to reproductive health by interfering with hormonal regulation and inducing sta- ble epigenetic changes that alter gene expression profiles critical for gametogenesis, steroidogenesis, and follicular development. This review highlights the multifaceted epi- genetic mechanisms, including DNA methylation, histone modifications, and ncRNA regulation, through which var- ious EDCs such as BPA, phthalates, pesticides, and heavy metal ions impair reproductive functions in both sexes. Accumulating evidence indicates that these epigenetic alterations are not only persistent but may also exert trans- generational effects, raising public health concerns regard- ing long-term reproductive consequences. However, gaps remain in our understanding of compound-specific epige- netic signatures, dose–response relationships, sex-specific effects, and reversibility of these modifications. Future studies should prioritize the identification of epigenetic biomarkers for the early detection of EDC expo- sure and susceptibility as well as development of targeted epigenetic therapies. Additionally, integrative approaches combining epigenomics, transcriptomics, and single-cell analysis are essential for elucidating the tissue- and cell- type-specific effects of EDCs. A deep understanding of these mechanisms will guide risk assessment, public poli- cies, and therapeutic intervention strategies for mitigating EDC-induced reproductive dysfunction. Author Contributions DHK and MHP conceived and designed the study. SH and HBK conducted the literature search, analyzed the data, and prepared the figure visualizations. SH, HBK, and MHP wrote the manuscript. DHK and MHP reviewed and edited the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work. Ethics Approval and Consent to Participate Not applicable. Acknowledgment Not applicable. Funding This research was supported by the Regional Innova- tion System & Education (RISE) program through the In- stitute for Regional Innovation System & Education in Bu- san Metropolitan City, funded by the Ministry of Education (MOE) and the Busan Metropolitan City, Republic of Ko- rea (2025-RISE-02-005-000). 10 Conflict of Interest The authors declare no conflict of interest. Declaration of AI and AI-Assisted Technologies in the Writing Process During the preparation of this work, the authors used ChatGPT to check spell and grammar. After using this tool, the authors reviewed and edited the content as needed and takes full responsibility for the content of the publication.

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