Endocrine disruptors and male reproductive health: mechanisms, epigenetics, and clinical perspectives
Disruptores endocrinos y salud reproductiva masculina: mecanismos, epigenética y perspectivas clínicas

2.4.1 Prevalence of male reproductive disorders associated with endocrine disruptors

Animal studies consistently demonstrate that EDCs disrupt multiple domains of male reproductive function. While these findings derive predominantly from experimental paradigms, human epidemiological data provide direct translational support. For example, diethylstilbestrol exposure impairs erectile tissue contractility in mice, mirroring erectile dysfunction (ED) [34]. Consistently, a U.S. cohort of 555 men reported a 33% increased risk of ED among individuals with the highest urinary levels of organophosphate metabolites [35]. Given that ED may contribute to up to 5% of male infertility cases, this association holds clinical significance [40]. Meta-analyses confirm that prenatal and postnatal EDC exposures elevate risks for male reproductive anomalies, including testicular germ cell tumors, cryptorchidism, and hypospadias [41]. The concept of testicular dysgenesis syndrome (TDS), proposed by Skakkebæk et al. [42], integrates these conditions as potentially linked developmental disorders with environmental origins, while BPA has been associated with increased cryptorchidism risk through disruption of androgen signaling during fetal development [43, 44]. Additionally, bisphenols and alkylphenols have been associated with reduced anogenital distance and structural testicular alterations [45, 46], indicating that EDCs affect male reproductive health across the lifespan.

2.4.2 Global trends in male infertility and its association with endocrine disruptors

Male infertility affects over 30 million men globally and contributes to approximately 50% of all couple-level infertility [47, 48, 49, 50]. Though multifactorial in origin, environmental exposures are emerging as central contributors. A 52% decline in sperm concentration has been documented between 1973 and 2011 among men in Western countries [51], a trend unlikely to be explained by genetics alone.

This decline correlates with increased exposure to phthalate metabolites, such as Mono(2-carboxymethylhexyl) phthalate (MCMHP), Mono(2-ethylhexyl) phthalate (MEHHP), Monobenzyl phthalate (MBzP), and Monoisononyl phthalate (MNP), which exhibit dose-dependent associations with reduced sperm concentration, total sperm count, motility and morphological integrity, including enlarged sperm head size [52]. These consistent temporal and geographic trends highlight EDCs as modifiable environmental risk factors in the ongoing deterioration of male reproductive capacity.

2.6.1 Interference with hormonal receptors and disruption of intracellular signaling

EDCs act through multiple converging mechanisms, primarily by binding to nuclear hormone receptors or interfering with intracellular signaling pathways. Bisphenols A, F and S (BPA, BPF, BPS) mimic 17β-estradiol, functioning as ER agonists, while concurrently antagonizing AR signaling. These dual effects alter gene transcription, reduce luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion, and inhibit the steroidogenic acute regulatory protein (StAR), leading to deficient testosterone synthesis in Leydig cells (Fig. 3) [64].

Fig. 3.Action of endocrine disruptors on nuclear and membrane receptors. (A) Bisphenol A. (B) Phthalates. (C) Pesticides. ER: Estrogen receptor; GPER: G Protein-Coupled Estrogen Receptor; DDT: dichlorodiphenyltrichloroethane; DBCP: dibromochloropropane.

Phthalates, such as DEHP and Diisononyl Phthalate (DiNP), inhibit AR expression and impair aromatase activity, further compromising the androgen-to-estrogen balance critical for spermatogenesis. These compounds also disrupt Sertoli cell architecture and Leydig cell differentiation, as evidenced by malformed seminiferous tubules and Leydig cell vacuolization in animal studies. Correlational human data consistently demonstrate reduced sperm quality in men with elevated urinary phthalate metabolites (Fig. 3) [64].

Pesticides, including chlorpyrifos and dioxins, impair testicular function by suppressing the Cyclic Adenosine Monophosphate (cAMP)/Protein Kinase A (PKA) signaling cascade in Leydig cells. This results in downregulation of steroidogenic enzymes—StAR, CYP11A1, and Hydroxy-Delta-5-Steroid Dehydrogenase, 3 Beta- and Steroid Delta-Isomerase 1 (HSD3B1)—thereby limiting testosterone production [61, 66, 67, 68, 69]. Moreover, inhibition of LH-mediated Luteinizing Hormone/Choriogonadotropin Receptor (LHCGR) activation compromises both steroidogenesis and cellular differentiation, exacerbating male reproductive dysfunction (Fig. 3).

2.6.2 Oxidative stress, sperm DNA damage, and apoptosis

EDCs, such as BPA, phthalates, and certain pesticides, compromise male fertility through the induction of oxidative stress and apoptosis. These compounds increase the generation of ROS while impairing the activity of antioxidant enzymes like superoxide dismutase (SOD) and glutathione peroxidase (GPx), leading to lipid peroxidation and damage to the sperm plasma membrane [70, 71, 72]. BPA further amplifies oxidative stress via activation of the Toll-Like Receptor 4 (TLR4)/Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, which increases pro-inflammatory cytokines, notably Tumor Necrosis Factor alpha (TNF-α), aggravating cellular dysfunction [70, 71, 72].

Experimental models demonstrate that chlorpyrifos, a common organophosphate pesticide, induces DNA fragmentation and mitochondrial dysfunction in rat testes through ROS-mediated mechanisms and endoplasmic reticulum (ER) stress—evidenced by upregulation of C/EBP Homologous Protein (CHOP) and caspase-3. Similarly, BPA initiates germ cell apoptosis through caspase-9 activation, driven by ER stress markers, such as Glucose-Regulated Protein 78 (GRP78) and Protein Kinase RNA-like Endoplasmic Reticulum Kinase (PERK), and enhanced lipid peroxidation [70, 71, 72]. Other EDCs, including dioxins and Per- and Polyfluoroalkyl Substances (PFAS), exacerbate these processes by suppressing anti-apoptotic Bcl-2 and compromising the blood-testis barrier, facilitating toxicant penetration and amplifying spermatogenic damage. These disruptions culminate in mitochondrial failure, DNA damage, and decreased sperm viability and motility—hallmarks of compromised male reproductive potential (Fig. 4) [66, 67, 68, 73].

Fig. 4.Oxidative stress, sperm DNA damage, and apoptosis. (A) Generation of reactive oxygen species (ROS). (B) DNA fragmentation and mitochondrial damage. SOD: Superoxide Dismutase; GPx: Glutathione Peroxidase; PM: Plasma Membrane; GRP78: Glucose-Regulated Protein 78; PERK: Protein Kinase RNA-like Endoplasmic Reticulum Kinase; Bcl-2: B-cell Lymphoma 2; PFAS: Per- and Polyfluoroalkyl Substances.

2.6.3 Epigenetic changes and transgenerational effects

EDCs also exert long-lasting effects through epigenetic modifications in the male germline, thereby propagating reproductive dysfunction across generations. The concept that environmental exposures can reprogram the epigenome of gametes and embryos, ultimately shaping reproductive capacity across the life course and even across generations, is supported by a substantial body of foundational literature [74, 75, 76, 77].

Animal studies reveal that BPA and phthalates induce hypermethylation of critical genes involved in testicular development and endocrine regulation, such as Estrogen Receptor 1 (Esr1) and H19, while dioxins promote hypomethylation of androgen-regulating gene promoters [78, 79, 80]. These DNA methylation aberrations can persist across F2 and F3 generations, as demonstrated in vinclozolin exposure models, which lead to sustained downregulation of spermatogenesis-related genes [76].

In addition to DNA methylation, BPA and glyphosate have been shown to alter histone acetylation patterns—particularly decreasing acetylation of histones H3 and H4—resulting in chromatin condensation defects that impair spermatogenesis [78, 79]. Oxidative stress has emerged as a key mediator linking environmental exposures to epigenetic instability in germ cells, with ROS-induced DNA damage directly impairing global sperm DNA methylation [81, 82].

Furthermore, organophosphates and phthalates disrupt the expression of sperm-specific microRNAs, including miR-34c and miR-202, which are essential for germ cell differentiation and maturation (Fig. 5) [78, 79, 80, 83]. Early-life and in utero exposures appear particularly critical, as demonstrated by studies showing that maternal exposure to BPA induces persistent DNA hypomethylation in offspring, an effect that can be partially mitigated by maternal methyl-donor supplementation [84, 85].

Fig. 5.Epigenetic changes and transgenerational effects. (A) Alterations in DNA methylation. (B) Modifications in histones and microRNAs. (C) Hereditary effects. DNA: Deoxyribonucleic acid; miR: Micro ribonucleic acid; Esr1: Estrogen Receptor 1.

While experimental studies provide compelling evidence for epigenetic inheritance following EDC exposure, several limitations must be acknowledged. Most transgenerational data derive from animal models using controlled exposure paradigms that may not fully recapitulate the complexity of human exposure scenarios, including mixed chemical exposures, variable timing, and interindividual susceptibility [75]. Moreover, the causal linkage between specific epigenetic marks and clinically manifest infertility phenotypes in humans remains incompletely established. Consequently, current evidence supports strong biological plausibility, rather than definitive causality, underscoring the need for longitudinal human studies integrating epigenomic profiling with reproductive outcomes.

It is critical to differentiate between intergenerational and true transgenerational epigenetic inheritance. Exposure of a pregnant female involves direct contact with the F1 fetus and the F2 germ cells; thus, phenotypic changes in these generations are considered intergenerational. In contrast, true transgenerational inheritance is defined by the persistence of epigenetic marks in the F3 generation and beyond, which were never directly exposed. While vinclozolin and BPA models provide compelling evidence in rodents, the current evidence in humans supports strong biological plausibility, rather than definitive clinical causality [74, 75, 76].

2.6.4 Adverse outcome pathways and male infertility

Adverse Outcome Pathways (AOPs) describe the progression from molecular disruptions induced by EDCs to adverse reproductive outcomes. In experimental models, BPA interacts with estrogen receptors and antagonizes androgen receptors, altering steroidogenic enzyme expression, increasing oxidative stress, and promoting germ cell apoptosis, processes that may contribute to impaired sperm quality [64, 77, 78, 79, 80]. Phthalates such as DEHP and DBP have been associated with disruption of androgen signaling, reduced testosterone biosynthesis, and altered spermatogenesis, while other EDCs, including dioxins, pesticides, and heavy metals such as cadmium, arsenic, and lead, are linked to pathways involving mitochondrial dysfunction, epigenetic alterations, and blood-testis barrier disruption. These mechanisms support the application of AOP frameworks in integrating toxicological evidence, although their translation to human reproductive outcomes remains heterogeneous [52, 81, 82, 83] (Table 1, Ref. [3, 65, 70, 72, 78, 79, 80]).

2.6.5 Dose relevance, non-monotonicity, and translational limitations

A critical challenge in interpreting the reproductive toxicity of EDCs lies in the discrepancy between experimental exposure levels and real-world human conditions. Many in vitro and in vivo studies employ concentrations that exceed those detected in biomonitoring studies, limiting direct toxicological extrapolation. At the same time, EDCs exhibit non-monotonic dose-response relationships, whereby low doses within environmentally relevant ranges may induce biological effects not predicted by traditional high-dose paradigms. For instance, BPA and certain phthalates exert endocrine and epigenetic effects at nanomolar to micromolar concentrations overlapping with levels reported in human serum and urine [17, 53, 54]. Population data indicate urinary BPA concentrations of 1–10 ng/mL and DEHP metabolites such as MEHP in the range of 20–200 ng/mL [17, 57, 58, 59, 60], levels that have been associated with altered sperm parameters and molecular changes, suggesting potential biological relevance under typical exposure conditions [52, 84, 85, 86].

However, not all mechanisms identified in experimental systems are necessarily operative in humans. High-dose models may overrepresent pathways such as severe oxidative stress, apoptosis, or mitochondrial dysfunction, which may not fully reflect responses at lower exposure levels. In parallel, epidemiological evidence remains heterogeneous, with some studies reporting associations between EDC exposure and impaired semen quality, while others show inconsistent findings. A recent systematic review and meta-analysis reported no uniform association between EDC exposure and male fertility outcomes [86]. This variability is largely explained by methodological limitations, including exposure misclassification, reliance on single time-point measurements, and incomplete adjustment for confounders such as diet, lifestyle, and co-exposure to other endocrine-active compounds, including dietary phytoestrogens [68, 86].

The interpretation of EDC-related reproductive risk is further complicated by real-world exposure scenarios. Individuals are exposed to complex chemical mixtures with potential additive or interactive effects, which are not adequately captured by conventional toxicological or epidemiological approaches. In addition, male infertility is a multifactorial condition influenced by environmental, behavioral, and biological factors, including obesity, smoking, alcohol use, heat exposure, psychosocial stress, dietary patterns, and genetic susceptibility. These overlapping influences limit causal inference and may contribute to inconsistencies across studies. Consequently, although mechanistic evidence supports the biological plausibility of EDC-induced reproductive toxicity, translation to human outcomes remains variable, underscoring the need for integrative approaches incorporating longitudinal biomonitoring, human-relevant exposure models, and mixture-based risk assessment frameworks [8, 26].

2.6.6 Multifactorial nature of male infertility and confounding factors

Importantly, male infertility is a multifactorial condition influenced by a wide range of environmental, lifestyle, and biological factors. Variables such as obesity, smoking, alcohol consumption, heat exposure, psychosocial stress, dietary patterns, and genetic susceptibility have been independently associated with impaired semen quality and reproductive outcomes [63, 65, 67]. In addition, occupational and environmental exposures unrelated to endocrine-disrupting chemicals may further contribute to reproductive dysfunction [16, 63]. Disentangling the relative contribution of EDC exposure from these factors remains a major challenge in human studies and may partially explain the inconsistency observed across epidemiological findings. Moreover, interactions between these variables and EDC exposure may result in additive or synergistic effects, further complicating causal inference and risk attribution in real-world scenarios [67, 68].

2.7.1 Broader public health risks of EDC exposure

Beyond infertility, EDC exposure is increasingly associated with systemic endocrine disruption affecting thyroid function, metabolism, and oncogenesis. BPA and phthalates exhibit dose-dependent thyroid-disrupting activity, altering circulating levels of T3 and T4, and perturbing thyroxine-binding globulin levels [87]. These hormonal imbalances may affect male reproductive function both directly and indirectly.

Moreover, exposure to EDCs such as Perfluorooctane Sulfonate (PFOS) and phthalates contributes to testicular carcinogenesis through oxidative DNA damage. Mechanistically, ROS-induced genomic instability leads to mutations during germ cell proliferation, predisposing to tumor development [88]. These findings highlight the multifaceted threat of EDCs to endocrine homeostasis and underscore the urgency of addressing their broader health impacts.

2.7.2 Regulatory challenges and the role of public policy

Although regulations such as the European Union’s Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) framework have designated several EDCs—e.g., DEHP, DBP—as Substances of Very High Concern (SVHC), critical gaps persist in global chemical governance. Current risk assessments often fail to account for low-dose and non-monotonic dose-response effects characteristic of EDCs. For example, DEHP causes testicular toxicity in rats at doses as low as 3.7 mg/kg/day, well below established safety thresholds [89, 90, 91].

Regulatory disparities between countries perpetuate exposure risks, especially in regions lacking harmonized standards. Bisphenol A Fluorinated (BPAF), a persistent BPA analog, remains widely used in certain markets, despite its long half-life and proven bioaccumulation [83]. The lack of comprehensive global policies creates a disconnect between scientific evidence and regulatory action, enabling continued use of hazardous EDCs. This reinforces the need for precautionary regulation that prioritizes public health even in the face of incomplete mechanistic data [89, 90, 91].

2.8.1 Exposure reduction strategies

Reducing EDC exposure requires comprehensive strategies encompassing personal behavior, environmental interventions, and public education. At the individual level, substituting plastic food containers with glass or stainless steel and avoiding canned and processed foods significantly lowers BPA and phthalate intake. Households can reduce indoor contamination through ventilation, regular wet cleaning, and limiting the use of phthalate-containing products and materials [92, 93]. Agricultural mitigation strategies, including improved pesticide management and sustainable agricultural practices, may reduce environmental contamination and pesticide-associated reproductive risks while supporting agricultural productivity [94]. At the population level, eliminating BPA and phthalates from medical equipment and food packaging has proven effective. Educational campaigns to raise awareness and drive behavior change are essential components of exposure reduction [95, 96].

2.8.2 Regulatory and policy-based interventions

Several countries have implemented regulatory measures to reduce EDC exposure, particularly in vulnerable populations. In North America, the U.S. banned the use of DEHP, BBzP, and DBP in children’s products, while Canada eliminated BPA from baby bottles [97, 98]. The EU enforces a 0.1% weight limit for these compounds in childcare products through its REACH regulation [99].

Despite these advances, regulatory fragmentation remains a key obstacle. Differences in pesticide maximum contaminant levels (MCLs) for drinking water reflect unresolved debates about dose thresholds and health risks [99]. Moreover, many EDCs in food contact materials and cosmetics remain unregulated. To close these gaps, a coordinated global approach based on biomonitoring data, precautionary risk assessment, and consistent regulatory frameworks is imperative for effective EDC exposure control [98, 99].

2.9.1 Environmental exposure history

Routine andrological evaluation of infertile men should incorporate a structured environmental and occupational exposure history. Clinicians should inquire about: (i) occupational contact with pesticides, solvents, plastics, or industrial chemicals; (ii) dietary habits, including frequency of canned or packaged food consumption and use of plastic containers for food storage or heating; and (iii) habitual use of personal care products containing phthalates, parabens, or synthetic fragrances. This exposure assessment is particularly relevant in cases of idiopathic infertility or unexplained poor semen parameters, where EDC-related mechanisms may constitute an underrecognized etiology [67].

2.9.2 Biomonitoring in clinical practice

Where available, urinary biomonitoring of key EDC metabolites including BPA, MEHP and related phthalate metabolites, and urinary or blood levels of heavy metals (cadmium, lead, arsenic) should be considered in men presenting with unexplained oligozoospermia, asthenozoospermia, or elevated sperm DNA fragmentation. Although biomonitoring is not yet standard of care in most clinical settings, emerging evidence supports its utility in stratifying EDC-related reproductive risk and guiding targeted counseling [57, 58, 59, 60].

2.9.3 Preventive counseling and exposure reduction

Reducing EDC exposure requires comprehensive strategies encompassing personal behavior, environmental interventions, and public education. At the individual level, substituting plastic food containers with glass or stainless steel and avoiding canned and processed foods may reduce BPA and phthalate exposure. Households can reduce indoor contamination through ventilation, regular wet cleaning, and minimizing the use of phthalate-containing products and materials [93]. Lifestyle and behavioral interventions aimed at reducing contact with endocrine-disrupting compounds have shown potential to decrease overall exposure levels [96]. Agricultural mitigation strategies, including the adoption of Good Agricultural Practices (GAPs), may help reduce pesticide residues [95]. Educational campaigns and policy-based interventions are essential components of exposure reduction strategies [96, 97].

2.9.4 Periconceptional counseling

Given the vulnerability of prenatal and perinatal exposure windows and their potential long-term impact on male reproductive capacity, preventive counseling should be initiated prior to conception and extended to both partners. Male patients planning fatherhood should be informed of the potential effects of preconceptional EDC exposure on sperm epigenetic integrity and early embryonic development. These recommendations are consistent with current guidance in reproductive medicine and support the integration of environmental health considerations into routine andrological care [31, 67, 84].