Endocrine disruptors and male reproductive health: mechanisms, epigenetics, and clinical perspectives

Disruptores endocrinos y salud reproductiva masculina: mecanismos, epigenética y perspectivas clínicas

Male infertility, a pressing public health issue, is increasingly linked to exposure to endocrine-disrupting chemicals (EDCs), such as phthalates, bisphenol A (BPA), organochlorines, pesticides, as well as natural EDCs such as phytoestrogens. This review synthesizes mechanistic and translational evidence on how EDCs impair male reproductive function through multifaceted pathways. EDCs disrupt the hypothalamic-pituitary-gonadal (HPG) axis, induce cytotoxic effects in Leydig and Sertoli cells, and impair steroidogenesis and spermatogenesis, leading to clinically significant reductions in sperm concentration, motility, and morphology. Emerging data highlight transgenerational effects via epigenetic modifications, including altered DNA methylation and microRNA expression, which may perpetuate infertility across generations. We critically evaluate epidemiological and experimental studies, revealing consistent associations between EDC exposure and adverse reproductive outcomes, such as cryptorchidism, testicular cancer, and idiopathic infertility. Notably, prenatal and perinatal exposure windows exhibit heightened vulnerability, with lifelong consequences. Despite progress, key gaps persist in understanding low-dose mixture effects, interindividual susceptibility, and the interplay between EDCs and lifestyle factors (e.g., oxidative stress, psychosocial stressors). Clinically, this review underscores the need for enhanced biomonitoring to quantify real-world EDC exposures and their interactions, mechanistic research elucidating dose-response relationships and non-monotonic effects, and evidence-based policies to regulate EDCs in consumer products, agriculture, and healthcare. We propose a translational framework integrating high-throughput toxicology, epigenetic biomarkers, and clinical interventions to mitigate risks. Addressing these challenges is urgent to safeguard male reproductive health amid rising global infertility rates. Future research should also explicitly consider the role of natural endocrine-disrupting compounds, particularly phytoestrogens, in shaping male reproductive outcomes.

Resumen

La infertilidad masculina, un problema creciente de salud pública, se asocia cada vez más con la exposición a disruptores endocrinos (EDCs), incluyendo ftalatos, bisfenol A (BPA), compuestos organoclorados, pesticidas, así como disruptores endocrinos naturales como los fitoestrógenos. Esta revisión sintetiza evidencia mecanística y traslacional sobre cómo los EDCs afectan la función reproductiva masculina a través de múltiples vías interrelacionadas. Los EDCs alteran el eje hipotálamo-hipófiso-gonadal (HPG), inducen efectos citotóxicos en células de Leydig y Sertoli, y afectan la esteroidogénesis y la espermatogénesis, lo que se traduce en reducciones clínicamente significativas en la concentración, motilidad y morfología espermática. Evidencia emergente destaca efectos transgeneracionales mediados por modificaciones epigenéticas, incluyendo alteraciones en la metilación del ADN y la expresión de microARN, que podrían perpetuar la infertilidad a lo largo de generaciones. Evaluamos críticamente los estudios epidemiológicos y experimentales, los cuales revelan asociaciones consistentes entre la exposición a EDCs y resultados reproductivos adversos, como criptorquidia, cáncer testicular e infertilidad idiopática. Las ventanas de exposición prenatal y perinatal representan períodos de especial vulnerabilidad, con consecuencias a largo plazo sobre la salud reproductiva. A pesar de los avances, persisten importantes lagunas en la comprensión de los efectos de mezclas a bajas dosis, la susceptibilidad individual y la interacción entre EDCs y factores de estilo de vida, como el estrés oxidativo y los factores psicosociales. Desde el punto de vista clínico, esta revisión subraya la necesidad de mejorar la biomonitorización para cuantificar exposiciones reales, profundizar en los mecanismos dosis-respuesta y en los efectos no monotónicos, y fortalecer las políticas regulatorias basadas en evidencia. Se propone un marco traslacional que integre toxicología de alto rendimiento, biomarcadores epigenéticos e intervenciones clínicas para mitigar riesgos. Abordar estos desafíos es fundamental para proteger la salud reproductiva masculina ante el aumento global de la infertilidad. Futuras investigaciones deberán considerar de manera explícita el papel de los disruptores endocrinos naturales, particularmente los fitoestrógenos, en los resultados reproductivos masculinos.

Endocrine disruptors; Male infertility; Spermatogenesis; Epigenetic transgenerational inheritance; Environmental toxicology; Clinical policy; Natural endocrine disrupting compounds

Palabras Clave

Disruptores endocrinos; Infertilidad masculina; Epigenética; Calidad espermática; Exposición ambiental; Fitoestrógenos; Disruptores endocrinos naturales

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