Molecular Mechanisms of Endocrine-Disrupting Chemicals and Emerging-Pollutant Toxicity in Human Reproduction: From Xenobiotic Exposure to Fertility Impairment and Reproductive Carcinogenesis

Abstract

Human fertility is declining across industrialised populations, while the incidence of hormone-dependent reproductive cancers rises. Endocrine-disrupting chemicals (EDCs) and structurally related emerging pollutants are implicated in both. These two outcomes are generally reviewed as separate studies. This review argues that they are two latencies of a single molecular toxicology. The compounds concerned are structurally diverse: phthalates, bisphenols, per- and polyfluoroalkyl substances (PFASs), pesticides, polychlorinated biphenyls (PCBs) and dioxins, brominated and organophosphate flame retardants, pharmaceuticals and personal-care products (PPCPs), and micro- and nanoplastics. They nonetheless converge on a limited repertoire of molecular lesions. These include the disruption of hypothalamic–pituitary–gonadal (HPG) signalling through kisspeptin/GnRH and gonadotropin gene expression and interference at nuclear and membrane hormone receptors (ERα/β, AR, GPER, thyroid receptors, AhR, PPARγ). They also include the inhibition of steroidogenesis at StAR and the CYP11A1–CYP17A1–CYP19A1/3β-HSD/17β-HSD cascade and reactive-oxygen-species generation with mitochondrial dysfunction and Keap1–Nrf2 disruption. Epigenetic reprogramming through DNA methylation, histone modification and non-coding RNAs, together with crosstalk with metabolic and immune signalling, completes the set. These lesions produce measurable cytotoxic and genotoxic damage to gametes and the early embryo: sperm DNA fragmentation and 8-oxo-dG accumulation, blood–testis-barrier breakdown, oocyte meiotic-spindle defects, and granulosa-cell apoptosis and pyroptosis. The same receptor, oxidative and genotoxic hubs drive hormone-dependent reproductive carcinogenesis over longer latencies. The review makes three contributions. First, it traces these shared hubs continuously from fertility impairment to malignancy rather than treating them as separate fields. Second, it grades the certainty of the human evidence class by class, so that robust associations can be distinguished from provisional ones. Third, it integrates pseudo-persistent pollutants alongside the classical persistent compounds. These are micro- and nanoplastics, which act as both toxicants and vectors for adsorbed co-contaminants, and pharmaceutical and personal-care residues sustained by continuous wastewater input. Their inclusion demonstrates that chronic low-dose exposure does not require chemical persistence. We conclude with mitigation strategies and an explicit account of what the current evidence base cannot yet support.