Sex-specific cellular and molecular mechanisms of PFAS-induced reproductive toxicity

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants widely detected in water, food, consumer products, and household dust, resulting in ongoing human exposure and bioaccumulation. Accumulating evidence increasingly implicates PFAS in reproductive dysfunction. Although PFAS-associated reproductive toxicity has been widely reviewed, critical knowledge gaps persist regarding the sex-specific cellular and molecular mechanisms mediating these effects and the reproductive toxicity of emerging replacement PFAS. Increasing epidemiological, in vivo, and in vitro evidence indicates that PFAS disrupt reproductive health through multiple mechanisms common to both sexes, including oxidative stress, mitochondrial dysfunction, endocrine perturbation, inflammation, epigenetic modifications, and dysregulation of cell survival pathways. However, emerging data reveal sex-specific differences in susceptibility and molecular responses. In males, PFAS specifically disrupt steroidogenesis, the blood-testis barrier (BTB), induce germ cell apoptosis, and impair spermatogenesis, leading to reduced sperm quality and fertility. In females, PFAS exposure perturbs ovarian homeostasis by impairing folliculogenesis, oocyte maturation, steroid hormone biosynthesis, and granulosa/cumulus cell function, thereby contributing to diminished ovarian reserve and reproductive dysfunction. Distinct alterations in hormone signaling, lipid metabolism, nuclear receptor activation, and epigenetic regulation mediate these sex-specific effects. Beyond gonadal toxicity, PFAS exposure during pregnancy disrupts placental development and endocrine signaling, contributing to placental dysfunction, adverse pregnancy outcomes, and developmental programming associated with metabolic, neurodevelopmental, and immune abnormalities in offspring. This review presents current epidemiological and mechanistic evidence to delineate shared and sex-specific pathways underlying reproductive toxicity induced by both legacy and emerging PFAS. The findings provide an updated perspective on PFAS-induced reproductive toxicity and have implications for future risk assessment and targeted interventions.