Prenatal PFHxS exposure alters ovarian development in female adolescent mice: Transcriptomic, hormonal, and structural evidence of disrupted steroidogenesis.

Perfluorohexane sulfonate (PFHxS), a persistent organic pollutant and developmental toxicant, poses significant health concerns. However, the long-term impacts of human-relevant prenatal PFHxS exposure on female reproductive development remain unclear. This study investigated its effects on ovarian development and estrous cyclicity outcomes in female adolescent using a mouse model. Pregnant mice were exposed to human relevant doses of PFHxS via oral gavage throughout gestation. Our findings showed that prenatal PFHxS exposure significantly delayed vaginal opening (VO) and disrupted estrous cyclicity in the adolescent, with prolonged diestrus. Ovarian histology revealed impaired folliculogenesis, including increased atretic follicles and reduced corpus lutea. Serum hormone analyses showed disrupted steroidogenesis with elevated testosterone and estradiol (E2), yet decreased anti-Müllerian hormone (AMH) and follicle-stimulating hormone (FSH). Ovarian transcriptomics identified dysregulation in steroid biosynthesis pathways (e.g., Cyp11a1, Cyp19a1, and Amh), validated by qRT-PCR. In silico simulations demonstrated PFHxS-induced structural reconfiguration of CYP11A1 and CYP19A1 substrate-binding sites. These findings demonstrated that prenatal PFHxS exposure altered female reproductive development by disrupting ovarian steroidogenesis and folliculogenesis. Our study provided experimental evidence for the risk assessment of PFHxS and underscores the potential health implications of this persistent environmental contaminant.