Prenatal Exposure to PFOA Induces Ovarian Function Impairment via the Disruption of the PPARγ/ANGPTL4 Pathway

Perfluorooctanoic acid (PFOA) has been implicated in female reproductive toxicity, while its long-term effects of prenatal exposure remain unclear. Herein, we conducted a comprehensive NHANES analysis to estimate the Hazard Ratio (HR) of earlier menopause associated with PFOA exposure and further investigated the underlying mechanisms through a prenatal mouse model and complementary cell-based assays. Higher serum PFOA levels were significantly associated with earlier age at natural menopause (2nd tertile: HR = 1.220, P = 0.004; third tertile: HR = 1.262, P = 0.002). In mice, prenatal PFOA exposure caused persistent ovarian dysfunction in middle-aged F1 offspring, characterized by ovarian cyst formation, a premature decline in ovulatory capacity, increased follicular atresia, and disrupted estrous cyclicity. PFOA induced granulosa cell cycle arrest at the G0/G1 phase, increasing the arrested population from 84.9% to 87.6%, thereby reducing proliferation as a key contributor to ovarian cyst formation. Transcriptomic profiling and qPCR validation demonstrated that PFOA activated PPARγ signaling, with PPARγ and ANGPTL4 upregulated by 1.6-fold and 12.6-fold, respectively. PFOA exposure further induced upregulation of ANGPTL4 as revealed by siRNA-mediated knockdown assays, which mediated reduced granulosa cell proliferation. Our findings link prenatal PFOA exposure to long-term ovarian toxicity through granulosa cell dysfunction mediated by PPARγ-ANGPTL4 signaling, providing new evidence and potential targets for adverse reproductive outcomes on PFOA.