Perfluorodecanoic Acid (PFDA) induces ovarian toxicity and premature aging via mitochondrial dysfunction

Perfluorodecanoic acid (PFDA) is a perfluoroalkyl substance characterized by high environmental persistence and bioaccumulation potential, with a propensity to accumulate in the reproductive system. However, its toxicological effects on ovarian function remain poorly understood. This study employed mouse primary ovarian granulosa cells (mGCs) and a human ovarian granulosa cell line (SVOG) as in vitro models, combined with in vivo exposure experiments in female C57 mice. We systematically assessed cell viability, oxidative stress, inflammation, and senescence-associated phenotypes using MTT assays, ROS detection, Sa-β-gal staining, Western blotting, immunofluorescence, H&E staining, and immunohistochemistry. The results demonstrated that PFDA dose‑dependently reduced the viability and proliferation of mouse primary granulosa cells (mGCs) and human SVOG cells, as determined by CCK8 and EdU assays, induced oxidative stress and inflammation, and triggered cellular senescence. Furthermore, PFDA exposure led to ovarian follicular depletion, significantly decreased serum AMH and E2 levels, and increased FSH levels, recapitulating a premature ovarian insufficiency‑like phenotype. Mechanistically, PFDA impaired mitochondrial function, causing ROS accumulation and disrupting mitochondrial dynamics, leading to excessive mitochondrial fission. The release of mitochondrial DNA into the cytoplasm activated the cGAS-STING signaling pathway. The subsequent oxidative stress-inflammatory cascade drove ovarian cellular senescence.This study presents new experimental evidence on PFDA's reproductive toxicity and its impact on ovarian aging, providing a foundation for risk assessment and intervention strategies concerning this environmental pollutant.