Perfluorooctanoic acid (PFOA) induces apoptosis by disrupting mitochondrial function via the SIRT1/FOXO1-SOD2 pathway in human granulosa cells: Implications for PCOS

Perfluorooctanoic acid (PFOA), a widely used perfluoroalkyl substance (PFAS), has been associated with adverse reproductive health outcomes, including polycystic ovary syndrome (PCOS). However, the molecular mechanisms remain poorly understood. In this study, we explored the effects of PFOA exposure on granulosa cell apoptosis, a key contributor to PCOS pathogenesis. Human ovarian granulosa-like tumor cell line (KGN) was exposed to PFOA (0–100 μM), resulting in a significant increase in cell apoptosis and impaired mitochondrial function, as evidenced by elevated reactive oxygen species (ROS) levels, decreased mitochondrial membrane potential (MMP), and reduced adenosine triphosphate (ATP) production. Mechanistically, PFOA exposure led to the downregulation of the SIRT1/FOXO1–SOD2 signaling pathway. Notably, activation of this pathway via pharmacological agonizts attenuated PFOA-induced apoptosis and restore mitochondrial function. These findings demonstrate that PFOA exposure can induce granulosa cell apoptosis by downregulating the SIRT1/FOXO1-SOD2 pathway, leading to impaired mitochondrial antioxidant capacity. This study provides novel mechanistic insights into the reproductive toxicity of PFOA and its potential role in the etiology of PCOS.