Perfluorooctanoic acid exposure leads to defect in follicular development through disrupting the mitochondrial electron transport chain in granulosa cells

Perfluorooctanoic acid (PFOA) is a persistent environmental pollutant that can impair ovarian function, while the underlying mechanism is not fully understood, and effective treatments are lacking. In this study, we established a mouse model of PFOA exposure induced by drinking water and found that PFOA exposure impaired follicle development, increased apoptosis of granulosa cells (GCs), and hindered normal follicular development in a 3D culture system. RNA-seq analysis revealed that PFOA disrupted oxidative phosphorylation in ovaries by impairing the mitochondrial electron transport chain. This resulted in reduced mitochondrial membrane potential and increased mitochondrial reactive oxygen species (mtROS) in isolated GCs or KGN cells. Resveratrol, a mitochondrial nutrient supplement, could improve mitochondrial function and restore normal follicular development by activating FoxO1 through SIRT1/PI3K-AKT pathway. Our results indicate that PFOA exposure impairs mitochondrial function in GCs and affects follicle development. Resveratrol can be a potential therapeutic agent for PFOA-induced ovarian dysfunction.