Bisphenol A and Its Analogues Exhibit Different Cytotoxic and Mitochondrial Dysfunction Potential in Human Granulosa Cells

Bisphenol A (BPA) is an environmental endocrine disruptor and has been strongly associated with the development of numerous diseases, including ovarian follicle development disorders. BPA is being replaced by structurally similar chemicals, such as bisphenol S (BPS), bisphenol F (BPF) and bisphenol AF (BPAF). However, the toxicity of these analogues in female reproduction is unclear. Here, we investigated the induction of cytotoxicity and mitochondrial dysfunction in the human granulosa cell line KGN by BPA and its selected analogues. We found that BPA and its analogues, especially BPAF, significantly reduced cell viability and caused cytotoxicity. Furthermore, we observed that BPA and BPAF significantly reduced mitochondrial function, including decreasing ATP generation, promoting ROS production and increasing intracellular Ca2+ levels. An oxidative-antioxidant imbalance was also detected after exposure to these chemicals. In contrast, the total antioxidant capacity was significantly reduced. To our knowledge, this is the first report on the evaluation of the potential of BPA and its analogues to induce cytotoxicity and mitochondrial dysfunction in ovarian granulosa cells. Our study revealed the possible mechanism of BPA and its analogues inducing granulosa cell damage and suggested that mitochondrial dysfunction may play an important regulatory role in bisphenol-induced follicular development disorders.