Bisphenol Z at environmentally relevant dose dysregulates mitochondrial metabolism and proliferative capacity in human ovarian granulosa cells by inducing changes in metabolic substrate utilization

The new generation of bisphenols, including bisphenol AF (BPAF), B (BPB), P (BPP) and Z (BPZ), has been detected within the environment of human ovarian follicles. It is therefore hypothesized that these bisphenols may interact directly with ovarian granulosa cells (GCs), which have high metabolic and proliferative activity that is crucial for oocyte development. Therefore, this study aimed to evaluate the effects of environmentally relevant concentrations (0.1–10 nM) of BPB, BPAF, BPP and BPZ on the mitochondrial function, metabolic fuel utilization and proliferation capacity of human GCs. While all bisphenols significantly increased GCs’ proliferation after a single (24 h) treatment, only BPZ enhanced its effect after subsequent (48 h) exposure. Simultaneously, BPZ increased ATP production, and this effect was accompanied by significant disruptions to substrate oxidation. Exposure to BPZ notably shifted metabolism from glucose and glutamine toward fatty acids and increased mRNA expression of peroxisome proliferator‑activated receptors α and δ. Additionally, glutamine and glucose were identified as the primary metabolic fuels that support basal and BPZ-induced proliferation of GCs. The results of this study demonstrate that BPZ disrupts the metabolic flexibility of GCs and stimulates their extensive proliferation. This can have a detrimental effect on follicular development, which in turn can affect ovulation and fertility.