Melatonin reverses bisphenol A-induced toxicity in granulosa cells: Restoration of FSHR and connexin 43 expression

Objective: Bisphenol A (BPA) is an estrogen-like endocrine-disrupting chemical commonly found in various daily consumer products. It causes female reproductive disorders by interfering with endocrine signaling. Normal folliculogenesis, oocyte maturation, ovulation, and luteal growth/involution rely on the gap junctional intercellular communication between granulosa cells (GCs) and oocytes. Connexin 43 (Cx43) is a key gap junction protein in GCs. The expression of Cx43 in GCs is regulated by follicle-stimulating hormone (FSH) at every stage of folliculogenesis. Melatonin, which exerts anti-inflammatory and antioxidative effects, is primarily released by the pineal gland and reproductive cells, including GCs. In this study. We investigated the protective role of melatonin against BPA-induced toxicity in GCs. Materials and methods: After controlled ovarian stimulation, GCs were collected from patients undergoing in vitro fertilization. To investigate the effect of melatonin on BPA-induced toxicity in GCs, we evaluated biological activity, gene expression, and protein expression in GCs treated with melatonin and BPA. Results: BPA downregulated the expression of FSH receptor (FSHR) and inhibited the FSH-induced expression of Cx43 in GCs. It also reduced the proportion of FSHR⁺Cx43⁺ cells population in GCs (10.2 %–6.3 %). Melatonin treatment in BPA-treated GCs reversed the BPA-induced downregulation of FSHR expression, restored the FSH-induced expression of Cx43, and the proportion of FSH-increased FSHR⁺Cx43⁺ cells population in GCs (8.6 %–21.3 %). Conclusion: Clinical trials in recent years have shown that melatonin could effectively prevent cell damage, and could also affect reproductive diseases and pregnancy outcomes. Our results elucidated the mechanisms underlying BPA-induced toxicity in GCs. Melatonin may mitigate the adverse effects of BPA on female reproductive function, which are interesting for exploring new targets in the prevention and treatment of reproductive diseases.