Involvement of autophagy and mitophagy modulation in the protective effect of melatonin against BPS-induced ovarian toxicity

Plastics pose a global health risk due to their detrimental effects, with bisphenol S (BPS) being a prominent plasticizer of concern. In this study, we aimed to investigate the effects of BPS exposure on ovarian function in Wistar rats and assess the protective potential of melatonin (MLT), with the goal of elucidating some of the underlying biochemical and molecular mechanisms involved. We first assessed changes in weight parameters and oxidative stress markers, including antioxidant enzymes (SOD and CAT), PSH, and MDA levels. Then, we investigated ovarian function parameters, namely those related to the estrous cycle, ovarian histology, folliculogenesis, and the molecular expression of markers associated with autophagy (LC3, P62, ATG5) and mitophagy (PINK1, PARKIN) processes. Our findings indicate that BPS induces oxidative stress, with increased CAT activity and decreased SOD activity, along with elevated PSH levels, without any effect on lipid peroxidation. Significant ovarian toxicity is also evident, manifested by a decrease in ovarian weight and anomalies related to the estrous cycle, such as irregularities and disruptions in the total duration and the different estrous phases, along with histological alterations in ovarian tissue that result in variations in the number of follicles at different maturation stages. Furthermore, BPS exposure induces an overexpression of LC3, ATG5, P62, PINK1 and PARKIN markers. Conversely, MLT supplementation significantly mitigated these effects, mainly through its ability to improve oxidative status and to modulate autophagy and mitophagy processes, resulting in the restoration of ovarian function parameters and highlighting its protective role against BPS-induced ovarian toxicity.