Melatonin ameliorates Pb-induced mitochondrial homeostasis and ovarian damage through regulating the p38 signaling pathway

Abstract

Lead (Pb), a widespread metallic pollutant in the environment, has been found to have detrimental effects on the female reproduction system. Recently, our group discovered a significant correlation between toxic metals and reproductive endocrine diseases. However, there is limited research on the relationship between blood concentration of Pb and the risk of diminished ovarian reserve function (DOR). Melatonin (MT), as a unique antioxidant, has been shown to reduce Pb toxicity both in vivo and in vitro，but the role of MT on follicle development in Pb-exposed female C57BL6 mice, and the underlying mechanisms, have not been clearly identified. In this study, blood Pb level was detected in the DOR patients, and a significant elevation in Pb levels was observed compared to the control group. Subsequently, we investigated the impact of lead acetate trihydrate (0.2 %), an endocrine disruptor of heavy metals, on follicle development in mice. We observed abnormal follicle development induced by lead acetate trihydrate without concurrent follicular apoptosis or excessive autophagy. Furthermore, we found that co-treatment with MT (30 mg/kg) rescued Pb-induced abnormal follicle development. Anti-Müllerian hormone (AMH) is a commonly utilized marker to evaluate ovarian reserve function. Our observation revealed that MT treatment effectively reversed the decrease in AMH levels induced by Pb. Importantly, our results revealed that MT not only protected against the Pb-induced increase of nucleus-encoded proteins, including SDHA, mitofilin and MTCO2, but also rescued Pb-induced the increase of mitochondrial dynamic-related proteins, such as OPA1, MFN and FIS1. In addition, MT protected against the decrease of mitochondrial dynamic-related protein anti-mitochondrial fission factor (MFF) antibody expression and mitochondrial membrane potential level. Finally, MT rescued the Pb-induced inhibition of phosphorylation in the P38 signaling pathway. Conclusively, these findings provide compelling evidence that exposure to Pb influences mitochondrial homeostasis, and MT effectively restores the imbalance between mitochondrial fusion and fission, nucleus-encoded proteins, and improves ovarian reserve function through regulating P38 signaling pathway. These results indicate that targeting the P38 signaling pathway with MT could be a potential therapeutic strategy for treating DOR.

Keywords: Lead; Melatonin; Mitochondrial homeostasis; Ovarian reserve function; Signaling pathway.