Melatonin Mitigates Bisphenol A- and MBP-Induced Damage in Leydig Cells by Alleviating Oxidative Stress and Endoplasmic Reticulum Stress via inhibition of PERK signaling pathway.

This study aims to elucidate the protective effects of melatonin against Bisphenol A (BPA) and its metabolite 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP)-induced apoptosis in Leydig cells, focusing on its ability to alleviate oxidative stress and endoplasmic reticulum stress. Results showed that melatonin significantly alleviated testicular damage caused by BPA, increased testicular index in mice, improved the function of seminiferous tubules, and enhanced the survival rate and density of epididymal sperm. Furthermore, melatonin treatment significantly reduced the number and proportion of TUNEL-positive Leydig cells, decreased cleaved caspase-3 expression and the cleaved caspase-3/total caspase-3 ratio, increased testosterone secretion from Leydig cells, and elevated the expression of steroidogenic enzymes cytochrome P450 17α-hydroxylase/20-lyase and 17β-hydroxysteroid dehydrogenase 3. Melatonin also significantly lowered the elevated reactive oxygen species levels in Leydig cells induced by MBP and enhanced the expression of antioxidant enzymes superoxide dismutase 1/2 and catalase. Additionally, melatonin effectively countered endoplasmic reticulum stress in Leydig cells induced by BPA and MBP, significantly decreasing levels of GRP94 and GRP78, while inhibiting activation of the PERK/EIF2α/ATF4/CHOP signaling pathway. Notably, melatonin significantly alleviated endoplasmic reticulum stress and apoptosis in TM3 cells, and this effect was associated with enhanced SIRT1 nuclear localization and deacetylase activity, as demonstrated by reduced acetylated-p53 levels. Collectively, melatonin effectively protects Leydig cells from BPA and MBP-induced damage by alleviating oxidative stress and endoplasmic reticulum stress through inhibition of the PERK signaling pathway, an effect that may involve SIRT1 activation. It may serve as a therapeutic agent to safeguard male reproductive health against environmental pollutants.