Zinc Alleviates Oxidative Stress Injury of the Testis Induced by Zearalenone through Sirt3-Foxo3 Pathway in Mice

Environmental pollutants, such as zearalenone (ZEA), a mycotoxin from Fusarium graminearum that contaminates cereal crops and animal feed, significantly threaten reproductive health. The main toxicity mechanism of ZEA involves triggering oxidative stress and apoptosis. Zinc (Zn), a critical antioxidant for reproductive health, may counteract ZEA toxicity, but its mechanism of action remains unclear. The objective of the study was to investigate the alleviating effects of Zn supplementation against ZEA-induced testicular toxicity. We combined network toxicology and animal experiments to evaluate Zn's efficacy. Male Kunming mice were divided into Control, ZEA (2 mg/kg), Zn (20 mg/kg) and ZEA + Zn (10/20/40 mg/kg) groups and treated for 28 days. The results revealed that ZEA exhibited marked reductions in sperm quality, accompanied by structural testicular injury to the testis. ZEA diminishes the activity of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), while simultaneously increasing the levels of malondialdehyde (MDA), which results in oxidative stress. ZEA down-regulates serum levels of testosterone (T), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and impairs steroidogenesis. Significant elevations in ROS levels and apoptotic protein expression were observed in the testicular tissue of the ZEA group. ZEA significantly decreased both the mRNA and protein expression levels of Sirt3 and Foxo3, as well as their immunofluorescence intensity. Zn significantly increased sperm quality, improved testicular morphology, increased Sirt3 and Foxo3 levels, reduced ROS, normalized antioxidant capacity, improved apoptosis, and restored serum hormone levels. These findings emphasize the reproductive risks associated with ZEA, while also highlighting Zn as a possible candidate for developing alleviating effects against mycotoxin-induced reproductive toxicity.