Zinc Attenuates Bisphenol A-Induced Reproductive Toxicity in Male Mice by Inhibiting Ferroptosis and Apoptosis Through Improving Zinc Homeostasis.

Abstract

Bisphenol A (BPA) is a contaminant widely found in food packaging that can reduce sperm quality and impair male fertility. Zinc (Zn) is an important antioxidant involved in many important biological functions. The aim of this study was to explore the protective effect and mechanism of Zn on reproductive toxicity induced by BPA. Male ICR mice were divided into a control group, a BPA group and a BPA + Zn group. The results showed that the body weight, sperm count and sperm motility of the animals in the BPA group were significantly reduced, and testicular structure was damaged. BPA decreased the levels of serum total Zn, testis-free zinc, ADH and ALP, upregulated the expression of ZnT4 protein, and down-regulated the expression levels of ZIP8, ZIP14, ZnT1, MT and MTF1 protein, resulting in the imbalance of testicular Zn homeostasis. BPA down-regulates the antioxidant enzymes SOD and GSH-Px, and increases MDA, leading to oxidative stress. BPA up-regulates TF, TFR and STEAP3 and down-regulates SLC7A11, GPX4, FPN1 and FTH protein levels, resulting in abnormal iron metabolism and ferroptosis. BPA down-regulated anti-apoptotic protein Bcl-2, up-regulated pro-apoptotic markers Bax, caspase-9, caspase-8 and caspase-3, and induced apoptosis. BPA also increased the phosphorylation of JNK and ERK1/2, but did not increase the phosphorylation of P38. Zn significantly increased body weight and sperm quality, improved testicular morphology, down-regulated p-JNK/JNK and p-ERK/ERK levels, improved oxidative stress, and reduced ferroptosis and apoptosis. In conclusion, Zn regulates Zn homeostasis and down-regulates the MAPK signaling pathway, thereby inhibiting ferroptosis and apoptosis, alleviating BPA-induced oxidative stress and ultimately improving male reproductive damage.