Chronic exposure to environmentally relevant benzophenones induces male reproductive dysfunction via ER-mediated disulfidptosis: therapeutic potential of zeaxanthin dipalmitate.

BACKGROUND: Benzophenones (BPs), widely used UV filters and endocrine disruptors globally known for their estrogenic effects, are raising growing concerns about chronic reproductive toxicity in males due to their increasing environmental concentrations. This study aims to reveal the effects and mechanisms of male reproductive injury induced by environmentally relevant concentrations of BPs exposure. METHODS: The study employed NHANES analysis, animal experiments, cell experiments, network toxicology, and molecular docking, and used transcriptome sequencing along with various biochemical and molecular experimental methods to measure downstream indicators. RESULTS: Analysis of the NHANES database indicates that BP-3 exposure showed dose-dependent associations with reduced total testosterone (TT)/estradiol (E2)/sex hormone-binding globulin (SHBG) and elevated testosterone deficiency (TD) risk. Effects attenuated but held direction after multi-pollutant adjustment. The results of animal experiments indicate that chronic exposure to BPs (PND1-PND240) impaired fertility and offspring development, reduced body weight, anogenital distance, and testis coefficient, and altered histopathology, sperm quantity, and quality. Differentially expressed genes were predominantly enriched in energy metabolism and integrity of actin cytoskeleton, and disulfidptosis-related metabolic/redox indicators were dysregulated in the testis. Notably, even short-term exposure to BP-3 disturbs the levels of disulfidptosis-associated metabolic drivers (PND1-PND56). In GC-2 cells, BP-3 reduced cell viability and antioxidant capacity, induced morphological alterations, elevated ROS level, and upregulated disulfidptosis markers. The involvement of disulfidptosis was confirmed by the addition of the antagonist TCEP and agonist KL-11743. Notably, estrogen receptor (ER) directly regulates disulfidptosis. Zeaxanthin dipalmitate (ZD) alleviates BPs-induced male reproductive injury by modulating disulfidptosis. Co-culture assays further confirmed BP-3 disrupts testicular metabolic coupling and triggers disulfidptosis. CONCLUSION: BPs exposure induces male reproductive dysfunction via ER-mediated disulfidptosis. ZD can alleviate this dysfunction.