TRPM2 mediates tire-derived pollutant 6PPD-Q-induced male reproductive impairment via autophagy in mice

N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine quinone (6PPD-Q) is an oxidation product of the tire rubber antioxidant 6PPD. Recent studies have detected 6PPD-Q in various environmental media, including water, air, and soil, and in human biospecimens such as urine, breast milk, blood and cerebrospinal fluid. These findings highlight its widespread presence in the environment and the potential for multi-route human exposure. Although previous research has demonstrated that 6PPD-Q induces multi-organ toxicity, particularly in the liver and nervous system, its effects on the male reproductive system and the associated molecular mechanisms remain unexplored. We developed a chronic exposure model in male mice to systematically assess the toxic effects of 6PPD-Q on the testes and its potential mechanisms. Our results indicate that 6PPD-Q accumulates in testicular tissue and induces histological damage, which is characterized by reduced serum testosterone levels, impaired sperm quality, sloughing of the spermatogenic epithelium, and disruption of the blood-testis barrier. Mechanistic investigations suggest that these effects are associated with impaired autophagy, elevated oxidative stress, and increased apoptosis in testicular tissue. Through integrated network toxicology and transcriptomics analyses, we identified TRPM2 (transient receptor potential cation channel subfamily M member 2)-mediated autophagy dysfunction as a critical event in 6PPD-Q-induced testicular injury. This study systematically unveils the toxic effects of 6PPD-Q on the male mouse reproductive system and elucidates the underlying molecular mechanisms. It elucidates that TRPM2-mediated autophagy plays a crucial role in the testicular injury induced by 6PPD-Q. This research provides essential evidence for understanding the reproductive health risks posed by emerging environmental pollutants and for developing prevention strategies.