2. Academic Validation
  3. TRPM2 mediates tire-derived pollutant 6PPD-Q-induced male reproductive impairment via autophagy in mice

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

  • Environ Pollut. 2026 Apr 1:394:127701. doi: 10.1016/j.envpol.2026.127701.
Yuhang Zhou 1,  Zhenjie Zang 2,  Xingzu Wang 3,  Yunhao Feng 1,  Zhenqing Wang 1,  Ziyao Li 4,  Tongxiang Diao 1,  Qiang Fu 5,  Hui Zhang 6
Affiliations

Affiliations

  • 1 Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
  • 2 Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China; College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250199, China.
  • 3 Department of Urology, Shandong Provincial Hospital, Associated with Shandong University, Jinan, 250021, China.
  • 4 Shandong Center for Disease Control and Prevention, Shandong Provincial Academy of Preventive Medicine, Jinan, 250014, China.
  • 5 Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China; College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250199, China; Department of Urology, Shandong Provincial Hospital, Associated with Shandong University, Jinan, 250021, China; Key Laboratory of Urinary Diseases in Universities of Shandong, Shandong First Medical University, Jinan, 250021, China. Electronic address: [email protected].
  • 6 Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China. Electronic address: [email protected].
PMID: 41554427 DOI: 10.1016/j.envpol.2026.127701
Abstract

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 testicular 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 demonstrates 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.

Keywords

6PPD-Q; Autophagy; Spermatogenesis impairment; TRPM2; Testicular damage.

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