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  3. Cholesterol metabolism as a key target in triphenyl phosphate-induced testosterone biosynthesis disorder: Implications for male reproductive health

Cholesterol metabolism as a key target in triphenyl phosphate-induced testosterone biosynthesis disorder: Implications for male reproductive health

  • J Hazard Mater. 2025 Oct 24:499:140253. doi: 10.1016/j.jhazmat.2025.140253.
Yuhan Ma 1,  Dihui Xu 1,  Zongli Huo 2,  Xi Wang 3,  Yabing Chen 4,  Xiaodong Han 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China.
  • 2 Jiangsu Provincial Center for Disease Control and Prevention, Nanjing 210009, China.
  • 3 Jiangsu Provincial Center for Disease Control and Prevention, Nanjing 210009, China. Electronic address: wangxi_sanjia@163.com.
  • 4 State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China; College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing 210095, China. Electronic address: chenyb@njau.edu.cn.
  • 5 State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China. Electronic address: hanxd@nju.edu.cn.
PMID: 41151519 DOI: 10.1016/j.jhazmat.2025.140253
Abstract

Testosterone (T) deficiency is a critical factor in male infertility, and environmental contaminants are increasingly recognized as contributors to T dysregulation. As a representative organophosphate flame retardant (OPFR), triphenyl phosphate (TPhP) raises significant concerns due to its potential reproductive toxicity. Here, we integrated epidemiological and mechanistic approaches to investigate TPhP-induced T reduction. Population-based analysis revealed a negative correlation between serum TPhP levels and circulating T in adult males. Consistent with this finding, animal models demonstrated that TPhP exposure significantly suppressed T synthesis. Mechanistic studies in vivo and in vitro identified disrupted Cholesterol metabolism as a key event, with RNA-seq analysis implicating the translocator protein (TSPO) as a pivotal target. Further experiments established that PPARα-mediated downregulation of TSPO impaired mitochondrial Cholesterol transport in Leydig cells, ultimately inhibiting T biosynthesis. Our study uncovers a novel pathway by which TPhP compromises androgen production via the PPARα-TSPO-cholesterol axis, providing the first evidence linking OPFR exposure to mechanisms of aberrant T biosynthesis. These findings highlight the urgent need to assess the reproductive risks of environmental OPFRs.

Keywords

Cholesterol metabolism; Reproductive toxicity; TPhP; Testosterone biosynthesis.

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