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

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.