BPDE and B[a]P induce mitochondrial compromise by ROS-mediated suppression of the SIRT1/TERT/PGC-1α pathway in spermatogenic cells both in vitro and in vivo.

There is increasing evidence that indicates benzo[ a ]pyrene (B[ a ]P) and its active metabolite benzo[ a ]pyrene-7, 8-dihydrodiol-9, 10-epoxide (BPDE) are endocrine disruptors that can cause reproductive toxicity. Nevertheless, the underlying mechanisms are still obscure. The present study investigates the impacts of B[ a ]P and BPDE on mitochondria, a sensitive target affected by multiple chemicals, in spermatogenic cells. It showed that BPDE treatment induced mitochondrial dysfunction and the inhibition of mitochondrial biogenesis in mouse spermatocyte-derived cells (GC-2). These effects were efficiently mitigated by pretreatment with ZLN005, an activator of PGC-1α, in GC-2 cells. TERT knockdown and re-expression cell models were established to demonstrate that TERT regulated the BPDE-induced mitochondrial damage via PGC-1α signaling in GC-2 cells. Moreover, upregulating or knockdown SIRT1 expression attenuated or aggravated BPDE-induced mitochondrial compromise by activating or inhibiting, respectively, the TERT and PGC-1α molecules in GC-2 cells. Finally, we observed that BPDE markedly elevated oxidative stress in GC-2 cells. Resveratrol and N -acetylcysteine, as reactive oxygen species (ROS) scavengers, attenuated BPDE-mediated mitochondrial damage by increasing SIRT1 activity and expression in GC-2 cells. The in vitro results were corroborated by in vivo experiments in rats treated with B[ a ]P for 4 weeks. B[ a ]P administration caused mitochondrial damage and mitochondria-dependent apoptosis in spermatogenic cells, as well as the decreased expression of SIRT1, TERT, and PGC-1α. In summary, the results of the present study demonstrate that B[ a ]P and BPDE induce mitochondrial damage through ROS production that suppresses SIRT1/TERT/PGC-1a signaling and mediate B[ a ]P- and BPDE-mediated reproductive toxicity. Unlabelled Image • Mitochondria are the target of male reproductive toxicity induced by BPDE/B[ a ]P. • BPDE and B[ a ]P induce mitochondrial compromise in spermatogenic cells. • SIRT1/TERT/PGC-1α pathway accounts for BPDE/B[ a ]P-induced mitochondrial damage. • BPDE/B[ a ]P-induced ROS causes the suppression of SIRT1/TERT/PGC-1α pathway. [ABSTRACT FROM AUTHOR]