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  2. 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

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

  • Toxicol Appl Pharmacol. 2019 Aug 1;376:17-37. doi: 10.1016/j.taap.2019.05.004.
Wang Yang 1 Guowei Zhang 2 Fan Jiang 1 Yingfei Zeng 1 Peng Zou 1 Huihui An 1 Qing Chen 1 Xi Ling 1 Fei Han 1 Wenbin Liu 1 Huan Yang 1 Jinyi Liu 1 Jia Cao 1 Lin Ao 3
Affiliations

Affiliations

  • 1 Key Lab for the Medical Protection of Electromagnetic Radiation, Ministry of Education of China, Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China.
  • 2 Department of Environmental Health, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China.
  • 3 Key Lab for the Medical Protection of Electromagnetic Radiation, Ministry of Education of China, Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China. Electronic address: [email protected].
Abstract

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.

Keywords

Benzo[a]pyrene; Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide; Male reproductive toxicity; Mitochondrial damage; Reactive oxygen species.

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