2. Academic Validation
  3. Benzo[a]pyrene inhibits testosterone biosynthesis via NDUFA10-mediated mitochondrial compromise in mouse Leydig cells: Integrating experimental and in silico toxicological approaches

Benzo[a]pyrene inhibits testosterone biosynthesis via NDUFA10-mediated mitochondrial compromise in mouse Leydig cells: Integrating experimental and in silico toxicological approaches

  • Ecotoxicol Environ Saf. 2022 Oct 1;244:114075. doi: 10.1016/j.ecoenv.2022.114075.
Wang Yang 1,  Haonan Cui 1,  Zili Chai 1,  Peng Zou 1,  Fuquan Shi 1,  Binwei Yang 1,  Guowei Zhang 2,  Huan Yang 1,  Qing Chen 1,  Jinyi Liu 1,  Jia Cao 3,  Xi Ling 4,  Lin Ao 5
Affiliations

Affiliations

  • 1 Key Lab of Medical Protection for 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 of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China. Electronic address: caojia1962@126.com.
  • 4 Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China. Electronic address: lingxi1024@126.com.
  • 5 Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China. Electronic address: aolin117@163.com.
PMID: 36108438 DOI: 10.1016/j.ecoenv.2022.114075
Abstract

Benzo[a]pyrene (B[a]P), a representative of polycyclic aromatic hydrocarbons (PAHs), is ubiquitously spread in the environment and showing deleterious impacts on male steroidogenesis, including testosterone synthesis disorder. However, the precise mechanisms involved in B[a]P-induced steroidogenesis perturbation remains obscure. In the present study, we integrated in vivo tests, transcriptome profiling, in vitro assays, and conjoint in silico toxicological approaches to delineate the detailed mechanisms. In mouse models, we observed that B[a]P administration remarkably inhibited testosterone synthesis accompanied by ultrastructural impairments of mitochondria and mitophagosome formation in mouse Leydig cells. Transcriptome profiling showed that B[a]P down-regulated the expression of Ndufa9, Ndufa6, Ndufa10, and Ndufa5 in mouse testes, which are identified as critical genes involved in the assembly and functionality of mitochondrial complex I. In the in vitro tests, the bioactive B[a]P metabolite BPDE induced perturbation of testosterone synthesis by NDUFA10-mediated mitochondrial impairment, which was further exacerbated by Mitophagy in TM3 Leydig cells. The findings of in silico toxicological analyses were highly consistent with the experimental observations and further unveiled that B[a]P/BPDE-involved PPARα activation could serve as a molecular initiating event to trigger the decline in Ndufa10 expression and testosterone synthesis. Overall, we have shown the first evidence that mitochondrial compromise in Leydig cells is the extremely crucial target in B[a]P-induced steroidogenesis perturbation.

Keywords

Benzo[a]pyrene; Leydig cell; Mitochondrial compromise; NDUFA10; Testosterone synthesis.

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