1. Academic Validation
  2. TERT transcription and translocation into mitochondria regulate benzo[a]pyrene/BPDE-induced senescence and mitochondrial damage in mouse spermatocytes

TERT transcription and translocation into mitochondria regulate benzo[a]pyrene/BPDE-induced senescence and mitochondrial damage in mouse spermatocytes

  • Toxicol Appl Pharmacol. 2023 Aug 12;116656. doi: 10.1016/j.taap.2023.116656.
Haonan Cui 1 Wang Yang 1 Shijun He 1 Zili Chai 2 Lihong Wang 3 Guowei Zhang 4 Peng Zou 1 Lei Sun 1 Huan Yang 1 Qing Chen 1 Jinyi Liu 1 Jia Cao 1 Xi Ling 5 Lin Ao 6
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 State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China.
  • 3 West China School of Public Health, Sichuan University, Chengdu 610041, China.
  • 4 Department of Environmental Health, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China.
  • 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: lingxi1024@126.com.
  • 6 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.
Abstract

Telomere and mitochondria may be the targets of Benzo[a]pyrene (BaP) -induced male reproductive damage, and further elucidation of the toxic molecular mechanisms is necessary. In this study, we used in vivo and in vitro exposure models to explore the molecular mechanisms of TERT regulation in BaP-induced telomere and mitochondrial damage in spermatocytes. The results showed that the treatment of benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), the active metabolite of BaP, caused telomere dysfunction in mouse spermatocyte-derived GC-2 cells, resulting in S-phase arrest and increased senescent secretory phenotype (SASP). These effects were significantly alleviated by Telomerase agonist (ABG) pretreatment in GC-2 cells. SIRT1, FOXO3a, or c-Myc overexpressing GC-2 cell models were established to demonstrate that BPDE inhibits TERT transcriptional expression through the SIRT1/FOXO3a/c-Myc pathway, leading to telomere dysfunction. We also observed that BPDE induced mitochondrial compromise, including complex I damage, accompanied by reduced mitochondrial TERT expression. Based on this, we constructed wild-type TERT-overexpressing (OE-TERTwt) and mitochondria targeting TERT-overexpressing (OE-TERTmst) GC-2 cell models and found that OE-TERTmst GC-2 cells improved mitochondrial function better than OE-TERTwt GC-2 cells. Finally, ICR mice were given BaP by intragastric administration for 35 days, which verified the results of the in vitro study. The results shown that BaP exposure can lead to spermatogenesis disturbance, which is related to the telomere and mitochondrial damage in spermatocytes. In conclusion, our results suggest that BPDE causes telomere and mitochondrial damage in spermatocytes by inhibiting TERT transcription and mitochondrial TERT expression. This study elucidates the molecular mechanism of male reproductive toxicity due to environmental pollutant BaP, and also provides a new perspective for the exploration of interventions and protective measures against male reproductive damage by BaP.

Keywords

Benzo[a]Pyrene; Benzo[a]Pyrene-7,8-Dihydrodiol-9,10-Epoxide; Mitochondrial Damage; Spermatocyte; Telomere Dysfunction; Telomeric Reverse Transcriptase.

Figures
Products