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

端粒 线粒体 苯并(a)芘 端粒酶 化学 分子生物学 DNA损伤 细胞生物学 衰老 生物 致癌物 生物化学 DNA 基因
作者
Haonan Cui,Yang Wang,Shi-Jun He,Zili Chai,Lihong Wang,Guowei Zhang,Peng Zou,Lei Sun,Huan Yang,Qing Chen,Jinyi Liu,Jia Cao,Ling Xi,Lin Ao
出处
期刊:Toxicology and Applied Pharmacology [Elsevier]
卷期号:475: 116656-116656 被引量:2
标识
DOI:10.1016/j.taap.2023.116656
摘要

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 senescence-associated 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 inhibited 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.
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