SIRT1-TERT/PGC-1α通路调控的端粒-线粒体互作在苯并[a]芘致生精障碍传代效应中的研究

环境内分泌干扰物苯并[a]芘（BaP）父代暴露导致显著的生精障碍传代效应，但发生机制不明。我们前期观察到BaP及其代谢物BPDE诱导生精细胞和精子的端粒/线粒体功能紊乱，发现SIRT1,TERT,PGC-1α基因表达改变及相互调控，由此提出BaP通过干扰SIRT1-TERT/PGC-1α通路诱导端粒-线粒体互作，介导生精障碍传代效应的假说。项目拟建立BaP亲代暴露的父-子生殖损伤小鼠和BPDE暴露生精细胞模型，探明端粒/线粒体功能紊乱介导BaP生精障碍中的靶细胞、靶分子及交互作用；通过基因敲减/过表达、化学激活/抑制等手段阐明SIRT1-TERT/PGC-1α通路关键分子在端粒-线粒体互作中的调控机制；通过亲代与子代多重损伤指标关联分析及体内干预实验揭示端粒-线粒体互作介导BaP生精障碍传代效应的作用机制。项目将为BaP生殖危害防治开拓新思路，为内分泌干扰物传代毒性研究提供新的理论依据。

Benzo[a]pyrene (BaP), a typical polycyclic aromatic hydrocarbon, has been regarded as an environmental endocrine disruptor. Paternal exposure to BaP results in significant spermatogenic disorder among male parents and their offsprings. However, the precise mechanisms are still remaining obscure. Our previous research has revealed that BaP and its active metabolite, BPDE, can induce telomere dysfunction and mitochondrial compromise in spermatogenic cells and sperms. We have also observed significant alterations in SIRT1, TERT, PGC-1α gene expression and their interaction. Thus, we hypothesized that BaP induces crosstalk between telomere and mitochondrial dysfunction through disruption of SIRT1-TERT/PGC-1α pathway, which finally causes transgenerational effect of spermatogenic disorder. This project is planned to establish mouse model of spermatogenic disorder with paternal exposure to BaP, combined with in vitro model of BPDE-treated spermatogonia. We firstly intend to explore the targeted cells and potential crosstalk between BaP-induced telomere and mitochondrial dysfunction, then to clarify the key genes in SIRT1-TERT/PGC-1α pathway and molecular mechanisms underlying BaP- and BPDE-induced crosstalk between telomere and mitochondrial dysfunction, by the knockdown and overexpression of related genes. Finally, we destine to reveal the role of crosstalk between telomere and mitochondrial dysfuction in BaP-induced transgenerational effect of spermatogenic disorder among offspring, through analyzing the associations between damage of paternal generation and offspring and intervention tests in vivo. The study will provide a deeper insight into the mechanism of BaP-induced male reproductive toxicity, and new clues for exploring the mechanism of paternal influence on the damage of offspring and involved targets for intervention.