基于mtDNA甲基化的大气颗粒物致心脏毒性机制及早期效应标志物探索

Cardiomyocytes are rich in mitochondria. Mitochondrial DNA (mtDNA) methylation plays important roles in the stability of mtDNA and mitochondrial function. However, the mechanism of mtDNA methylation is yet to be elucidated. The applicant discovered PM-induced morphological and functional effects in mouse heart, which is likely to be associated with altered PPARa expression level and myocardium fatty acid metabolism. This project planned to establish a real-life exposure model with IVC system and implantation of PPAR alpha knock out/agonist-exposed mouse, with which the morphology, function and molecular biology of the hearts following PM exposure will be investigated. This project will reveal the roles of mtDNA methylation, PPARa/PGC1a and malfunction of fatty acid metabolism in PM-induced morphological and functional changes of mouse heart. Additionally, mtDNA methylation and PM exposure levels in the blood samples of population chronically exposed to high level of PM will be investigated. Echocardiography will also be performed in this population to assess the morphology and function of heart, revealing the impact of PM exposure and mtDNA methylation on cardiac functional parameters. This project will provide evidence for the etiology of PM-induced cardiac diseases and help to identify early biomarkers for this particular endpoint.

心肌富含线粒体，线粒体DNA（mtDNA）甲基化在mtDNA稳定和线粒体功能中发挥重要作用。目前，大气颗粒物（PM）致mtDNA甲基化的表观遗传效应机制尚不清楚。申请人前期发现，PM暴露对小鼠心脏功能及形态的影响，很可能与其改变PPARα表达水平从而影响心肌脂肪酸代谢有关，可能为PM重要毒性分子机制之一。基于mtDNA甲基化修饰可能对脂肪酸氧化代谢通路具有调控作用，本课题拟采用IVC系统建立外界PM真实暴露小鼠模型，以PPARa敲除/激动剂为工具、心脏形态功能测定及分子生物学为方法，揭示PM暴露致小鼠心脏形态功能改变中，mtDNA甲基化、PPARa/PGC1a及脂肪酸代谢障碍所扮演角色。在大气PM暴露人群，检测血液mtDNA甲基化和个体PM暴露水平，心脏彩超对心脏形态功能做出客观判断，探讨PM暴露及mtDNA甲基化对心功能参数的影响，这对解析PM致心脏疾病机理及早期效应标志物提供理论依据。