生命早期丙烯酰胺持续暴露对远期心血管发育及表观遗传的毒性机制

心血管疾病是威胁我国居民健康的重大公共卫生问题，环境暴露来源污染物作为危险因子已成为最新关注热点，但毒理效应和表观遗传毒性机制知之甚少。本项目以丙烯酰胺为对象，研究生命早期持续暴露对远期心血管系统发育及表观遗传的毒性机制。首先，运用斑马鱼模型深入探索丙烯酰胺致幼鱼血管中脂质和髓系细胞分布、血管内皮结构功能活性以及巨噬细胞脂质摄取等过程发生异常的毒性效应；研究其致胚胎发育过程中心血管系统损伤的分子机制，诠释与DNA甲基转移酶活性以及DNA甲基化修饰的关联性。其次，运用大鼠模型验证丙烯酰胺对远期心血管系统的影响及代际效应，揭示其致心血管系统异常的表观、代际和跨代遗传毒性效应。总体上基于暴露组学策略在丙烯酰胺持续低剂量暴露条件下开展集毒理、分子和信号三位一体的特色研究，预期成果将加深对丙烯酰胺心血管及表观遗传毒性机制的认识，为完善环境暴露来源污染物在生命早期持续暴露下的毒理效应评价体系提供依据。

Cardiovascular disease is a major public health problem threatening the health of Chinese residents. As a risk factor, environmental exposure derived contaminants have been the latest focus of attention, but little is known about toxicological effects and epigenetic toxicity mechanisms. The aim of this project is to investigate the long-term cardiovascular development and epigenetic toxic mechanisms of early exposure to acrylamide. First, we will use zebrafish model (i) to reveal toxic effects of exposure to acrylamide on abnormal occurrence of the distribution of lipids and myeloid cells in blood vessels, the structural and functional activities of vascular endothelial tissues, and the process of macrophage lipid uptake in zebrafish infants; and (ii) to investigate the molecular mechanism of cardiovascular system damage induced by acrylamide, and elucidate its associations with DNA methyltransferase activity and DNA methylation modification during embryonic development. Then, we will use rat model (i) to validate intergenerational effects of continuous exposure to acrylamide in early life on the long-term cardiovascular system; and (ii) to unravel the epigenetic, intergenerational and transgenerational inheritance effects of exposure to acrylamide on abnormal occurrence of cardiovascular system. Overall, we will conduct a characteristic study of the trinity of toxicology, molecules and signals under continuous low-dose exposure to acrylamide based on the exposomics strategy. The anticipated outcomes will be beneficial for (i) further understanding toxic mechanisms of cardiovascular and epigenetics under the exposure to acrylamide; and (ii) improving the evaluation system for toxicological effects of continuous exposure to environmental derived contaminants in early life.