多环芳烃暴露对胎儿先天性心脏病的影响及其机制研究

Congenital heart disease (CHD) is the most common birth defects in China, which the major causes are considered the interaction of genetic and environmental factors. As polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants, prenatal exposure is found to be associated with a variety of birth defects occurrence in human. But there are few studies for evaluating the potential association between PAHs exposure and CHD in offspring. We had found that prenatal exposure contaminate related with PAHs may increase the risk of CHD in offspring in our previous studies, but it need the further study with a large sample to obtain the powerful evidences. In this study, we will conduct a case-control study，first analyze the association between pregnant women PAHs exposure level, the interaction of PAHs exposure and gene polymorphisms on fetal intrauterine PAHs exposure and fetal CHD; then analyze the association between fetal intrauterine PAHs exposure level, the interaction of PAHs exposure and gene polymorphisms on CHD occurrence; next detect the methylation levels of the promoter of genes associated tightly with the development of CHD and the corresponding mRNA level of genes that the methylation are different, analyze the the association between fetal intrauterine PAHs exposure and candidate genes that the methylation and mRNA are all different, explore the PAHs exposure effect on epigenetic mechanism of the CHD occurrence. This study will reveal the interaction of environmental exposure and genetic susceptibility on the occurrence of CHD, further explore the epigenetic mechanism. These findings will provide scientific basis for further exploration of the cause, mechanism and early prevention of CHD.

先天性心脏病(先心病，CHD)是我国最常见的出生缺陷，致病原因大多是遗传和环境因素交互作用的结果。多环芳烃（PAHs）是环境中广泛存在的污染物，孕期暴露与多种人类出生缺陷存在关联，但与先心病的研究报道较少。我们前期研究提示孕期多环芳烃暴露可能导致胎儿患先心病的风险增加，但缺乏大样本量的有效研究证据。本项目采用病例对照设计,首先对孕妇PAHs暴露与代谢酶基因多态性交互作用与胎儿宫内PAHs暴露水平及胎儿CHD发生关系进行分析；而后进行胎儿宫内PAHs暴露与代谢酶基因多态性交互作用与CHD发生的关系分析；并进一步检测与CHD发生密切相关基因的甲基化状态和甲基化差异基因的mRNA表达水平，探索PAHs暴露导致CHD发生的表观遗传机制。本研究从环境暴露与遗传的交互作用研究对CHD发生的影响，并对其表观遗传机制进行探讨，其结果将为进一步探索CHD的发病原因和防治策略提供理论依据。

先天性心脏病(先心病，CHD)是我国最常见的出生缺陷，致病原因大多是遗传和环境因素交互作用的结果。多环芳烃（PAHs）是环境中广泛存在的污染物，孕期暴露与多种人类出生缺陷存在关联，但与先心病的研究报道较少。本项目采用病例对照设计，首先进行孕妇多环芳烃暴露和胎儿CHD的相关性分析，其次进行孕妇PAHs暴露与代谢酶基因多态性交互作用与胎儿CHD发生关系进行分析，并进一步检测与CHD发生密切相关基因的甲基化状态和甲基化差异基因的mRNA表达水平，最后进行孕妇PAHs暴露和基因甲基化水平的相关性分析。研究结果发现：孕妇多环芳烃暴露可增加胎儿CHDs的发生风险，母亲AHR基因的多态性可修饰母亲多环芳烃暴露对CHDs的影响，孕妇多环芳烃暴露和心脏发育相关基因的甲基化水平无相关性，与心脏发育相关基因CITED2存在差异甲基化片段和mRNA的差异表达。这些研究发现将为制定相关环境防治策略以及CHD的早期干预策略提供科学依据，同时为进一步探索胎儿CHD发生的表观遗传机制增加了理论依据。