先天性心脏病（先心病）病因未明，环境污染物是重要的危险因素，但具体物质及机理不清楚。我们前期研究发现，备受关注的重金属铅或新型持久性污染物全氟辛烷磺酸（PFOS）在母婴体内的水平与先心病的发生呈正相关，而且铅与其他污染物具有交互作用。然而，围孕期父母双方PFOS与铅复合暴露导致先心病发生的可能性及其致病机制尚未见报道。我们还证明了心脏发育关键基因Gata4和Tbx5启动子的甲基化参与了污染物抑制心脏分化的过程。据此提出假说：PFOS和铅交互影响，促进甲基化而抑制心脏发育关键基因的表达，从而影响胚胎干细胞向心脏细胞分化并促进先心病发生。本项目拟从人群队列、生物标本、分子和细胞等多层次明确心脏发育敏感时期，父母双方PFOS和铅复合暴露对先心病发生的影响；探讨PFOS和铅对心脏分化关键基因的调控作用；揭示两物质通过甲基化修饰影响心脏发育的分子机制。本研究将从公共卫生层面为先心病防治提出新的思路。

The etiology of congenital heart disease (CHD) is unknown. Environmental pollutants are important risk factors for CHD. However, the specific substances and mechanisms are unclear. Previously, we found that elevation of the widespread heavy metal, lead, and the new type of persistent pollutant, perfluorooctanesulfonate (PFOS), in the maternal blood and cord blood, is closely related to the occurrence of CHD. In addition, lead interacts with other pollutants to increase the odds of CHD occurrence. However, there are no reports about the effect of parents’ co-exposure to PFOS and lead on the occurrence of CHD during the perinatal period. We also proved that the methylation at the promoters’ area of the key genes of heart differentiation, like Gata4 and Tbx5, is involved in the inhibition of environmental contaminant on cardiac heart development. Basing on this, we hypothesize that, PFOS interacts with lead, inhibits the expression of key genes in cardiac development by promoting the related genes’ methylation, thereby affects the differentiation of embryonic stem cells into cardiac cells and promotes the occurrence of CHD. This project intends to identify 1) the effects of co-exposure of PFOS and lead on the occurrence of CHD from the multiple levels, including population cohort, biological specimens, molecules and cells; 2) the effects of PFOS and lead affecting the transcription and translation of the key genes for cardiac differentiation; 3) unveiling the molecular mechanism that the two substances affect cardiac development through methylation modification. This study is expected to propose a new strategy for the prevention and treatment of CHD from the public health perspective.