Ethanol Teratogenesis and Genomic Imprinting

描述(由申请人提供)：我们建议研究乙醇致畸效应的不同易感性的遗传机制。以前的研究已经确定了母体效应在产前酒精暴露后调节不同的致畸结果。在这项提案中，我们将研究基因组印迹作为这种效应的一种机制。我们首先建议进一步研究C57BL/6J和DBA/2J小鼠群体中乙醇致畸的遗传结构，并对介导致畸的印记QTL进行数量性状基因座(QTL)定位。我们将研究DNA甲基化、组蛋白修饰以及产前酒精暴露后胚胎和胎盘中几个已知在生长和发育中发挥作用的印记基因的基因表达变化。此外，我们还将研究宫内酒精暴露胎儿的整体基因表达变化。我们还将研究为水坝提供甲基强化饮食对畸形发生的影响。鉴于在美国，估计每年有13万名女性将她们的胎儿暴露在高酒精环境中，估计相关成本为40-110亿美元，因此我们的提案对公共健康的相关性至关重要。如果我们确定胎儿期酒精暴露后小鼠的表观遗传修饰和/或印记基因的基因表达变化，它们将成为人类研究的目标。如果我们发现DAMS饮食中的甲基补充可以改善乙醇的一些致畸作用，这就提出了一种可能适用于人类怀孕的有效策略。

DESCRIPTION (provided by applicant): We propose to study the genetic mechanisms mediating differential susceptibility to the teratogenic effects of ethanol. Previous research has identified a maternal effect mediating different teratogenic outcomes following prenatal ethanol exposure. In this proposal, we will examine genomic imprinting as a mechanism for the effect. We first propose to further characterize the genetic architecture underlying ethanol teratogenesis in populations of mice derived from C57BL/6J and DBA/2J mice and perform quantitative trait locus (QTL) mapping for imprinted QTLs mediating teratogenesis. We will examine DMA methylation, histone modifications and changes in gene expression, in embryos and placentae, following prenatal ethanol exposure, of several imprinted genes known to play a role in growth and development. In addition, we will examine global gene expression changes in fetuses exposed to alcohol in utero. We also will examine the effects of providing dams with a methyl-enriched diet on teratogenesis. Given that, in the US, an estimated 130,000 per year women expose their fetuses to high levels of alcohol, and the estimated associated costs are $4-$11 billion, the relevance of our proposal to public health is paramount. If we identify epigenetic modifications and/or gene expression changes in imprinted genes following prenatal alcohol exposure in mice, they become targets for human studies. If we find that methyl-supplementation of dams diets' ameliorates some of the teratogenic effects of ethanol, it suggests an effective strategy that may be applicable to human pregnancy.