Ethanol Teratogenesis and Genomic Imprinting

描述（由申请人提供）：我们建议研究介导乙醇致畸效应差异易感性的遗传机制。先前的研究已经确定了母体效应介导产前乙醇暴露后不同的致畸结局。在这一建议中，我们将研究基因组印迹作为影响的机制。我们首先提出进一步表征C57BL/6J和DBA/2J衍生小鼠群体中乙醇致畸的遗传结构，并对介导致畸的印迹QTL进行数量性状位点（QTL）定位。我们将研究在胚胎和胎盘中，在产前乙醇暴露后，DMA甲基化，组蛋白修饰和基因表达的变化，已知在生长和发育中起作用的几个印迹基因。此外，我们将检查胎儿在子宫内暴露于酒精的整体基因表达变化。我们还将研究给幼鼠提供富含甲基的饮食对致畸的影响。在美国，估计每年有13万名妇女将胎儿暴露在高浓度酒精中，估计相关成本为40亿至110亿美元，鉴于此，我们的建议与公共卫生的相关性至关重要。如果我们在小鼠产前酒精暴露后确定印迹基因的表观遗传修饰和/或基因表达变化，它们将成为人类研究的目标。如果我们发现在母鼠饮食中添加甲基可以改善乙醇的一些致畸作用，那么这就提出了一种可能适用于人类妊娠的有效策略。

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.