Ethanol Teratogenesis and Genomic Imprinting

描述（由申请人提供）：我们建议研究介导对乙醇致畸作用的不同易感性的遗传机制。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果。在这个建议中，我们将研究基因组印记作为一种机制的影响。我们首先建议进一步描述遗传结构的乙醇致畸作用的小鼠群体C57 BL/6 J和DBA/2 J小鼠和执行数量性状基因座（QTL）定位的印记QTL介导的致畸作用。我们将研究DMA甲基化，组蛋白修饰和基因表达的变化，在胚胎和胎盘，产前乙醇暴露后，已知在生长和发育中发挥作用的几个印记基因。此外，我们将研究胎儿在子宫内暴露于酒精的整体基因表达变化。我们还将研究为母鼠提供富含甲基的饮食对致畸作用的影响。鉴于在美国，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，我们的提案对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识别出印记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补充甲基可以改善乙醇的某些致畸作用，这就表明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.