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.
