Altered genomic imprinting as a basis for FASD placental growth defects

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DESCRIPTION (provided by applicant): Alcohol consumption during pregnancy is widespread in our society despite its proven association with the development of birth defects and severe mental impairment. Forty percent of all women report the consumption of some alcohol during the course of their pregnancy and 3-5% drink heavily as a result of addiction. Consequently, 9.1 cases per 1000 live births exhibit some degree of fetal alcohol spectrum disorder (FASD) with an associated annual health care cost of approximately 5 billion dollars. From studies using a diverse range of model organisms, we now acknowledge epigenetic modifications to chromatin structure provide a plausible link between environmental teratogens and alterations in gene expression leading to disease phenotypes. Work from a number of independent laboratories has demonstrated that ethanol has the capacity to act as a powerful epigenetic disruptor and derail the transcriptional processes directing mammalian development. Although these epigenetic alterations do not induce genetic mutations, they none-the-less alter the course of development and cause disease. This is especially true during early pregnancy when epigenetic processes establish the complex transcriptional regulation of imprinted genes. The proper control of genes regulated by genomic imprinting is perhaps one of the most important regulatory pathways involved in the development and function of the placenta. Importantly, placental abnormalities and growth retardation are defining phenotypes of FASDs. Of further note, several instances have been reported where infants were born with characteristic FASD associated growth defects to mothers who had not consumed alcohol during pregnancy; but whose fathers were chronic alcoholics. The innovative aspect of this application lies in its approach to utilize an established model of epigenetic developmental programming to simultaneously examine two poorly studied aspects of FASD biology: 1) the role of altered imprinted gene expression in the genesis of FASD placental growth defects and 2) the impact of male ethanol consumption on developmental programming. Epigenetic-based treatments now constitute a significant portion of front-line cancer therapies and have achieved remarkable progress in blocking cancer progression. As our understanding of the epigenetic mechanisms controlling early development increases, it is likely these compounds will find utility in other therapeutic applications including the prenatal treatment of FASDs. However, understanding how prenatal exposure to alcohol impacts chromatin organization and the nature of the epigenetic changes that result from prenatal ethanol exposure remain major barriers in the field of fetal alcohol research.