The long-term goal of the thesis work proposed here is to elucidate the contribution of epigenetic effects of ethanol to the developmental susceptibility to depression and anxiety disorders seen after fetal alcohol exposure. Maternal ethanol consumption is a widespread problem and this research will be highly instructive as to potential reversal strategies after completion of the proposed specific aims. These include the determination of the time course of ethanol-mediated hormonal and epigenetic changes in the brain and placenta, and the experimental dissociation of epigenetic effects from the effects of ethanol-induced maternal hypothyroidism. We will also determine the epigenetic mechanism by which ethanol alters imprinting and thyroid hormone metabolism, unveiling the specific genomic regions that will be targeted by future reversal paradigms. Together, the information gained about the distinct but related epigenetic and hormonal aspects of ethanol exposure will create a comprehensive understanding of the timing and nature of ethanol's actions in the fetal brain. The temporal and physiological outline to be generated by our data is absolutely necessary before we can implement targeted, timed approaches to reverse each of the ethanol effects we uncover. We place high value on the health relevance of this project as it is based on a moderate but sustained level of fetal alcohol exposure. This paradigm is highly relevant in human populations in which maternal alcohol consumption is accepted or under-reported, resulting in neurological problems in the offspring. These deficits persist throughout postnatal development and adulthood, creating public health issues that manifest over the entire lifespan. These include negative effects on the education system attributable to childhood learning disabilities and hyperactivity, and subsequently, the social, financial, and health care-related repercussions of adult mental illness.
|Sittig, Laura J; Redei, Eva E (2014) Fine-tuning notes in the behavioral symphony: parent-of-origin allelic gene expression in the brain. Adv Genet 86:93-106|
|Sittig, Laura J; Shukla, Pradeep K; Herzing, Laura B K et al. (2011) Strain-specific vulnerability to alcohol exposure in utero via hippocampal parent-of-origin expression of deiodinase-III. FASEB J 25:2313-24|
|Sittig, L J; Herzing, L B K; Shukla, P K et al. (2011) Parent-of-origin allelic contributions to deiodinase-3 expression elicit localized hyperthyroid milieu in the hippocampus. Mol Psychiatry 16:786-7|