Rat models of fetal alcohol exposure (FAE) emulate many symptoms observed in children of alcohol consuming mothers including cognitive impairments of the offspring. We hypothesize that FAE induces epigenetic alterations of neurodevelopmental genes contributing to these impairments in adult offspring. We selected to study imprinted genes that are known to be involved in spatial learning and memory, and whose deficit or overexpression causes cognitive impairment. These genes include, the Delta-like (Dlk), type 3 deiodinase (Dio3), G-protein -subunit, Gs (Gnas) and its variants, necdin (Ndn), ubiquitin protein ligase E3A (Ube3a) and RAS protein-specific guanine nucleotide-releasing factor 1 (Rasgrf1). We will investigate:
Specific Aim 1. The epigenetic effects of ethanol exposure in utero on imprinted and total expression of selected genes. We will initially corroborate that these genes are imprinted in the rat and then we will determine the short and long-term effects of FAE on the expression patterns of these imprinted genes.
Specific Aim 2. The mechanism of altered expression/imprinting by FAE through characterization of DNA and histone modifications and transcription factor binding at known regulatory loci. We will examine the imprinting mechanisms of candidate genes, which show expression alterations by FAE.
Specific Aim 3. Different strategies to reverse FAE-induced epigenetic dysregulation. We will administer dietary supplement regimes, known to affect epigenetic mechanisms, to animals during lactation, or post- weaning, and subsequently screen for improvement in spatial learning and memory as well as gene expression patterns and DNA/chromatin modifications.
Specific Aim 4. The trans-generational effects of FAE on the cognitive phenotype and the epigenetic alterations of candidate genes. A two-generational cross will be carried out where only the first generation dam receives alcohol. Reciprocal crossing will tests both maternal and paternal transmission.
These aims will bring us closer to understanding the mechanisms by which prenatal ethanol induce behavioral deficits in the offspring. Transgenerational inheritance of FAE effects is a significant question with relevance from treatment alternatives to the sociological consequences of multigenerational dysfunction. Identifying the mechanisms and potential reversibility of transgenerational effects and devising novel interventions in the animal model of FAE is a major goal that could potentially be beneficial for human FAE.

Public Health Relevance

Rat models of fetal alcohol exposure (FAE) emulate many symptoms observed in children of alcohol consuming mothers including cognitive deficits of the offspring. In this application, we hypothesize that epigenetic alterations in response to prenatal alcohol exposure contribute to the cognitive deficits of FAE, and that these alterations are transgenerationally inherited. This latter possibility has multiple implications from the significance of treatment alternatives to the sociological consequences of multigenerational dysfunction. Identifying the mechanisms and potential reversibility of transgenerational effects is an important goal.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
3R01AA017978-05S1
Application #
8901348
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Reilly, Matthew
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Harper, Kathryn M; Tunc-Ozcan, Elif; Graf, Evan N et al. (2014) Intergenerational and parent of origin effects of maternal calorie restriction on Igf2 expression in the adult rat hippocampus. Psychoneuroendocrinology 45:187-91
Tunc-Ozcan, Elif; Ullmann, Timothy M; Shukla, Pradeep K et al. (2013) Low-dose thyroxine attenuates autism-associated adverse effects of fetal alcohol in male offspring's social behavior and hippocampal gene expression. Alcohol Clin Exp Res 37:1986-95
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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