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.
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.
|Tunc-Ozcan, E; Wert, S L; Lim, P H et al. (2018) Hippocampus-dependent memory and allele-specific gene expression in adult offspring of alcohol-consuming dams after neonatal treatment with thyroxin or metformin. Mol Psychiatry 23:1643-1651|
|Tunc-Ozcan, Elif; Harper, Kathryn M; Graf, Evan N et al. (2016) Thyroxine administration prevents matrilineal intergenerational consequences of in utero ethanol exposure in rats. Horm Behav 82:1-10|
|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|
|Harper, Kathryn M; Tunc-Ozcan, Elif; Graf, Evan N et al. (2014) Intergenerational effects of prenatal ethanol on glucose tolerance and insulin response. Physiol Genomics 46:159-68|
|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|
|Dietz, William H; Masterson, Kevin; Sittig, Laura J et al. (2012) Imprinting and expression of Dio3os mirrors Dio3 in rat. Front Genet 3:279|
|Sittig, Laura J; Redei, Eva E (2012) Novel polymorphisms within the Dlk1-Dio3 imprinted locus in rat: a putative genetic basis for strain-specific allelic gene expression. Front Genet 3:296|
|Sittig, L J; Herzing, L B K; Xie, H et al. (2012) Excess folate during adolescence suppresses thyroid function with permanent deficits in motivation and spatial memory. Genes Brain Behav 11:193-200|
|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|
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