Epigenetic Consequences of Prenatal Alcohol Exposure

描述（由申请人提供）：胎儿酒精暴露（FAE）的大鼠模型模拟了在饮酒母亲的孩子中观察到的许多症状，包括后代的认知障碍。我们假设 FAE 会诱导神经发育基因的表观遗传改变，从而导致成年后代出现这些损伤。我们选择研究已知参与空间学习和记忆的印记基因，其缺陷或过度表达会导致认知障碍。这些基因包括 Delta 样 (Dlk)、3 型脱碘酶 (Dio3)、G 蛋白亚基、Gs (Gnas) 及其变体、necdin (Ndn)、泛素蛋白连接酶 E3A (Ube3a) 和 RAS 蛋白特异性鸟嘌呤核苷酸释放因子 1 (Rasgrf1)。我们将研究： 具体目标 1. 子宫内乙醇暴露对选定基因的印记和总表达的表观遗传效应。我们将首先证实这些基因在大鼠中被印记，然后我们将确定 FAE 对这些印记基因表达模式的短期和长期影响。具体目标 2. FAE 通过表征 DNA 和组蛋白修饰以及转录因子在已知调控位点的结合来改变表达/印记的机制。我们将检查候选基因的印记机制，该机制显示 FAE 的表达改变。具体目标 3. 逆转 FAE 诱导的表观遗传失调的不同策略。我们将在哺乳期或断奶后对动物进行已知会影响表观遗传机制的膳食补充剂方案，并随后筛选空间学习和记忆以及基因表达模式和 DNA/染色质修饰的改善情况。具体目标 4. FAE 对认知表型和候选基因表观遗传改变的跨代影响。将进行两代杂交，其中只有第一代母鼠接受酒精。相互杂交将测试母本和父本传播。这些目标将使我们更深入地了解产前乙醇引起后代行为缺陷的机制。 FAE 效应的跨代遗传是一个重要问题，涉及治疗方案与多代功能障碍的社会学后果。确定跨代效应的机制和潜在可逆性并在 FAE 动物模型中设计新颖的干预措施是一个主要目标，可能对人类 FAE 有益。公共卫生相关性：胎儿酒精暴露 (FAE) 的大鼠模型模拟了在饮酒母亲的孩子中观察到的许多症状，包括后代的认知缺陷。在本申请中，我们假设产前酒精暴露引起的表观遗传改变会导致 FAE 的认知缺陷，并且这些改变是跨代遗传的。后一种可能性具有多种含义，从治疗替代方案的重要性到多代功能障碍的社会学后果。确定跨代效应的机制和潜在的可逆性是一个重要的目标。

DESCRIPTION (provided by applicant): 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.