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诱导神经发育基因的表观遗传学改变，从而导致成年后代的这些损害。我们选择研究印记基因，这些基因已知与空间学习和记忆有关，其缺陷或过度表达会导致认知障碍。这些基因包括Delta-like(DLK)、3型脱碘酶(Dio3)、G蛋白亚基Gs(GNas)及其变异体、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：特定目标1。子宫内乙醇暴露对选定基因印迹和总表达的表观遗传学影响。我们将首先证实这些基因在大鼠体内是印记的，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。特定目的2.FAE通过DNA和组蛋白修饰以及转录因子在已知调控位点结合的特征来改变表达/印记的机制。我们将研究候选基因的印记机制，这些基因显示FAE的表达变化。具体目的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实施已知的影响表观遗传机制的饮食补充方案，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。特定目的4.FAE对候选基因的认知表型和表观遗传学改变的跨代效应。将进行两代杂交，只有第一代水坝接受酒精。反向杂交将检测母系和父系的传播。这些目标将使我们更接近于了解产前酒精导致后代行为缺陷的机制。FAE效应的跨代遗传是一个重要的问题，从治疗方案到多代功能障碍的社会学后果都具有相关性。确定跨代效应的机制和潜在的可逆性，并在FAE的动物模型中设计新的干预措施，是一个可能对人类FAE有利的主要目标。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。在这个应用中，我们假设响应产前酒精暴露的表观遗传改变有助于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重含义，因为替代治疗的重要性超过了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.