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改变，导致成年后代出现这些损伤。我们选择研究已知与空间学习和记忆有关的印迹基因，这些基因的缺失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）。我们将调查：具体目标1。子宫内乙醇暴露对所选基因印迹和总表达的表观遗传影响。我们将首先证实这些基因在大鼠中有印记，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。通过DNA和组蛋白修饰的表征以及转录因子在已知调控位点的结合，FAE改变表达/印迹的机制。我们将研究候选基因的印迹机制，这些基因显示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。我们将在哺乳期间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，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。具体目标FAE对候选基因认知表型和表观遗传改变的跨代影响。将进行两代杂交，只有第一代大坝接受酒精。互惠杂交将测试母亲和父亲的传播。这些目标将使我们更接近于理解产前乙醇诱导后代行为缺陷的机制。从治疗方案到多代功能障碍的社会学后果，FAE效应的跨代遗传是一个重要的问题。确定跨代效应的机制和潜在可逆性，并在FAE动物模型中设计新的干预措施，是一个可能对人类FAE有益的主要目标。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。在这项应用中，我们假设产前酒精暴露的表观遗传改变导致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重含义，从治疗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.