Epigenetics of alcohol effects on stress axis development

描述（由申请人提供）：胎儿期暴露于酒精的儿童和年轻人表现出情绪障碍，如抑郁、焦虑、注意力缺陷和多动。动物研究已经将行为异常与应激轴功能问题联系起来，特别是对各种应激事件的促肾上腺皮质激素释放激素（CRH）神经元活动的高反应性。对压力事件的适应部分取决于个体产生压力轴激素水平增加的能力，以及在压力源消退后降低这些激素水平的能力。最近的报告表明，在关键的发育阶段接触激素和毒物会导致关键基因的改变，从而导致暴露个体及其后代的生理和/或行为改变。因此，提出CRH神经元功能的表观遗传改变是否由发育过程中的酒精暴露引起的问题。我们假设，发育过程中的酒精暴露通过改变β -内啡肽神经元中DNA甲基化和POMC基因的表达来损害应激轴功能，而β -内啡肽神经元调节下丘脑的CRH分泌。该提案的目的是验证大脑发育过程中的酒精暴露通过改变下丘脑中CRH和/或其调控基因POMC的DNA甲基化和mRNA表达，对应激轴功能产生表观遗传跨代效应的假设。这将通过确定应激轴高反应性是否伴随着β -内啡肽和/或CRH神经元中基因启动子活性的DNA甲基化改变，以及评估基因沉默活性是否伴随着在发育期间暴露于酒精的后代下丘脑中这些神经元中DNA甲基转移酶表达的改变来实现。此外，胎儿酒精暴露是否会对应激轴功能产生跨代影响将被研究。提出的研究应提供对酒精对应激神经内分泌轴发育不利影响的分子机制的更好理解，并应揭示新的假定的表观遗传疾病生物标志物，这些生物标志物可能增强早期检测策略，并作为胎儿酒精暴露患者应激轴功能障碍的治疗靶点。

DESCRIPTION (provided by applicant): Children and young adults who were exposed to alcohol during fetal life show emotional disturbances such as depression, anxiety, attention deficit, and hyperactivity. Animal studies have linked the behavioral abnormalities to problems in the stress axis function, particularly the hyperresponsiveness of corticotrophin-releasing hormone (CRH) neuronal activity, to a variety of stressful events. Adaptation to a stressful event depends in part on an individual's ability to produce increased levels of the hormones of the stress axis and to reduce the levels of these hormones once the stressor has subsided. Recent reports indicated that hormone and toxicant exposure at crucial developmental stages results in alteration of key genes, resulting in physiological and/or behavioral changes not only in exposed individuals but also in their offspring. Hence, the question is raised whether epigenetic alterations of the CRH neuronal function are caused by alcohol exposure during the development. We hypothesize that alcohol exposure during development impairs stress axis function by altering DNA methylation and expression of proopiomelanocortin (POMC) gene in beta-endorphin neurons, which regulate CRH secretion from the hypothalamus. The objective of the proposal is to test the hypothesis that alcohol exposure during brain development produces epigenetic transgenerational effect on the stress axis function by altering DNA methylation and mRNA expression of CRH and/or its regulatory POMC genes in the hypothalamus. This will be achieved by identifying whether the stress axis hyperresponsiveness is accompanied by altered DNA methylation of gene-promoter activities in beta-endorphin and/or CRH neurons, and by evaluating whether gene-silencing activity is accompanied by the alteration in the expression of DNA methyltransferases in these neurons in the hypothalamus of offspring exposed to alcohol during the developmental period. Furthermore, whether fetal alcohol exposure induces transgenerational effects on the stress axis function will be studied. The proposed studies should provide a better understanding of the molecular mechanisms responsible for the detrimental effects of alcohol on the development of the neuroendocrine axis of stress and should reveal new putative epigenetic disease biomarkers that may enhance early detection strategies and serve as therapeutic targets for stress axis dysfunction in fetal alcohol exposed patients. PUBLIC HEALTH RELEVANCE: Recent reports have indicated that hormone and toxicant exposure at crucial developmental stages cause an alteration in the function of key genes, resulting in physiological and/or behavioral changes not only in exposed individuals but also in their offspring. Hence, the question is raised whether an inheritance of epigenetic alteration of the corticotrophin releasing hormone neuronal function induced by alcohol exposure during development causing the stress axis dysfunction that leads to various affective disorders in fetal alcohol exposed patients. The goal of this proposal is to determine the epigenetic transgenerational effect of alcohol on the stress axis function in order to identify new putative epigenetic disease biomarkers as well as to develop early detection strategies and therapeutic targets for stress axis disorders in fetal alcohol exposed patients.