Epigenetics of alcohol effects on stress axis development

描述（由申请人提供）：在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、注意力缺陷和多动症。动物研究已经将行为异常与应激轴功能问题联系起来，特别是促肾上腺皮质激素释放激素（CRH）神经元活动对各种应激事件的高反应性。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，以及一旦压力源消退就降低这些激素水平的能力。最近的报告表明，在关键发育阶段暴露于激素和有毒物质会导致关键基因的改变，不仅会导致暴露个体，而且还会导致其后代的生理和/或行为变化。因此，提出了一个问题，即CRH神经元功能的表观遗传改变是否是由发育过程中的酒精暴露引起的。我们推测，酒精暴露在发展过程中损害应激轴功能，通过改变DNA甲基化和β-内啡肽神经元，调节CRH分泌的阿黑皮素原（POMC）基因的表达。该提案的目的是测试的假设，在大脑发育过程中，酒精暴露产生的压力轴功能的表观遗传跨代效应，通过改变下丘脑CRH和/或其调节POMC基因的DNA甲基化和mRNA表达。这将通过以下方式实现：鉴定应激轴高反应性是否伴随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。此外，胎儿酒精暴露是否会引起跨代影响的压力轴功能将进行研究。拟议的研究应该提供一个更好的理解的分子机制负责酒精对神经内分泌轴的发展压力的有害影响，并应揭示新的推定的表观遗传疾病的生物标志物，可能会提高早期检测策略，并作为胎儿酒精暴露患者的应激轴功能障碍的治疗目标。 公共卫生相关性：最近的报告表明，在关键发育阶段接触激素和有毒物质会导致关键基因功能的改变，不仅会导致接触者的生理和/或行为变化，还会导致其后代的变化。因此，提出了一个问题，是否遗传的促肾上腺皮质激素释放激素神经元功能的表观遗传改变引起的酒精暴露在发展过程中的压力轴功能障碍，导致各种情感障碍的胎儿酒精暴露患者。本提案的目的是确定酒精对应激轴功能的表观遗传跨代效应，以确定新的推定的表观遗传疾病生物标志物，以及开发早期检测策略和胎儿酒精暴露患者应激轴疾病的治疗靶点。

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.