PRENATAL ETHANOL EXPOSURE: PROGRAMMING, DNA METHYLATION AND THE HPS AXIS

产前乙醇暴露：编程、DNA 甲基化和 HPS 轴

• 批准号: 7216586
• 负责人: JOANNE WEINBERG
• 金额: $ 15.53万
• 依托单位: UNIVERSITY OF BRITISH COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7216586
• 关键词: DNA methylation; choline; corticosteroid receptors; developmental genetics; embryo /fetus toxicology; environmental stressor; epigenetics; ethanol; fetal alcohol syndrome; gene environment interaction; gene expression profiling; genetic regulation; high performance liquid chromatography; hippocampus; homocysteine; hypothalamic pituitary adrenal axis; hypothalamus; laboratory rat; liquid chromatography mass spectrometry; methionine; neurogenetics; neuropathology; polymerase chain reaction; radioimmunoassay; receptor expression

DESCRIPTION (provided by applicant): Prenatal ethanol exposure programs the fetal hypothalamic-pituitary-adrenal (HPA) axis such that HPA tone is increased throughout life, resulting in HPA hyperresponsiveness to stressors. The developmental programming concept states that early environmental stimuli can program metabolic and physiologic processes and as such increase vulnerability to illnesses or disorders later in life. Thus a long-term increase in HPA function will increase exposure to glucocorticoids over the lifespan and have adverse consequences for health. The mechanism(s) underlying such programming are unknown, but probably involve an interaction between environmental stimuli and epigenetic regulation of gene expression, such as changes in DNA methylation and/or chromatin structure (e.g. histone methylation, acetylation). An organism is especially vulnerable to epigenetic changes during development and the epigenome is highly susceptible to environmental stimuli such as maternal diet (including drugs and other toxic agents) and maternal behavior. We propose that in utero ethanol exposure is an environmental stimulus that elicits epigenetic changes with long-term adverse consequences. Because of the metabolic link of ethanol to methyl group metabolism we speculate that the HPA programming observed in adult animals exposed in utero to ethanol is a consequence of alterations in methyl group metabolism, gene-specific changes in DNA methylation patterns and a gene expression profile that promotes hyperresponsiveness to stress. Utilizing our well established model of prenatal ethanol exposure, we will test the hypothesis that prenatal ethanol exposure alters the methionine cycle and programs the fetal HPA axis through gene-specific changes in DNA methylation patterns and expression of the genes crucial to normal HPA activity and regulation. Our Specific Aims are to determine if fetal ethanol exposure results in: 1) altered methyl status in offspring; and 2) changes in DNA methylation patterns and the expression profile in brain of the glucocorticoid receptor (Nr3c1) and the mineralocorticoid receptor (Nr3c2) genes. The proposed studies will begin to elucidate possible mechanisms underlying HPA programming and altered behavioral responses to stress in animals exposed to ethanol in utero. Our goal is to provide a framework for the future development of interventions that could be effective in rescuing these systems.

描述（由申请人提供）：产前乙醇暴露会影响胎儿下丘脑-垂体-肾上腺（HPA）轴，使HPA张力在整个生命周期中增加，导致HPA对压力源的高反应性。发展规划概念指出，早期的环境刺激可以规划代谢和生理过程，因此增加了以后生活中对疾病或障碍的脆弱性。因此，HPA功能的长期增加将增加一生中对糖皮质激素的暴露，并对健康产生不利后果。这种编程的机制尚不清楚，但可能涉及环境刺激和基因表达的表观遗传调控之间的相互作用，例如DNA甲基化和/或染色质结构的变化（如组蛋白甲基化、乙酰化）。生物在发育过程中特别容易受到表观遗传变化的影响，表观基因组极易受到环境刺激的影响，如母亲的饮食（包括药物和其他有毒物质）和母亲的行为。我们认为，子宫内乙醇暴露是一种环境刺激，可引起具有长期不良后果的表观遗传变化。由于乙醇与甲基代谢的代谢联系，我们推测，在子宫内暴露于乙醇的成年动物中观察到的HPA编程是甲基代谢改变的结果，DNA甲基化模式的基因特异性变化和促进应激高反应性的基因表达谱。利用我们完善的产前乙醇暴露模型，我们将验证产前乙醇暴露通过DNA甲基化模式和对正常HPA活性和调节至关重要的基因表达的基因特异性改变蛋氨酸循环和编程胎儿HPA轴的假设。我们的具体目的是确定胎儿乙醇暴露是否会导致：1)后代甲基状态改变；2)脑内糖皮质激素受体（Nr3c1）和矿皮质激素受体（Nr3c2）基因甲基化模式和表达谱的变化。拟议的研究将开始阐明子宫内暴露于乙醇的动物HPA编程和应激行为反应改变的可能机制。我们的目标是为未来干预措施的发展提供一个框架，以有效地挽救这些系统。