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: 7295785
• 负责人: JOANNE WEINBERG
• 金额: $ 12.45万
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7295785
• 关键词: Acetylation; Adrenal Glands; Adverse effects; Alcohol consumption; Animals; Behavioral; Behavioral Research; Brain; Brain region; Choline; Chromatin Structure; Chronic; Control Groups; DNA Methylation; Development; Diet; Disease; Environment; Epigenetic Process; Ethanol; Event; Exposure to; Female; Fetal Alcohol Exposure; Fetus; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Generations; Genes; Global Change; Glucocorticoid Receptor; Glucocorticoids; Goals; Health; Hippocampus (Brain); Histones; Homocysteine; Homocystine; Human; Hypothalamic structure; Individual; Life; Link; Liver; Liver diseases; Longevity; Maternal Behavior; Metabolic; Metabolism; Methionine; Methylation; Mineralocorticoid Receptor; Modeling; Molecular; Molecular Profiling; Neurosecretory Systems; Organism; Pattern; Pharmaceutical Preparations; Physiological; Physiological Processes; Pituitary Gland; Plasma; Pregnancy; Rattus; Regulation; Research Personnel; Stimulus; Stress; System; Testing; Time; Tissues; alcohol consumption during pregnancy; alcohol exposure; chronic alcohol ingestion; concept; day; disorder risk; environmental agent; feeding; fetal; fetal programming; hypothalamic-pituitary-adrenal axis; in utero; male; mature animal; metabolomics; methyl group; postnatal; prenatal; programs; response; stressor; therapy development; young adult

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(申请人提供)：产前酒精暴露使胎儿下丘脑-垂体-肾上腺(HPA)轴产生程序，使HPA在整个生命过程中张力增加，导致HPA对应激源的高反应。发展规划概念指出，早期环境刺激可以规划新陈代谢和生理过程，因此在以后的生活中增加了对疾病或障碍的易感性。因此，HPA功能的长期增加将增加一生中接触糖皮质激素的次数，并对健康产生不利后果。这种编程的机制(S)尚不清楚，但可能涉及环境刺激和基因表达的表观遗传调节之间的相互作用，例如DNA甲基化和/或染色质结构的变化(例如组蛋白甲基化、乙酰化)。生物体在发育过程中特别容易受到表观遗传变化的影响，表观基因组对环境刺激非常敏感，如母体饮食(包括药物和其他有毒物质)和母体行为。我们认为，宫内酒精暴露是一种环境刺激，会引起表观遗传变化，并带来长期的不良后果。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、DNA甲基化模式的基因特异性变化以及促进应激高反应的基因表达谱的结果。利用我们已建立的产前酒精暴露模型，我们将检验这一假设，即产前酒精暴露改变蛋氨酸循环，并通过DNA甲基化模式和对正常HPA活动和调节至关重要的基因表达的特定基因改变来编程胎儿HPA轴。我们的具体目标是确定胎儿酒精暴露是否导致：1)子代甲基状态改变；2)DNA甲基化模式和脑内糖皮质激素受体(NR3c1)和盐皮质激素受体(Nr3c2)基因表达谱的变化。拟议的研究将开始阐明HPA编程和子宫内暴露于乙醇的动物对应激的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，这些干预措施可能有效地拯救这些系统。

项目成果

Prenatal alcohol exposure alters methyl metabolism and programs serotonin transporter and glucocorticoid receptor expression in brain.

产前酒精暴露会改变甲基代谢并调节大脑中血清素转运蛋白和糖皮质激素受体的表达。

• DOI: 10.1152/ajpregu.00075.2015
• 发表时间: 2015
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Ngai,YingFai;Sulistyoningrum,DianC;O'Neill,Ryan;Innis,SheilaM;Weinberg,Joanne;Devlin,AngelaM
• 通讯作者: Devlin,AngelaM

Focus on: epigenetics and fetal alcohol spectrum disorders.

重点研究：表观遗传学和胎儿酒精谱系障碍。

• 发表时间: 2011
• 期刊: Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism
• 作者: Kobor,MichaelS;Weinberg,Joanne
• 通讯作者: Weinberg,Joanne