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

基本信息

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
项目类别：
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

项目摘要

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）：产前乙醇暴露会对胎儿下丘脑-垂体-肾上腺（HPA）轴进行编程，使HPA张力在一生中增加，导致HPA对压力源过度反应。发育编程概念指出，早期环境刺激可以编程代谢和生理过程，因此增加了以后生活中患疾病或紊乱的可能性。因此，HPA 功能的长期增强将增加一生中糖皮质激素的暴露，并对健康产生不利后果。这种编程背后的机制尚不清楚，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（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，并且表观基因组非常容易受到环境刺激的影响，例如母亲的饮食（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，会引起表观遗传变化，并产生长期不良后果。由于乙醇与甲基代谢之间的代谢联系，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基因表达谱改变的结果。促进对压力的过度反应。利用我们完善的产前乙醇暴露模型，我们将检验以下假设：产前乙醇暴露会改变蛋氨酸循环，并通过 DNA 甲基化模式的基因特异性变化以及对正常 HPA 活性和调节至关重要的基因表达来编程胎儿 HPA 轴。我们的具体目标是确定胎儿乙醇暴露是否会导致：1）后代甲基状态改变； 2) DNA 甲基化模式以及糖皮质激素受体 (Nr3c1) 和盐皮质激素受体 (Nr3c2) 基因在大脑中表达谱的变化。拟议的研究将开始阐明 HPA 编程的可能机制，以及子宫内接触乙醇的动物对压力的行为反应的改变。我们的目标是为未来开发可有效拯救这些系统的干预措施提供一个框架。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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。