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Transgenerational effect of gestational ethanol exposure

妊娠期乙醇暴露的跨代效应

基本信息

批准号：
9215617
负责人：
Nicole Marguerite Cameron
金额：
$ 21.24万
依托单位：
STATE UNIVERSITY OF NY,BINGHAMTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-05 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9215617
关键词：
Adolescence Adolescent Affect Alcohol abuse Alcohol consumption Alcoholism Alcohols Aminobutyric Acids Animal Model Anterior Area Base Pairing Behavior Therapy Brain Brain region Breeding Centers for Disease Control and Prevention (U.S.)Cognitive deficits DNA Methylation Data Desire for food Developmental Delay Disorders Disease Environmental Risk Factor Epigenetic Process Ethanol Exposure to Female Fetal Alcohol Exposure Future Gene Targeting Generations Genes Genetic Markers Germ Lines Growth Human Infant Investigation Laboratories Life Mammals Medial Mediating Nucleus Accumbens Opioid Receptor Pharmaceutical Preparations Phenotype Plants Prefrontal Cortex Pregnancy Pregnant Women Probability Property Psychological reinforcement Puberty Public Health Rattus Reflex action Research Resolution Risk Rodent Syndrome System Techniques Testing Transference Uterus Variant Ventral Tegmental Area Water Work alcohol effect alcohol exposure alcohol reward alcohol risk alcohol sensitivity alcohol use disorder animal breeding binge drinking cingulate cortex experimental study fetal fungus gamma-Aminobutyric Acid genome-wide hypnotic innovation interest male model development neuromechanism offspring postnatal prenatal prenatal exposure prenatal testing protein expression public health relevance receptor expression statistics trait transgenerational epigenetic inheritance transmission process whole genome

项目摘要

DESCRIPTION (provided by applicant): Prenatal alcohol exposure has been shown to increase the probability of use and abuse of ethanol later in life. One question remaining to be answered is, can it also be transmitted across generations? Our data suggest that low/moderate ethanol exposure results in increased ethanol intake and reduced sensitivity to ethanol's hypnotic effects during puberty not only in those infant rats exposed to ethanol in the womb but also in their offspring. Our central hypothesis is that inheritance of ethanol use/abuse liability s transgenerational and associated with variations in DNA methylation in specific brain regions known to be involved in alcohols rewarding proper- ties. The transformative objective of the present proposal is to identify the specific genes in these brain areas that are involved in ethanol programming as well as the lineage involved in transgenerational transmission of the ethanol-exposed phenotype. This project uses an animal model of prenatal ethanol exposure to investigate the transmission of increased liability for ethanol abuse in the offspring directly exposed to alcohol in the womb and their progeny. Specific Aim 1 will determine the contribution of maternal and paternal lineages in the effect of gestational ethanol exposure on ethanol sensitivity and consumption in three generation of off- spring. This will be achieved through testing prenatally exposed animals and breeding male and female rats prenatally exposed (F1) to 1) ethanol, 2) water, or 3) non-manipulated in all possible combinations (9; see table in approach) to determine the lineage involved in transmission. Our hypothesis, that inheritance is through paternal lineage, will be tested by examining ethanol intake at postnatal day (PD) 14 and in adolescence, and sensitivity to the hypnotic effects (loss of righting reflex test) of ethanl at PD 42. Specific Aim 2 will identify the effect of ethanol exposure during gestation on genome-wide DNA methylation of F1 and F2 of the extreme lineage (affected lineage and control), using a whole-genome bisulfate sequencing technique. Results obtained after completion of this work will allow us to direct future work towards target genes involved in the transmission of ethanol-exposed phenotype, and to better understand the mechanisms involved in transgenerational inheritance of increased risk for ethanol abuse.

描述（由申请人提供）：产前接触酒精已被证明会增加以后生活中使用和滥用乙醇的可能性。尚待回答的一个问题是，它是否也可以代代相传？我们的数据表明，低/中度乙醇暴露不仅会导致在子宫内暴露于乙醇的幼鼠，而且会导致其后代在青春期期间乙醇摄入量增加并降低对乙醇催眠作用的敏感性。我们的中心假设是，乙醇使用/滥用倾向的遗传是跨代的，并且与已知与酒精奖励特性有关的特定大脑区域的 DNA 甲基化变化有关。本提案的变革性目标是确定这些大脑区域中参与乙醇编程的特定基因，以及参与乙醇暴露表型跨代传递的谱系。该项目使用产前乙醇暴露的动物模型来研究在子宫内直接暴露于酒精的后代及其后代中乙醇滥用倾向增加的传播情况。具体目标 1 将确定母系和父系谱系对妊娠期乙醇暴露对三代后代乙醇敏感性和消耗的影响的贡献。这将通过测试产前暴露的动物和繁殖雄性和雌性大鼠，使其产前暴露于 1) 乙醇、2) 水或 3) 所有可能的组合（9；参见方法中的表格）中的非操纵物质，以确定传播所涉及的谱系。我们的假设是通过父系遗传，将通过检查出生后第 14 天和青春期的乙醇摄入量以及 PD 42 对乙醇催眠作用（翻正反射测试丧失）的敏感性进行测试。具体目标 2 将确定妊娠期间乙醇暴露对极端谱系（受影响的 F1 和 F2）的全基因组 DNA 甲基化的影响。谱系和对照），使用全基因组硫酸氢盐测序技术。完成这项工作后获得的结果将使我们能够将未来的工作导向参与乙醇暴露表型传递的靶基因，并更好地了解乙醇滥用风险增加的跨代遗传机制。