Paternal preconception alcohol on epigenetics and offspring drinking

父亲孕前饮酒对表观遗传学和后代饮酒的影响

基本信息

批准号：
8594397
负责人：
Andrey Finegersh
金额：
$ 4.72万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8594397
关键词：
Aberrant DNA Methylation Accounting Acetylesterase Adult Affect Air Alcohol consumption Alcohol dependence Alcoholism Alcohols Behavior Behavioral Behavioral Assay Biological Assay Biological Markers Birth Brain Brain region Cessation of life Child Cocaine Consumption DNA DNA Methylation DNA Methyltransferase DNA Modification Methylases Dependence Development Drug Targeting Environment Enzymes Epigenetic Process Ethanol Event-Related Potentials Fathers Female Fetal Alcohol Syndrome Future Gene Expression Gene-Modified Generations Genes Genetic Genetic Transcription Germ Germ Cells H19 gene Heritability Histones Measures Medial Mediating Mediator of activation protein Metabolism Methylation Methyltransferase Mothers Mus Muscle Form Glycogen Phosphorylase Parents Partner in relationship Phosphorylases Physiological Prefrontal Cortex Prevalence Prevention Research Research Proposals Risk Rodent Self Administration Societies Spermatogenesis Testing Transferase alcohol behavior alcohol exposure alcohol response alcohol use disorder alcoholism therapy base bisulfite chromatin modification clinical application cocaine exposure cost drinking drinking behavior histone modification imprint improved innovation male men novel novel strategies offspring public health relevance socioeconomics sperm cell transmission process

项目摘要

DESCRIPTION (provided by applicant): Alcohol use disorders (AUDs) are pervasive in society. Collectively, they incur enormous socioeconomic costs and contribute to tens of thousands of deaths each year. Therefore, it is of critical importance to develop new strategies for identifying people at increased risk for developing AUDs, which will likely improve prevention and treatment initiatives. Our proposal presents a novel approach to study transmission of alcohol drinking behaviors that contribute to risk for AUDs. About half of the risk for alcohol dependence (alcoholism) is transmitted from parents to offspring. While past research has focused on genes that modify risk for alcoholism, recent evidence suggests that acquired, epigenetic factors can be transmitted to offspring and affect their behavior. These epigenetic factors include DNA methylation and histone modifications, which are involved in regulating gene transcription. There is also strong evidence that preconception alcohol consumption by both mothers and fathers leads to behavioral deficits in offspring; moreover, a recent study showed that maternal preconception alcohol exposure induces changes in DNA methylation of offspring. However, no studies have examined the effect of paternal preconception alcohol consumption on alcohol drinking behaviors and the epigenetic landscape of offspring. To study the effects of paternal preconception alcohol exposure, we will expose male mice to alcohol for 5 weeks (one cycle of spermatogenesis) and mate them to alcohol-naive females. After mating, we will measure changes in DNA methylation in paternal germ cells. Offspring from these matings will be tested for changes in expression of enzymes that methylate DNA and modify histones in a key brain region for alcohol response. We will also use a comprehensive set of behavioral assays to test offspring for alcohol drinking behaviors and alcohol-induced behaviors during adulthood. Successful completion of the aims in our proposal will establish the effects of paternal preconception alcohol exposure on offspring behavior and uncover epigenetic changes that are likely mediators of these effects. These findings will be important for studying transgenerational inheritance of behaviors in the following generation. Our findings may also reveal new epigenetic targets for the treatment of alcoholism and fetal alcohol syndrome (FAS).

描述（由申请人提供）：酒精使用障碍（AUD）在社会上普遍存在。他们总体而言，他们会产生巨大的社会经济成本，并每年造成数万人死亡。因此，制定新策略以确定有更多的AUD风险的人至关重要，这可能会改善预防和治疗计划。我们的建议提出了一种研究饮酒行为的传播的新方法，这有助于auds风险。大约一半的酒精依赖风险（酒精中毒）从父母传播到后代。尽管过去的研究集中在改变酒精中毒风险的基因上，但最近的证据表明，获得的表观遗传因素可以传播到后代并影响其行为。这些表观遗传因素包括DNA甲基化和组蛋白修饰，这些因素与调节基因转录有关。也有强有力的证据表明，母亲和父亲的饮酒剂饮酒会导致后代的行为赤字。此外，最近的一项研究表明，孕产妇的饮酒暴露会导致后代DNA甲基化的变化。但是，尚无研究检查父亲先入饮酒对饮酒行为和后代的表观遗传景观的影响。为了研究父亲先入饮酒的影响，我们将使雄性小鼠暴露于酒精5周（一个精子发生周期），并将其与酗酒的女性相结合。交配后，我们将测量父亲生殖细胞中DNA甲基化的变化。这些分子的后代将测试，以确保甲基甲基DNA并在关键大脑区域中修饰组蛋白的酶的表达变化以进行酒精反应。我们还将使用一组全面的行为分析来测试成年期间饮酒行为和酒精引起的行为的后代。在我们的提案中，成功完成目标将确定父亲先入为主的酒精暴露对后代行为的影响，并发现可能是这些影响的介体的表观遗传变化。这些发现对于研究下一代行为的跨代遗传至关重要。我们的发现还可能显示出用于治疗酒精中毒和胎儿酒精综合征（FAS）的新表观遗传靶标。