Paternal preconception alcohol on epigenetics and offspring drinking

描述(申请人提供)：酒精使用障碍(AUD)在社会上很普遍。总体而言，它们造成了巨大的社会经济成本，并导致每年数万人死亡。因此，至关重要的是制定新的战略，以确定患AUDS风险增加的人，这可能会改善预防和治疗举措。我们的建议提出了一种新的方法来研究酒精饮酒行为的传播，这些行为有助于AUDS的风险。大约一半的酒精依赖风险(酒精中毒)是从父母传给后代的。虽然过去的研究主要集中在改变酗酒风险的基因上，但最近的证据表明，后天的表观遗传因素可以传递给后代，并影响他们的行为。这些表观遗传因子包括DNA甲基化和组蛋白修饰，它们参与调节基因转录。也有强有力的证据表明，母亲和父亲先入为主的饮酒会导致后代的行为缺陷；此外，最近的一项研究表明，母亲先入为主的酒精暴露会导致后代DNA甲基化的变化。然而，还没有研究考察父亲先入为主的饮酒对饮酒行为和后代表观遗传格局的影响。为了研究父性早孕酒精暴露的影响，我们将雄性小鼠暴露在酒精中5周(一个生精周期)，并将它们与酒精天真的雌性小鼠交配。交配后，我们将测量父系生殖细胞中DNA甲基化的变化。来自这些交配的后代将接受测试，以了解酶的表达变化，这些酶使DNA甲基化，并修改大脑中一个关键区域的组蛋白，以应对酒精反应。我们还将使用一套全面的行为测试来测试后代成年后的饮酒行为和酒精诱导行为。成功完成我们建议中的目标将建立父亲先入为主的酒精暴露对后代行为的影响，并揭示可能是这些影响的中介的表观遗传变化。这些发现将对研究下一代行为的跨代遗传具有重要意义。我们的发现也可能为酒精中毒和胎儿酒精综合征(FAS)的治疗揭示新的表观遗传学靶点。

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).