Paternal preconception alcohol on epigenetics and offspring drinking

描述（由申请人提供）：酒精使用障碍（AUDs）在社会中普遍存在。它们共同造成巨大的社会经济成本，每年造成数万人死亡。因此，制定新的策略来识别患AUDs风险增加的人群至关重要，这可能会改善预防和治疗措施。我们的建议提出了一种新的方法来研究导致AUDs风险的饮酒行为的传播。大约一半的酒精依赖（酒精中毒）风险是由父母传给后代的。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遗传给后代，影响他们的行为。这些表观遗传因素包括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，母亲和父亲在怀孕前饮酒会导致后代的行为缺陷；此外，最近的一项研究表明，母亲孕前酒精暴露会引起后代DNA甲基化的变化。然而，没有研究调查父亲孕前饮酒对饮酒行为和后代表观遗传景观的影响。为了研究父亲孕前酒精暴露的影响，我们将雄性小鼠暴露在酒精中5周（一个精子发生周期），并将它们与未接触酒精的雌性交配。交配后，我们将测量父亲生殖细胞中DNA甲基化的变化。这些交配的后代将被检测DNA甲基化酶的表达变化，并修改大脑中酒精反应关键区域的组蛋白。我们还将使用一套全面的行为分析来测试后代在成年期的饮酒行为和酒精引起的行为。成功完成我们提议的目标将确定父亲孕前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。这些发现对于研究下一代行为的跨代遗传具有重要意义。我们的发现可能还揭示了治疗酒精中毒和胎儿酒精综合征（FAS）的新表观遗传学靶点。

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).