Effects of Alcohol on Gene Expression & Epigenetics of Progeny

描述(由申请人提供)：酗酒和与酒精相关的疾病影响了大量的美国家庭，对每年的医疗和照顾者费用产生了重大的经济影响。此外，人们认识到并宣传在怀孕期间长期饮酒会产生各种不利的妊娠结局和出生缺陷。然而，在怀孕期间急性饮酒的影响还相对未知。在这个早期发育阶段，支配基因表达的表观遗传标记最初是沿着所有哺乳动物的基因组建立的，从老鼠到人类。因此，卵母细胞到胚胎的转变是发育的关键时期，因为全能胚胎产生整个个体，在这个阶段发生的任何‘表观遗传错误’都会遗传到整个身体。例如，此时一些母亲的饮食改变了小鼠胚胎特定基因的表观遗传状态，影响了后代的毛色和新陈代谢。因此，母体环境可能会影响成年后代的表型。因此，在这个关键的发育期，即使是低剂量的酒精暴露，也可能对后代日后的健康产生不利影响。我的研究结果表明，在卵母细胞体外成熟过程中，专门接触酒精的小鼠在成年后会有更高的代谢性疾病的发生率，如肥胖和糖尿病。作为了解这一现象的起点，我们将评估酒精暴露在卵母细胞和植入前胚胎中诱导的基因表达和甲基化状态的变化。这项研究的创新之处在于，通过使用体外成熟和体外受精技术，在这一发育阶段将精确控制急性酒精暴露。这使得可以研究酒精对卵子和早期胚胎的影响，这为成年后代的异常表型奠定了基础。这些实验将有助于识别和描述在早期母体和胚胎环境中建立和影响的表观遗传机制，这些机制可能使个人易于患上代谢性疾病，如肥胖症和糖尿病。

DESCRIPTION (provided by applicant): Alcoholism and alcohol-related illness affect multitudes of American families at a significant financial impact on annual medical and caregiver costs. Furthermore, it is recognized and publicized that chronic alcohol consumption during gestation produces a variety of adverse pregnancy outcomes and birth defects. Yet, the influence of acute alcohol consumption near the time of conception is relatively unknown. Around this early developmental stage, the epigenetic marks, which govern gene expression, are initially established along the genome for all mammals, from mice to humans. Consequently, the oocyte-to-embryo transition is a critical period of development because the totipotent embryo gives rise to the entire individual and any 'epigenetic misprints' occurring during this stage are inherited throughout the body. For instance, some maternal diets at this time change the epigenetic status for specific genes of the mouse embryo, impacting both coat color and metabolism of the offspring. Therefore, the maternal environment may influence the phenotype of the progeny in adulthood. Accordingly, alcohol exposure, even at low amounts, at this critical developmental period may adversely affect the health of offspring later in life. The results from my studies suggest that mice specifically exposed to ethyl alcohol during in vitro maturation of oocytes have a higher incidence of metabolic disease, such as obesity and diabetes in adulthood. As a starting point to understand this phenomenon, alterations in gene expression and methylation status induced by alcohol exposure will be assessed in oocytes and pre-implantation embryos. This study is innovative in that the acute alcohol exposure will be precisely controlled during this developmental stage by using in vitro maturation and in vitro fertilization techniques. This permits investigation of the impacts of alcohol on the egg and early embryo, which sets the stage for abnormal phenotype of the adult offspring. These experiments will help to identify and characterize the epigenetic mechanisms that are established and influenced within the early maternal and embryonic environment, which may predispose individuals to metabolic disease, such as obesity and diabetes.