Effects of Alcohol on Gene Expression & Epigenetics of Progeny

酒精对基因表达的影响

• 批准号: 7669371
• 负责人: Carrie de Evsikova
• 金额: $ 25.01万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-05 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7669371
• 关键词: Acute; Adult; Adult Children; Affect; Alcohol consumption; Alcoholic Beverages; Alcoholism; Alcohols; American; Biological Markers; Candidate Disease Gene; Caregivers; Chronic; Color; Conceptions; Congenital Abnormality; DNA; DNA Methylation; Development; Diabetes Mellitus; Diagnosis; Diet; Disease; Dose; Elderly; Embryo; Environment; Epigenetic Process; Ethanol; Exposure to; Family; Fertilization; Fertilization in Vitro; Foundations; Future; Future Generations; Gene Expression; Genes; Genome; Genomics; Goals; Health; Heavy Drinking; Human; In Vitro; Incidence; Individual; Inherited; Investigation; Lead; Life; Medical; Metabolic Diseases; Metabolism; Methods; Methylation; Modification; Mus; Obesity; Onset of illness; Oocytes; Outcomes Research; Pathway interactions; Pattern; Phenotype; Predisposition; Pregnancy; Pregnancy Outcome; Productivity; Quality of life; Research; Staging; System; Systems Biology; Techniques; Testing; Therapeutic Intervention; Time; Tissues; Trisomy; Woman; Work; alcohol effect; alcohol exposure; chronic alcohol ingestion; cost; critical developmental period; critical period; daughter cell; egg; embryo culture; genome-wide; histone modification; in utero; in vivo; innovation; offspring; oocyte maturation; outcome forecast; preimplantation; research study

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.

描述（由申请人提供）：酗酒和与酒精相关的疾病影响着众多美国家庭，对年度医疗和护理费用产生重大财务影响。此外，人们认识到并宣传，妊娠期间长期饮酒会产生各种不良妊娠结局和出生​​缺陷。然而，受孕期间急性饮酒的影响相对未知。在这个早期发育阶段，控制基因表达的表观遗传标记最初沿着所有哺乳动物（从小鼠到人类）的基因组建立。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，并且在此阶段发生的任何“表观遗传错误”都会遗传到全身。例如，此时一些母体饮食会改变小鼠胚胎特定基因的表观遗传状态，影响后代的毛色和新陈代谢。因此，母体环境可能会影响后代成年后的表型。因此，在这个关键的发育时期接触酒精，即使是少量，也可能会对后代以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暴露于乙醇的小鼠，成年后患肥胖症和糖尿病等代谢疾病的发病率较高。作为理解这种现象的起点，我们将在卵母细胞和植入前胚胎中评估酒精暴露引起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，可以精确控制该发育阶段的急性酒精暴露。这使得研究酒精对卵子和早期胚胎的影响成为可能，从而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表征在早期母体和胚胎环境中建立和影响的表观遗传机制，这些机制可能使个体易患代谢疾病，例如肥胖和糖尿病。