Transgenerational epigenetic effects induced by paternal preconception ethanol

父本孕前乙醇诱导的跨代表观遗传效应

• 批准号: 8624580
• 负责人: DARIO BOFFELLI
• 金额: $ 29.43万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8624580
• 关键词: Address; Adverse effects; Animals; Biological Assay; Breeding; Cell Differentiation process; Cells; Chronic; Complex; Development; Environmental Risk Factor; Epigenetic Process; Ethanol; Exposure to; Frequencies; Gene Expression; Generations; Genes; Genetic; Genetic Variation; Genome; Germ Cells; Health; Heritability; Inherited; Left; Molecular; Molecular Structure; Morbidity - disease rate; Mouse Strains; Mus; Parents; Plants; Public Health; Regulator Genes; Risk; Solid; Structure of primordial sex cell; System; Testing; Time; Variant; Work; alcohol effect; alcohol exposure; cell type; epigenetic variation; epigenome; functional outcomes; genome-wide; male; monocyte; mortality; next generation; non-genetic; offspring; preimplantation; public health relevance; transcriptome sequencing; transmission process

Abstract Chronic exposure to ethanol (EtOH) has a variety of adverse effects on health, and is responsible for a substantial amount of morbidity and mortality in the US and worldwide. Evidence that exposure to EtOH in parents can have effects on their offspring has raised the possibility that EtOH has effects on the epigenome. The epigenome is the complex assortment of molecular structures that are associated with the genome to control gene expression and cell differentiation. An epigenetic variant is a change in the molecular components of the epigenome at a specific transcriptional regulatory element and in a specific cell type: it is functionally relevant if it results in a stable change in the expression of a gene. Epigenetic variants induced in the germline can be passed to succeeding generations, a phenomenon termed epigenetic inheritance. The extent to which epigenetic variants can be induced by EtOH, and transmitted from parents to offspring through multiple generations, has never been established. We hypothesize that paternal preconception EtOH exposure induces epigenetic variants that are heritable in the absence of any genetic variation. Since changes in gene expression levels are the functional outcome of epigenetic variants, we will use gene expression variants, in a single homogeneous cell type, as the functional readout of epigenetic variation; the study will be carried out in an isogenic mouse strain in order to minimize confounding genetic and environmental factors, and use an established system of ethanol exposure. We will ask if paternal preconception EtOH exposure can induce epigenetic variants that persist for a generation past the cessation of EtOH exposure. The study will assess the frequency with which paternal preconception EtOH exposure induces gene expression variants in the offspring of exposed males, and the frequency with which such variants are transmitted to the next generation. This proposal addresses directly the subject of PA-13-004, "Epigenetic Inheritance and Transgenerational Effects of Alcohol"; evidence for the heritability of EtOH-induced epigenetic variants would have major public health implications.

抽象的 长期暴露于乙醇（ETOH）对健康有多种不良影响，并负责 美国和全球的大量发病率和死亡率。证据表明暴露于EtOH中 父母可以对他们的后代产生影响，这增加了EtoH对表观基因组有影响的可能性。 表观基因组是与基因组相关的分子结构的复杂分类 控制基因表达和细胞分化。表观遗传变体是分子成分的变化 在特定的转录调节元件和特定细胞类型中的表观基因组的 相关是否会导致基因表达的稳定变化。种系中诱导的表观遗传变异 可以传递给后代，这种现象称为表观遗传。在多大程度上 表观遗传变体可以由EtOH诱导，并通过多个从父母传播到后代 几代人从未建立过。我们假设父亲的先选ETOH暴露会诱导 在没有任何遗传变异的情况下，可以遗传的表观遗传变异。由于基因的变化 表达水平是表观遗传变异的功能结果，我们将在A中使用基因表达变异。 单个均质细胞类型，作为表观遗传变异的功能读数；该研究将在 等源性小鼠菌株，以最大程度地减少混杂的遗传和环境因素，并使用 建立的乙醇暴露系统。我们将询问父亲的先入eTOH暴露是否会引起 表观遗传变体持续存在超过EtoH暴露的一代。该研究将评估 父亲祖先的频率ETOH暴露在后代中诱导基因表达变异 暴露的雄性以及此类变体传播到下一代的频率。这 提案直接解决了PA-13-004的主题，“表观遗传遗传和跨代作用 酒精”；证据证明了ETOH诱导的表观遗传变异的证据将具有主要的公共卫生 含义。