Transgenerational epigenetic effects induced by paternal preconception ethanol

摘要 长期暴露于乙醇（EtOH）对健康有各种不利影响，并导致 在美国和世界范围内有大量的发病率和死亡率。有证据表明， 父母可能对他们的后代产生影响，这增加了EtOH对表观基因组产生影响的可能性。 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。表观遗传变异是一种分子组成的变化 在特定的转录调控元件和特定的细胞类型的表观基因组：它是功能性的 如果它导致基因表达的稳定变化，则相关。在生殖系中诱导的表观遗传变异 可以传给后代，这种现象被称为表观遗传。的程度 表观遗传变异可以由EtOH诱导，并通过多种途径从父母传递给后代。 一代人，从未建立。我们假设父亲的孕前接触乙醇会导致 在没有任何遗传变异的情况下可遗传的表观遗传变异。因为基因的改变 表达水平是表观遗传变异的功能结果，我们将使用基因表达变异，在一个 单一同质细胞类型，作为表观遗传变异的功能读数;研究将在 一个同基因小鼠品系，以尽量减少混淆的遗传和环境因素，并使用 建立乙醇暴露系统。我们会问父亲的孕前接触乙醇是否会导致 表观遗传变异持续一代人以上的EtOH暴露停止。该研究将评估 父亲孕前EtOH暴露诱导后代基因表达变异的频率 暴露的男性，以及这种变异传播给下一代的频率。这 该提案直接涉及PA-13-004的主题，“表观遗传遗传和跨代影响， 酒精”; EtOH诱导的表观遗传变异的遗传性的证据将对公共健康产生重大影响。 影响

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.