HERITABLE, EPIGENETIC EFFECTS OF PATERNAL ALCOHOL USE ON FASD PHENOTYPES

项目摘要(&A) 在美国，据估计，至少有1%的儿童患有与酒精相关的发育和神经认知 与胎儿酒精谱障碍(FASD)相关的缺陷。其中一个主要的混杂因素是 对这种疾病的研究是在发病率和严重程度上观察到的巨大差异。观测到的差异 在FASD中，表型表明，母亲饮酒以外的多种因素起着显着的作用 在这一状况的发展中扮演着重要的角色。在过去的40年里，临床研究报告称，75%的 FASD儿童的生父要么是酗酒者，要么是慢性酗酒者。然而，这个角色 先入为主的男性饮酒在FASD出生缺陷发生中的作用仍未被探索， 这在很大程度上是由于一种误解，即精子不会传递遗传密码以外的可遗传信息。 利用一种成熟的小鼠模型，先入为主的男性酒精暴露与这两种情况都有关联 出生前和出生后生长受限，胎盘生长异常和性别特异性改变 后代的长期新陈代谢健康。在这些动物研究中发现的缺陷与那些 描述了对FASD儿童的长期临床研究，并揭示了父亲使用药物是一个重要的 后代健康的修饰者。然而，父亲在感染前暴露的分子机制 受孕对后代发育的影响仍然没有明确的定义。此外，父亲饮酒的能力 与孕期酒精暴露相互作用，并加剧FASD的发展，从未进行过测试。这 提案回应《PA-18-507-宫内酒精暴露对成人健康和疾病的影响》，并将 明确男性早孕接触酒精影响的基本基本机制 胎儿的发育计划，并导致FASD出生缺陷的发生率。标识链接 男性饮酒和一种疾病之间的关系，到目前为止，这种疾病几乎完全与 生母的决定，有望促使流行病学观点的转变，从而更全面地 考虑生父在酒精相关生长发育和神经认知发展中的生活方式选择 缺陷。

Project Summary & Abstract In the US, it is estimated that at least 1% of children suffer from alcohol-related growth and neurocognitive defects associated with fetal alcohol spectrum disorders (FASDs). One of the major confounding elements in the study of this disorder is the enormous variation observed in both incidence and severity. The observed variance in FASD phenotypes indicates that multiple factors beyond the incidence of maternal drinking play a significant role in the development of this condition. Over the past 40 years, clinical studies have reported that 75% of FASD children have biological fathers who were either heavy drinkers or chronic alcoholics. However, the role of preconception male alcohol consumption in the development of FASD birth defects remains unexplored, largely due to the misconception that sperm do not transmit heritable information beyond the genetic code. Using a well-established mouse model, preconception male alcohol exposure has been associated with both prenatal and postnatal growth restriction, abnormalities in placental growth and sex-specific alterations in the long-term metabolic health of the offspring. The defects identified in these animal studies are similar to those described in long-term clinical studies of FASD children and reveal that paternal drug use is a significant modifier of offspring health. However, the molecular mechanisms by which paternal exposures prior to conception impact offspring development remain poorly defined. Further, the ability of paternal alcohol use to interact with gestational alcohol exposures and exacerbate the development FASDs has never been tested. This proposal responds to `PA-18-507 - Effects of In Utero Alcohol Exposure on Adult Health and Disease' and will define the basic fundamental mechanisms by which male preconception exposure to alcohol impacts the developmental program of the fetus and contributes to the incidence of FASD birth defects. Identifying a link between male alcohol use and a disorder that, until now, has been almost exclusively associated with the decisions of the birthmother, will hopefully prompt a shift of epidemiological perspectives that will more fully consider the lifestyle choices of the birthfather in the development of alcohol-related growth and neurocognitive defects.