HERITABLE, EPIGENETIC EFFECTS OF PATERNAL ALCOHOL USE ON FASD PHENOTYPES

项目概要和摘要 在美国，估计至少有1%的儿童患有与酒精相关的生长和神经认知障碍。 与胎儿酒精谱系障碍（FASD）相关的缺陷。其中一个主要的混淆因素是 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变化。观察到的方差 在FASD表型中，除了母亲饮酒的发生率外， 在这种情况的发展中起着重要作用。在过去的40年里，临床研究报告说，75%的 FASD儿童的生父要么是酗酒者，要么是长期酗酒者。然而，作用 在FASD出生缺陷的发展中，孕前男性饮酒的可能性仍然未被探索， 这主要是因为人们误以为精子不会传递遗传密码以外的遗传信息。 使用一个完善的小鼠模型，孕前男性酒精暴露与这两种疾病有关。 产前和产后生长受限，胎盘生长异常和性别特异性改变， 后代的长期代谢健康。在这些动物研究中发现的缺陷与那些 在FASD儿童的长期临床研究中描述，并揭示父亲使用药物是一个重要的因素， 后代健康的调节剂。然而，父亲暴露于癌症之前的分子机制， 受孕对后代发育的影响仍不明确。此外，父亲饮酒的能力， 与妊娠期酒精暴露相互作用并加剧FASD的发展从未被测试过。这 提案响应了“PA-18-507 -尿中酒精暴露对成人健康和疾病的影响”，并将 确定男性先入为主地接触酒精影响 胎儿的发育程序，并有助于FASD出生缺陷的发病率。识别链接 男性饮酒和一种疾病之间的联系，到目前为止，这种疾病几乎完全与 母亲的决定，将有望促使流行病学观点的转变， 在酒精相关的生长和神经认知的发展中考虑生父的生活方式选择 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.