Functional and Epigenetic Consequences of Paternal Alcohol Exposure

父亲酒精暴露的功能和表观遗传后果

基本信息

  • 批准号:
    9768298
  • 负责人:
  • 金额:
    $ 1.76万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-07 至 2020-01-15
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract Alcohol use disorder (AUD) is a highly heritable disease affecting millions of people in the United States. Although the heritability of AUD has been estimated to be ~50%, genetic variants only account for less than 1% of the risk for developing AUD. Recent evidence suggests that epigenetic factors, which alter gene expression without affecting the underlying DNA sequence, may explain some of the missing heritability of AUD. The most well studied epigenetic mechanism is DNA methylation occurring at sites within the promoter regions of genes, and it is mostly, although not always, associated with gene repression. Human and preclinical studies report that alcohol can alter the DNA methylation profile in male germ cells. Work in mice has shown that these changes can be transmitted to first generation progeny and that paternal alcohol exposure affects offspring's alcohol drinking behaviors and behavioral sensitivity to alcohol. However, no study has examined the effects of paternal alcohol exposure on operant alcohol self-administration in offspring. Thus, the overall goal of the proposed project is to use Wistar rats to examine alcohol self-administration behaviors and alterations to DNA methylation levels in the offspring of alcohol-dependent males. To do this, male Wistar rats will be exposed to alcohol vapor over 6 weeks to induce alcohol dependence. After alcohol exposure, males will be left undisturbed for 8 weeks (one cycle of spermatogenesis in rats) and then mated with alcohol naïve females. Offspring from these mating pairs will be tested on self-administration behaviors and assessed for DNA methylation changes in adulthood. The first aim of the proposed project is to identify whether paternal alcohol exposure changes acquisition and maintenance of operant alcohol self-administration in male and female offspring. Additionally, the second aim will determine if DNA methylation levels are altered in the sperm of alcohol sires, and if these changes are maintained in brain and tissue of offspring. The results will further knowledge as to the long term consequences of paternal preconception alcohol exposure and may elucidate novel inherited behaviors and/or biomarkers that can be used to develop new, or refine existing, preventive and therapeutic strategies for AUD.
项目总结/摘要 酒精使用障碍(AUD)是一种高度遗传性疾病,影响着美国数百万人。 虽然AUD的遗传率估计为~ 50%,但遗传变异仅占不到50%。 1%的风险发展澳元。最近的证据表明,表观遗传因素,改变基因 表达而不影响潜在的DNA序列,可以解释一些缺失的遗传性, 澳元。表观遗传机制研究得最多的是启动子内的DNA甲基化 基因的区域,它主要是,虽然不总是,与基因抑制。人力和 临床前研究报告说,酒精可以改变男性生殖细胞中的DNA甲基化特征。在小鼠中工作 研究表明,这些变化可以传递给第一代后代, 暴露影响后代的饮酒行为和对酒精的行为敏感性。然而,没有研究 研究了父亲酒精暴露对后代操作性酒精自我管理的影响。因此,在本发明中, 该项目的总体目标是使用Wistar大鼠检查酒精自我管理行为 以及酒精依赖男性后代DNA甲基化水平的改变。为了做到这一点,雄性Wistar 将大鼠暴露于酒精蒸汽超过6周以诱导酒精依赖。在酒精暴露后, 雄性将不受干扰地保持8周(大鼠精子发生的一个周期),然后与酒精交配 天真的女人将对这些交配对的后代进行自我给药行为测试, DNA甲基化的变化。该项目的第一个目标是确定父亲是否 酒精暴露改变了男性操作性酒精自我给药的获得和维持, 雌性后代此外,第二个目标将确定精子中的DNA甲基化水平是否发生改变。 以及这些变化是否在后代的大脑和组织中得以维持。结果将进一步 了解父亲孕前酒精暴露的长期后果,并可能阐明 新的遗传行为和/或生物标志物,可用于开发新的,或完善现有的, 和治疗策略。

项目成果

期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Paternal alcohol exposure has task- and sex-dependent behavioral effect in offspring.
父亲的酒精暴露对后代具有任务和性别依赖性的行为影响。
Paternal alcohol exposure reduces acquisition of operant alcohol self-administration and affects Bdnf DNA methylation in male and female offspring.
  • DOI:
    10.1111/adb.13078
  • 发表时间:
    2022-01
  • 期刊:
  • 影响因子:
    3.4
  • 作者:
    Nieto SJ;Haile CN;Quave CB;Harding MJ;Nielsen DA;Meisch RA;Kosten TA
  • 通讯作者:
    Kosten TA
Persistence of Operant Responding for Food After Prior Cocaine Exposure in Fischer 344 But Not Lewis Rats.
Fischer 344 大鼠先前接触可卡因后,操作者对食物的反应持续存在,但 Lewis 大鼠则不然。
  • DOI:
    10.1111/ajad.13152
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Forouzan,Shadab;Nieto,StevenJ;Kosten,ThereseA
  • 通讯作者:
    Kosten,ThereseA
Female Sprague-Dawley rats display greater appetitive and consummatory responses to alcohol.
  • DOI:
    10.1016/j.bbr.2017.03.037
  • 发表时间:
    2017-06-01
  • 期刊:
  • 影响因子:
    2.7
  • 作者:
    Nieto SJ;Kosten TA
  • 通讯作者:
    Kosten TA
On the path towards personalized medicine: Implications of pharmacogenetic studies of alcohol use disorder medications.
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Steven J Nieto其他文献

Steven J Nieto的其他文献

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{{ truncateString('Steven J Nieto', 18)}}的其他基金

Applying behavioral economics to screen medications for alcohol use disorder
应用行为经济学筛选酒精使用障碍药物
  • 批准号:
    10473518
  • 财政年份:
    2021
  • 资助金额:
    $ 1.76万
  • 项目类别:
Applying behavioral economics to screen medications for alcohol use disorder
应用行为经济学筛选酒精使用障碍药物
  • 批准号:
    10315908
  • 财政年份:
    2021
  • 资助金额:
    $ 1.76万
  • 项目类别:
Functional and Epigenetic Consequences of Paternal Alcohol Exposure
父亲酒精暴露的功能和表观遗传后果
  • 批准号:
    9563947
  • 财政年份:
    2017
  • 资助金额:
    $ 1.76万
  • 项目类别:

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