Effects of paternal nicotine exposure on sncRNA expression in sire sperm and offspring hippocampus

项目摘要/摘要 最近的证据表明，父亲的药物暴露可以影响儿童的行为和生理表型 未暴露的后代。作为支持，来自我的实验室的初步数据表明，情境恐惧加剧 尼古丁暴露雄性小鼠子代海马区功能的条件化和变化。这 提出了一个与解释来自人类和动物的数据相关的潜在严重问题 未考虑父母尼古丁暴露的人群。“遗漏遗传能力”和 研究之间遗传力估计的差异可能部分是由亲本的变异性造成的 曝光。描述了这种遗传方式背后的机制，称之为“多代遗传” 表观遗传，“是必要的，以补偿这些影响在实验设计和开始 以了解特定于暴露的多代后果。父亲接触毒品的其他模式 已经指出通过生殖系SncRNA表达的遗传是一种潜在的潜在机制 多代遗传。为了确定尼古丁多代影响的潜在途径 暴露在情境恐惧学习中，我将对暴露于 尼古丁(F0)及其后代的海马体(F1)。这些数据将与我们现有的F1一起进行分析 海马区DNA甲基化和mRNA表达数据集揭示SncRNA之间的关系 精子中的表达和后代多代表型表达的潜在途径。这个 拟议的工作将为尼古丁的多代影响提供基础性的见解，丰富电流 对成瘾遗传性的理解。

PROJECT SUMMARY/ABSTRACT Recent evidence suggests that paternal drug exposure can affect behavioral and physiological phenotypes in unexposed offspring. In support, preliminary data from my laboratory indicates enhanced contextual fear conditioning and changes in hippocampal functioning in the offspring of nicotine-exposed male mice. This presents a potentially serious issue related to interpretation of data derived from both human and animal populations for which parental nicotine exposure was not taken into account. “Missing heritability” and discrepancies in heritability estimates between studies may be explained partially by variability in parental exposures. Characterization of mechanisms underlying this mode of inheritance, termed “multigenerational epigenetic inheritance,” is essential in order to compensate for these effects in experimental design and begin to understand exposure-specific multigenerational consequences. Other models of paternal drug exposure have pointed to inheritance through germline sncRNA expression as a potential underlying mechanism of multigenerational inheritance. In order to identify pathways underlying multigenerational effects of nicotine exposure on contextual fear learning, I will sequence sncRNA derived from sperm of male mice exposed to nicotine (F0) and the hippocampus of their offspring (F1). This data will be analyzed alongside our existing F1 hippocampus DNA methylation and mRNA expression datasets to reveal relationships between sncRNA expression in sperm and pathways underlying expression of multigenerational phenotypes in offspring. The proposed work will provide foundational insight into nicotine’s multigenerational effects, enriching current understanding of addiction heritability.