Project 3: Epigenomic Consequences of Early Life Environmental Tobacco Smoke

生命早期环境烟草烟雾（ETS）暴露与神经发育的有害结果有关，包括注意力缺陷/多动障碍（ADHD），但其机制尚不清楚。暴露于ETS引起的表观遗传变化可能是这些关联的基础。我们的长期目标是利用DNA甲基化谱来识别有不良神经发育结果风险的儿童。目的是揭示生命早期暴露于ETS与ADHD相关表型之间的表观遗传机制。我们假设生命早期暴露于ETS会诱导与神经发育表型相关的DNA甲基化的持续和靶向功能变化。其基本原理是，定义ETS诱导的功能性DNA甲基化变化的曲目将为风险分层和早期干预提供令人兴奋的新机会，以减少和预防ETS暴露的不良行为和认知结果。我们的目标如下：1)确定与ets相关的甲基化靶点。我们将测试假设，早期暴露在大鼠的ETS将诱发可测量的

Early life environmental tobacco smoke (ETS) exposure is associated with detrimental outcomes on neurodevelopment, including Attention-Deficit / Hyperactivity Disorder (ADHD), but the mechanisms are unclear. Epi-genetic changes induced by ETS exposure may underlie these associations. Our long-term goal is to utilize DNA methylation profiles to identify children at risk for developing adverse neurodevelopmental outcomes. The objective is to uncover the epigenetic mechanism linking ETS exposure in early life to phenotypes associated with ADHD. We hypothesize that early life ETS exposure induces persistent and targeted functional changes in DNA methylation that associate with neurodevelopmental phenotypes. The rationale for is that defining the repertoire of ETS-induced functional DNA methylation changes will offer exciting new opportunities for risk stratification and early interventions to reduce and prevent adverse behavioral and cognitive outcomes of ETS exposure. Our aims are as follows: 1) Identify ETS-related methylation targets. We will test the hypothesis that early life ETS exposure in rats will induce measurable shifts in methylation at loci relevant to neurobehav-loral outcomes that are detectable in both brain and blood. Whole genome bisulfite sequencing will identify ETS-vulnerable loci with validation by pyrosequencing. 2) Identify ETS-altered methylation-expression relationships in frontal cortex. We hypothesize that early life ETS exposure in rats induces changes in frontal cortex gene expression at ADHD-relevant genes. Whole transcriptome profiling will identify these changes. We will also evaluate methylation expression relationships from the in vivo results and in an in vitro model of neuronal differentiation. 3) Determine if DNA methylation varies with ETS dose in humans. Prenatal and peri-natal cotinine levels and DNA methylation in children, from bisulfite pyrosequencing at ADHD-related genes and candidate loci from the above aims, will determine if methylation varies with exposure. The proposed research is expected to reveal ETS-related epigenetically vulnerable genes that mechanistically explain the link between ADHD and exposure to ETS and that may serve as biomarkers of past exposure.