Impact of endocrine disruptors on the human sperm methylome: a risk factor for autism?

项目概述：尽管有报道称自闭症谱系障碍(ASD)是最易遗传的 基于同卵双胞胎和兄弟姐妹符合率的神经发育障碍，迅速上升 自闭症在美国和全世界的流行表明环境因素也可能起到作用 对ASD来说意义重大。这些尚未确定的环境因素可能会影响相关基因的表达 通过基因与环境(GxE)的相互作用导致自闭症表型的自闭症，或通过修改 生殖系表观基因组，进而导致自闭症的跨代遗传。建议的研究直接 解决自闭症的环境风险，这可能是由于人类生殖细胞的表观遗传修饰造成的 接触一种特定类型的内分泌干扰物(EDCs)，即有机氯化合物。 在这项拟议的研究中，我们将检验以下假设：1)环境暴露于内分泌干扰 有机氯化合物在环境和身体组织中有很长的半衰期，与 通过生物信息学分析确定影响自闭症风险基因的人类精子细胞的表观遗传修饰 甲基组数据，2)基因的表达和表观遗传调控映射到差异甲基化 在神经细胞模型中，特定的内分泌细胞改变区域(DMR)。 具体目标是：1)对已知的男性精子进行大规模、全基因组DNA甲基化分析 暴露于不同的EDC的水平，如在他们的血清中定量的；2)执行生物信息学和路径分析 差异甲基化区域/基因以确定与自闭症相关基因和途径的关系；3) 验证与ASD相关关键基因的差异甲基化，这些基因与高水平的 4)使用神经细胞模型直接测试特定的内分泌细胞的能力 改变精子中差异甲基化的ASD驱动基因的表达和甲基化。 影响：这项研究特别令人信服，因为最近发现一群人的精子中DNA甲基化发生了变化 自闭症风险升高的孩子的父亲。我们预计，这项研究将表明，内分泌细胞是一个重要的 ASD的环境危险因素，可能通过修改精子表观基因组而增加易感性，从而导致 对神经发育和功能至关重要的特定自闭症风险基因的失调。此外，设立 精子甲基组中EDC相关变化的数据库有望成为研究 与环境暴露有关的其他疾病/状况，如癌症、肥胖症、糖尿病和不孕症。 创新：这项研究将首次调查量化的EDC暴露与表观基因组学之间的关系 人类精子DNA的变化，特别关注与自闭症有关的基因/途径。这些研究将填补一个 我们对环境诱导的人类生殖细胞表观遗传变化与风险增加的认识差距 对于ASD。由于生殖系中的表观遗传修改可能会跨代传递，因此这种变化可能 导致自闭症的“缺失遗传性”。

Project Summary: Although autism spectrum disorder (ASD) has been reported to be among the most heritable of neurodevelopmental disorders based on concordance rates among identical twins and siblings, the rapidly rising prevalence of autism in the United States and worldwide suggests that environmental factors may also contribute significantly to ASD. These as yet undefined environmental factors may impact the expression of genes associated with autism through gene by environment (GxE) interactions leading to an autism phenotype, or by modification of the germline epigenome which in turn can lead to transgenerational inheritance of autism. The proposed study directly addresses environmental risk for autism that may arise from epigenetic modifications in human germline cells as a result of exposure to a specific class of endocrine disrupting compounds (EDCs), the organochlorines. In the proposed study, we will test the hypotheses that: 1) environmental exposure to endocrine disrupting organochlorine compounds, which have long half-lives in the environment and bodily tissues, is associated with epigenetic modifications in human sperm cells that affect autism risk genes, identified through bioinformatics analyses of the methylomic data, 2) that the expression and epigenetic regulation of genes mapped to differentially methylated regions (DMRs) are altered by the specific EDCs in a neuronal cell model. Specific Aims are: 1) conduct large-scale, genome-wide DNA methylation analyses of sperm from men with known exposure levels to different EDCs, as quantified in their serum; 2) perform bioinformatics and pathway analyses of the differentially methylated regions/genes to determine the relationship to genes and pathways implicated in autism; 3) validate differential methylation associated with key ASD-related genes that correlate with high levels of exposure to specific EDCs in the respective serum samples; 4) use a neuronal cell model to directly test the ability of specific EDCs to alter gene expression and methylation of “ASD-driver” genes found to be differentially methylated in sperm. Impact: This study is particularly compelling given recent findings of altered DNA methylation in the sperm of a cohort of fathers of children with elevated risk for autism. We anticipate that this study will show that EDCs are a significant environmental risk factor for ASD that may increase susceptibility by modifying the sperm epigenome, thereby causing dysregulation of specific autism risk genes critical to neurological development and function. Moreover, establishment of a database of EDC-associated changes in the sperm methylome is expected to be a valuable resource for studies on other diseases/conditions, such as cancer, obesity, diabetes and infertility, which are linked to environmental exposures. Innovation: This study will be the first to investigate the relationship between quantified EDC exposures and epigenomic changes to human sperm DNA, with a particular focus on genes/pathways implicated in autism. These studies will fill a gap in our knowledge of environmentally-induced epigenetic changes in human germline cells in relation to increased risk for ASD. Since epigenetic modifications in the germline may be transmitted transgenerationally, such changes may contribute to the “missing heritability” in ASD.