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

项目概述：虽然自闭症谱系障碍（ASD）已被报道是最可遗传的 基于同卵双胞胎和兄弟姐妹之间一致率的神经发育障碍， 在美国和世界范围内，自闭症的流行表明环境因素也可能起作用。 对于ASD来说，这些尚未确定的环境因素可能会影响基因的表达， 自闭症通过基因与环境（GxE）的相互作用导致自闭症表型，或通过修饰 生殖系表观基因组，这反过来又会导致自闭症的跨代遗传。研究建议直接 解决了自闭症的环境风险，可能源于人类生殖系细胞的表观遗传修饰， 暴露于一类特定的内分泌干扰化合物（EDCs），即有机氯。 在本研究中，我们将检验以下假设：1）环境暴露于内分泌干扰物 有机氯化合物在环境和身体组织中具有长半衰期， 通过生物信息学分析确定的人类精子细胞中影响自闭症风险基因的表观遗传修饰 2）基因的表达和表观遗传调控映射到差异甲基化， 在神经元细胞模型中，特定的EDC改变了DMR区域。 具体目的是：1）对来自已知患有前列腺癌的男性的精子进行大规模的全基因组DNA甲基化分析。 暴露于不同的内分泌干扰物的水平，如在其血清中定量的; 2）进行生物信息学和途径分析， 差异甲基化区域/基因，以确定与自闭症相关的基因和途径的关系; 3） 验证与关键ASD相关基因相关的差异甲基化，这些基因与高水平暴露于 4）使用神经元细胞模型来直接测试特异性EDCs的能力， 改变基因表达和“ASD驱动”基因的甲基化，发现精子中存在差异甲基化。 影响：考虑到最近在一个队列的精子中发现DNA甲基化改变，这项研究特别引人注目。 自闭症风险较高的儿童的父亲。我们预计，这项研究将表明，内分泌干扰物是一个重要的 ASD的环境风险因素，可能通过修改精子表观基因组增加易感性，从而导致 特定自闭症风险基因对神经发育和功能至关重要。此外，建立 精子甲基化组中EDC相关变化的数据库有望成为研究以下方面的宝贵资源： 其他疾病/病症，如癌症、肥胖症、糖尿病和不育症，这些都与环境暴露有关。 创新：这项研究将是第一个调查量化EDC暴露与表观基因组之间关系的研究。 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 我们对环境诱导的人类生殖系细胞表观遗传变化与风险增加相关的知识存在差距 自闭症由于生殖系中的表观遗传修饰可以通过转代传递，因此这种变化可能 导致了ASD的“遗传性缺失”

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.