Are endocrine disrupting compounds environmental risk factors for autism?

描述（由申请人提供）：自闭症谱系障碍（ASD）是所有精神疾病中最具遗传性的，但越来越多的证据表明，环境因素也会增加患ASD的风险。然而，关于可能增加ASD风险的特定基因-环境相互作用以及环境触发改变基因表达的分子机制，我们的知识还存在空白。本实验室发现了一种新的、激素反应性的ASD候选基因，视黄酸相关孤儿受体- α (RORA)，其在ASD中的缺乏不仅可能导致与自闭症风险相关的睾酮水平升高，还可能导致ASD中强烈的男性偏见，这可能与男性和女性激素对RORA表达的相反方向调控有关。我们最近证明，RORA可以潜在地调节bbbb2500个基因的转录，其中超过400个基因被列入自闭症基因数据库。假设：我们提出干扰激素信号的环境污染物内分泌干扰化合物（EDCs）可能干扰RORA的正常表达，导致ASD的风险增加。本研究的长期目标是确定可能增加ASD风险的特定基因-环境（GxE）相互作用，并了解GxE相互作用的表观遗传机制。具体目的：1)研究环境分散的EDCs对RORA表达的影响；2)研究edc介导的RORA表达改变的表观遗传机制。创新：这项研究在解决一种特定的、高度关键的GxE相互作用方面具有创新意义，这种相互作用可能与ASD的明显增加有关。尽管对一个基因的关注可能被视为“高风险”，但由于RORA转录调节了许多与大脑发育和功能有关的基因，因此确定RORA失调的化学物质具有很高的影响。这项研究还将加深对EDC诱导的表观遗传变化的了解，如果发生在生殖细胞中，这些表观遗传变化可以传递给下一代，并导致高通量筛选可能通过RORA失调增加ASD风险的化合物。影响/公共卫生意义：该研究将通过证明EDCs可能通过破坏特定基因RORA的表达来增加ASD的风险，从而推动该领域的发展，而RORA反过来又调节大量与ASD发病机制相关的基因。我们进一步预计，通过这些研究获得的信息将导致制定公共卫生政策，以实施保护公众免受可能导致发育障碍和神经功能障碍的环境物质暴露的战略，并刺激制定治疗方案，以抵消暴露于这些化合物的影响。了解EDCs导致RORA失调的表观遗传学机制，将有助于开发新的以表观遗传学为目标的干预措施，纠正或改善RORA缺陷，从而为自闭症的治疗提供机制基础。

DESCRIPTION (provided by applicant): Autism spectrum disorders (ASD) are among the most heritable of all psychiatric disorders, but there is increasing evidence that environmental factors also contribute to the risk for ASD. However, there is a gap in our knowledge regarding specific gene-environment interactions that may increase risk for ASD and the molecular mechanisms through which environmental triggers alter gene expression. Our laboratory has identified a novel, hormonally-responsive candidate gene for ASD, retinoic acid-related orphan receptor- alpha (RORA), whose deficiency in ASD may contribute not only to higher levels of testosterone associated with risk for autism, but also to the strong male bias in ASD, which may be related to the regulation of RORA expression in opposite directions by male and female hormones. We recently demonstrated that RORA can potentially regulate the transcription of >2500 genes, of which over 400 are listed in autism gene databases. Hypothesis: we propose that endocrine disrupting compounds (EDCs), environmental pollutants that interfere with hormonal signaling, may interfere with the normal expression of RORA, leading to increased risk for ASD. Long-term objectives of this study are to identify specific gene-environment (GxE) interactions that may increase risk for ASD and to understand the epigenetic mechanisms underlying GxE interactions. Specific Aims: 1) investigate the impact of environmentally dispersed EDCs on RORA expression; 2) investigate epigenetic mechanisms associated with EDC-mediated alteration of RORA expression. Innovation: This study is innovative in addressing a specific and highly critical GxE interaction that could plausibly relate to an apparent increase in ASD. Although the focus on one gene may be viewed as "high risk", identification of chemicals that dysregulate RORA is of high impact because RORA transcriptionally regulates many genes that are involved in brain development and function. This study will also increase insight into EDC- induced epigenetic changes which can be transmitted to the next generation if occurring in germline cells, and result in a high-throughput screen for compounds that may increase risk for ASD via dysregulation of RORA. Impact/Public health significance: This study will move the field forward by demonstrating that EDCs may increase risk for ASD by disrupting expression of a specific gene, RORA, which in turn, regulates a large number of genes already implicated in the pathogenesis of ASD. We further anticipate that the information gained through these studies will lead to the development of public health policies to implement strategies to protect the public against exposure to environmental agents that might promote developmental disorders and neurological dysfunction, as well as stimulate the development of treatment protocols to counteract the effects of exposure to these compounds. Understanding the epigenetic mechanisms underlying the dysregulation of RORA by EDCs will lead to the development of novel epigenetics-targeted interventions that correct or ameliorate RORA deficiency, thus providing a mechanistic rationale for treatment of autism.