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易遗传的，但越来越多的证据表明环境因素也会导致ASD的风险。然而，我们对可能增加ASD风险的特定基因-环境相互作用以及环境触发物改变基因表达的分子机制的认识存在差距。我们的实验室已经确定了一种新的，对ASD有免疫反应的候选基因，维甲酸相关孤儿受体-α（RORA），其在ASD中的缺乏不仅可能导致与自闭症风险相关的较高水平的睾酮，而且可能导致ASD中强烈的男性偏见，这可能与男性和女性激素以相反方向调节RORA表达有关。我们最近证明，RORA可以潜在地调节超过2500个基因的转录，其中超过400个基因列在自闭症基因数据库中。假设：我们提出内分泌干扰化合物（EDCs），干扰激素信号的环境污染物，可能干扰RORA的正常表达，导致ASD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。具体目标：1）研究环境分散的EDCs对RORA表达的影响; 2）研究与EDCs介导的RORA表达改变相关的表观遗传机制。创新：这项研究是创新的，在解决一个特定的和高度关键的GxE相互作用，可能与ASD的明显增加。虽然对一个基因的关注可能被视为“高风险”，但对RORA失调的化学物质的鉴定具有很高的影响，因为RORA转录调节许多参与大脑发育和功能的基因。这项研究还将增加对EDC诱导的表观遗传变化的了解，如果发生在生殖系细胞中，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：这项研究将通过证明内分泌干扰物可能通过破坏特定基因RORA的表达来增加ASD的风险，进而调节大量已经参与ASD发病机制的基因来推动该领域的发展。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促进发育障碍和神经功能障碍的环境因子暴露的战略，并刺激制定治疗方案，以抵消暴露于这些化合物的影响。了解内分泌干扰物对RORA调节异常的表观遗传机制将导致开发新的表观遗传靶向干预措施，纠正或改善RORA缺陷，从而为自闭症的治疗提供机械原理。

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.