Are endocrine disrupting compounds environmental risk factors for autism?

内分泌干​​扰物是自闭症的环境危险因素吗？

• 批准号: 8838132
• 负责人: VALERIE W HU
• 金额: $ 19.81万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8838132
• 关键词: Address; Affect; Autistic Disorder; Behavior; Biological Markers; Brain; Candidate Disease Gene; Cells; Chemicals; Circadian Rhythms; Complex; Coupled; Databases; Development; Disease; Endocrine Disruptors; Environment; Environmental Exposure; Environmental Pollutants; Environmental Risk Factor; Epigenetic Process; Evidence based treatment; Exposure to; Female; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Glutamate Receptor; Health; Health Policy; Heritability; Hormonal; Hormones; Individual; Inflammation; Intervention; Knowledge; Laboratories; Language Development; Lead; Measures; Mediating; Mental disorders; Modification; Molecular; Nervous System Physiology; Neurites; Neurodevelopmental Disorder; Neurologic; Neurologic Dysfunctions; Nuclear Hormone Receptors; Orphan; Outcome; Oxidative Stress; Pathogenesis; Pathway interactions; Physiological; Prevalence; Preventive; Public Health; Receptor Signaling; Regulation; Relative (related person); Research; Risk; Signal Transduction; Sleep disturbances; Social Interaction; Stereotyping; Susceptibility Gene; Synaptic Transmission; Synaptic plasticity; Testosterone; Treatment Protocols; Tretinoin; autism spectrum disorder; axon guidance; brain tissue; developmental disease; environmental agent; environmental toxicology; gene environment interaction; high risk; high throughput screening; innovation; insight; interest; lymphoblast; male; neurogenesis; neuroprotection; neurotransmission; next generation; novel; receptor; synaptogenesis

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.

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疾病之一，但越来越多的证据表明，环境因素也会增加自闭症谱系障碍的风险。然而，我们对可能增加自闭症谱系障碍风险的特定基因与环境相互作用以及环境触发因素改变基因表达的分子机制的了解存在差距。我们的实验室发现了一种新的、对自闭症谱系障碍激素敏感的候选基因，即视黄酸相关孤儿受体-α（RORA），该基因在自闭症谱系障碍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，而且还导致自闭症谱系障碍的强烈男性偏见，这可能与男性和女性激素对 RORA 表达的反向调节有关。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 400 多个基因已在自闭症基因数据库中列出。假设：我们提出内分泌干扰化合物（EDC），即干扰激素信号传导的环境污染物，可能会干扰 RORA 的正常表达，导致 ASD 风险增加。这项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 相互作用背后的表观遗传机制。具体目标：1）研究环境分散的EDC对RORA表达的影响； 2) 研究与 EDC 介导的 RORA 表达改变相关的表观遗传机制。创新：这项研究在解决特定且高度关键的 GxE 相互作用方面具有创新性，该相互作用可能与 ASD 的明显增加有关。尽管关注某一基因可能被视为“高风险”，但识别出导致 RORA 失调的化学物质具有很大影响，因为 RORA 在转录上调节许多与大脑发育和功能有关的基因。这项研究还将加深对 EDC 诱导的表观遗传变化的了解，这些变化如果发生在生殖细胞中，则可以传递给下一代，并导致对可能通过 RORA 失调增加 ASD 风险的化合物进行高通量筛选。影响/公共卫生意义：这项研究将推动该领域向前发展，证明 EDC 可能通过破坏特定基因 RORA 的表达来增加 ASD 风险，而 RORA 反过来又调节大量已经与 ASD 发病机制有关的基因。我们进一步预计，通过这些研究获得的信息将有助于制定公共卫生政策，以实施战略，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素的影响，并刺激治疗方案的制定，以抵消接触这些化合物的影响。了解 EDCs 对 RORA 失调的表观遗传机制将有助于开发新的表观遗传学靶向干预措施，以纠正或改善 RORA 缺陷，从而为自闭症的治疗提供机制原理。

项目成果

Sex Differences in the Effects of Prenatal Bisphenol A Exposure on Genes Associated with Autism Spectrum Disorder in the Hippocampus.

产前双酚 A 暴露对海马自闭症谱系障碍相关基因影响的性别差异。

• DOI: 10.1038/s41598-019-39386-w
• 发表时间: 2019
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Thongkorn,Surangrat;Kanlayaprasit,Songphon;Jindatip,Depicha;Tencomnao,Tewin;Hu,ValerieW;Sarachana,Tewarit
• 通讯作者: Sarachana,Tewarit

Are endocrine disrupting compounds environmental risk factors for autism spectrum disorder?

• DOI: 10.1016/j.yhbeh.2017.10.003
• 发表时间: 2018-05
• 期刊: Hormones and behavior
• 影响因子: 3.5
• 作者: Moosa A;Shu H;Sarachana T;Hu VW
• 通讯作者: Hu VW

Integrated genome-wide Alu methylation and transcriptome profiling analyses reveal novel epigenetic regulatory networks associated with autism spectrum disorder.

• DOI: 10.1186/s13229-018-0213-9
• 发表时间: 2018
• 期刊: Molecular autism
• 影响因子: 6.2
• 作者: Saeliw T;Tangsuwansri C;Thongkorn S;Chonchaiya W;Suphapeetiporn K;Mutirangura A;Tencomnao T;Hu VW;Sarachana T
• 通讯作者: Sarachana T