Identification of candidate environmental risks for autism

识别自闭症的候选环境风险

• 批准号: 9525549
• 负责人: Mark J. Zylka
• 金额: $ 25万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9525549
• 关键词: Acute; Affect; Autistic Disorder; Behavior; Behavioral; Birth; Brain; Brain Diseases; Cerebral cortex; Chemicals; Chronic; Data; Development; Disease; Dose; Electron Transport Complex III; Embryo; Environmental Exposure; Environmental Risk Factor; Exposure to; Food; Future; Future Generations; Gene Expression; Gene Expression Profile; Gene Mutation; Genes; Genetic; Genetic Transcription; Heritability; Histologic; Human; In Vitro; Individual; Industrial fungicide; Joints; Knowledge; Life; Ligation; Link; Mediating; Microtubules; Mitochondria; Modeling; Molecular Models; Mus; Mutation; Neuroimmune; Neurons; Oligonucleotides; Oral; Pathology; Pesticides; Phenotype; Physiology; Poison; Pregnancy; Prevalence; Public Health; RNA; Reactive Oxygen Species; Risk; Robotics; Source; Synapses; Synaptic Transmission; Technology; Testing; UBE3A gene; Wild Type Mouse; building materials; candidate identification; chemical group; critical period; environmental chemical; experimental study; exposed human population; in vivo; innovation; molecular modeling; mouse model; neuroinflammation; prenatal; prospective; screening; social; targeted sequencing; transcriptome sequencing

PROJECT SUMMARY Heritability studies indicate that genetic and environmental factors contribute to autism risk. While new sequencing technologies were used to identify hundreds of de novo gene mutations linked to autism, only a small number of environmental risks for autism have been identified to date. Moreover, these environmental risks were identified retrospectively, after a large number of people were exposed. There is thus a significant public health need to identify environmental risks for autism prospectively, before these risks contribute to disease. Brain transcriptional changes differentiate individuals with autism from neurotypical controls. This transcriptional signature of autism is defined by reduced expression of synaptic transmission genes and elevated expression of neuroimmune/microglial genes. Here, we hypothesize that candidate environmental risks for autism can be prospectively identified using the transcriptional signature of autism as a guide. We recently found that strobilurin fungicides reproducibly produce this transcriptional signature in embryonic cortical neuron cultures, making these fungicides ideal chemicals to test this hypothesis. Strobilurin fungicides poison mitochondrial complex III and, as we found, generate reactive oxygen species (ROS) and destabilize microtubules in neurons. Usage of these fungicides is surging on a diversity of food crops and one strobilurin is now being used in wallboards, posing a potential source for chronic exposure. Here we will comprehensively evaluate the extent to which prenatal fungicide exposure produces autism-related phenotypes in wild-type mice and exacerbates pathology in a new mouse line that models a human de novo autism-linked mutation. We will use a low dose that approximates human exposures and a higher dose that effects physiology and behavior when administered orally. To greatly accelerate the pace at which additional environmental risks for autism are identified, we will transcriptionally profile thousands of environmental-use chemicals on primary neuron cultures using an innovative targeted sequencing approach. We found that primary neuron cultures model the molecular and cellular diversity of the intact brain. Our preliminary data indicate this targeted sequencing approach can be performed robotically in 384-well dishes with cultured primary neurons and can identify chemicals that produce the transcriptional signature of autism. This targeted sequencing approach can also identify chemicals that produce transcriptional changes associated with other brain disorders.

项目摘要 遗传性研究表明，遗传和环境因素有助于自闭症的风险。而新 测序技术被用来识别数百个与自闭症有关的新生基因突变，只有一个 到目前为止，已经确定了少数自闭症的环境风险。此外，这些环境 风险是在大量人员接触后进行回顾性确定的。因此，有一个重要的 公共卫生需要前瞻性地识别自闭症的环境风险，在这些风险导致自闭症之前， 疾病大脑转录的变化区分自闭症个体和神经正常对照。这 自闭症的转录特征由突触传递基因的表达减少定义， 神经免疫/小胶质细胞基因表达升高。在这里，我们假设候选环境 自闭症的风险可以通过使用自闭症的转录特征作为一种 为着力我们最近发现嗜球果伞素杀真菌剂可重复地产生这种转录标记， 胚胎皮层神经元培养，使这些杀菌剂理想的化学品来测试这一假设。Strobilurin 杀真菌剂毒害线粒体复合物III，正如我们发现的，产生活性氧（ROS）， 使神经元中的微管不稳定。这些杀真菌剂在多种粮食作物上的使用正在激增， 嗜球果伞素现在被用于墙板，成为长期接触的潜在来源。这里我们将 全面评估产前杀菌剂暴露产生自闭症相关的程度 在野生型小鼠中的表型，并加剧了一个新的小鼠系，模拟人类从头 自闭症连锁突变我们将使用接近人体暴露的低剂量和 影响生理和行为。为了大大加快额外的 自闭症的环境风险被确定，我们将转录分析成千上万的环境使用， 使用创新的靶向测序方法对原代神经元培养物进行化学处理。我们发现 原代神经元培养物模拟完整脑的分子和细胞多样性。我们的初步数据 表明这种靶向测序方法可以在384孔培养皿中自动进行， 初级神经元，并可以识别产生自闭症转录签名的化学物质。此次定向 测序方法还可以识别产生与其他基因相关的转录变化的化学物质。 脑部疾病。