Identification of candidate environmental risks for autism

项目总结 遗传性研究表明，遗传和环境因素导致了自闭症的风险。虽然是新的 测序技术被用来识别数百个与自闭症有关的从头基因突变，只有 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 在大量人暴露之后，风险被追溯地识别出来。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，然后这些风险才会导致 疾病。大脑转录变化将自闭症患者与典型的神经对照组区分开来。这 自闭症的转录特征定义为突触传递基因和 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 自闭症的风险可以使用自闭症的转录签名作为一种前瞻性识别 导游。我们最近发现，杀百菌灵类杀菌剂可在 胚胎皮质神经元培养，使这些杀菌剂成为检验这一假设的理想化学物质。施多比林 我们发现，杀菌剂会毒害线粒体复合体III，并产生活性氧(ROS)和 破坏神经元内微管的稳定性。这些杀菌剂在多种粮食作物上的使用正在激增，其中一种 斯特比林现在被用于墙板，构成了长期接触的潜在来源。在这里，我们将 综合评估产前接触杀菌剂可导致自闭症相关的程度 野生型小鼠的表型并加剧了一种新的人类新生模型小鼠的病理 自闭症相关突变。我们将使用接近人体暴露的低剂量和高剂量 口服时会影响生理和行为。以极大的速度加快其他 自闭症的环境风险被识别后，我们将转录描述数千种环境使用情况 使用创新的靶向测序方法对原代神经元培养中的化学物质进行分析。我们发现 原代神经元培养模拟完整大脑的分子和细胞多样性。我们的初步数据 表明这种定向测序方法可以在384个培养好的培养皿中自动进行 原代神经元，并能识别产生自闭症转录特征的化学物质。这是有针对性的 测序方法也可以识别产生与其他基因相关的转录变化的化学物质 大脑紊乱。

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.