Identification of candidate environmental risks for autism

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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.