Autism spectrum disorder (ASD or autism) is a highly heritable and heterogeneous neurodevelopmental disorder that is characterized by deficits in social interactions, stereotyped behaviors, and impaired language development. In the past 4 years, the incidence of ASD has risen from 1 in 110 to 1 in every 68 children, with a bias towards males of 4:1. To date, there is no explanation for the rapid rise in ASD incidence or the apparent male sex-bias. In this study, we propose that the impact of a common herbicide, Atrazine, on the expression of a novel ASD-candidate gene, retinoic acid-related orphan receptor alpha ( RORA), may serve as a model to elucidate how gene-environment interactions may increase risk for ASD. Our past research revealed that RORA is oppositely regulated by male and female sex hormones and can potentially regulate the transcription of hundreds of ASD-associated genes. Therefore, dysregulation of this gene by environmental agents may elicit genome-wide changes in expression of genes relevant to the pathobiology of ASD.
In this pilot study, we demonstrate that RORA is dysregulated biphasically in a neuronal cell model by “low-dose” exposure to Atrazine, an endocrine disrupting compound (EDC). Additionally, using microarrays for expression profiling, we were able to observe that exposure to subnanomolar and nanomolar concentrations of Atrazine induces differential gene expression at the whole genome level, notably affecting genes with ASD-associated neurological and psychological functions. Additionally, a number of genes impacted by Atrazine exposure are contained within the SFARI database of annotated ASD risk genes.
We have also developed a high-throughput assay to rapidly screen for additional EDCs that may increase risk for ASD based on RORA promoter-driven luciferase reporter activity in neurologically relevant cell models. We anticipate that this screen will prove invaluable in providing additional insight into gene-environmental interactions that impact neurodevelopment as well as increased awareness of the biological consequences of “low dose” levels of EDCs that are well below current EPA-approved limits. Moreover, because exposures to EDCs that cause phenotypic changes are often the result of epigenetic mechanisms, the expression changes induced by EDCs may be passed transgenerationally through germline cells, and may account for the increased incidence of ASD in recent years.
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|Advisor:||Hu, Valerie W.|
|School:||The George Washington University|
|Department:||Biochemistry and Molecular Biology|
|School Location:||United States -- District of Columbia|
|Source:||MAI 55/05M(E), Masters Abstracts International|
|Keywords:||Atrazine, Autism, Endocrine disrupting compounds, Environmental risks, Screening assays|
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