Electronic Thesis/Dissertation


An Investigation of the In Vitro Effect of Endocrine Disrupting Compounds on RORA, a Candidate Gene for Autism Open Access

Autism spectrum disorders (ASD) are clinically assessed on the basis of behavioral deficiencies in reciprocal social interactions and communication, in addition to repetitive behavioral stereotypies. Genome-wide analyses have revealed a number of genes differentially expressed in individuals with ASD. One particular gene, which encodes retinoic acid-related nuclear orphan receptor alpha (RORA), was found to be hypermethylated in lymphoblastoid cells from individuals with ASD and significantly down-regulated in post-mortem brain tissue taken from the frontal cortex of autistic individuals. Importantly, this novel candidate gene for ASD is reciprocally regulated by both male and female hormones in a manner that may explain increased levels of testosterone and the extreme male bias in ASD. These studies suggest the involvement of the endocrine system in ASD. Endocrine disruption has been postulated to have a causal role in ASD pathogenesis. This study uses quantitative RT-PCR to measure the response of RORA expression in neuronal cells to treatment with bisphenol A (BPA) and valproic acid (VPA), exogenous compounds that can affect endocrine function. Here, we show that brief exposure to low doses of BPA and VPA produce similar biphasic trends in the transcription of RORA. Furthermore, we have noted a dose and time-dependent response in a neuronal cell line (SH-SY5Y). Both BPA and VPA are shown to elicit rapid changes in RORA expression. In this report, we present our original findings on the impact of these endocrine disruptors on RORA in conjunction with a review of previous studies to suggest a potential role for EDCs in the pathobiology of ASD.

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