Autism spectrum disorders (ASD) are among the most heritable of all psychiatric disorders, but there is increasing evidence that environmental factors also contribute to the risk for ASD. However, there is a gap in our knowledge regarding specific gene-environment interactions that may increase risk for ASD and the molecular mechanisms through which environmental triggers alter gene expression. Our laboratory has identified a novel, hormonally-responsive candidate gene for ASD, retinoic acid-related orphan receptor- alpha (RORA), whose deficiency in ASD may contribute not only to higher levels of testosterone associated with risk for autism, but also to the strong male bias in ASD, which may be related to the regulation of RORA expression in opposite directions by male and female hormones. We recently demonstrated that RORA can potentially regulate the transcription of >2500 genes, of which over 400 are listed in autism gene databases. Hypothesis: we propose that endocrine disrupting compounds (EDCs), environmental pollutants that interfere with hormonal signaling, may interfere with the normal expression of RORA, leading to increased risk for ASD. Long-term objectives of this study are to identify specific gene-environment (GxE) interactions that may increase risk for ASD and to understand the epigenetic mechanisms underlying GxE interactions.
Specific Aims : 1) investigate the impact of environmentally dispersed EDCs on RORA expression;2) investigate epigenetic mechanisms associated with EDC-mediated alteration of RORA expression. Innovation: This study is innovative in addressing a specific and highly critical GxE interaction that could plausibly relate to an apparent increase in ASD. Although the focus on one gene may be viewed as """"""""high risk"""""""", identification of chemicals that dysregulate RORA is of high impact because RORA transcriptionally regulates many genes that are involved in brain development and function. This study will also increase insight into EDC- induced epigenetic changes which can be transmitted to the next generation if occurring in germline cells, and result in a high-throughput screen for compounds that may increase risk for ASD via dysregulation of RORA. Impact/Public health significance: This study will move the field forward by demonstrating that EDCs may increase risk for ASD by disrupting expression of a specific gene, RORA, which in turn, regulates a large number of genes already implicated in the pathogenesis of ASD. We further anticipate that the information gained through these studies will lead to the development of public health policies to implement strategies to protect the public against exposure to environmental agents that might promote developmental disorders and neurological dysfunction, as well as stimulate the development of treatment protocols to counteract the effects of exposure to these compounds. Understanding the epigenetic mechanisms underlying the dysregulation of RORA by EDCs will lead to the development of novel epigenetics-targeted interventions that correct or ameliorate RORA deficiency, thus providing a mechanistic rationale for treatment of autism.
This study will fill a gap in our knowledge of specific gene-environment interactions that increase risk for autism spectrum disorders (ASD). In particular, we anticipate that this study will show that endocrine disrupting compounds (EDCs) are a significant, but modifiable, environmental risk factor for ASD, in part through their impact on retinoic acid-related orphan receptor-alpha (RORA), which is a gene that regulates brain development as well as many neurological functions disrupted in ASD, including synaptogenesis, synaptic plasticity, axon guidance, neurotransmission, and neurite extension. The anticipated outcomes will help guide public health policies regarding preventive measures to reduce environmental exposure to such compounds as well as stimulate the development of evidence-based treatment protocols targeting RORA deficiency to counteract the effects of exposure to these compounds.