Dioxin (2,3,7,8 -tetrachlorodibenzo-p-dioxin; TCDD) is a ubiquitous and persistent environmental contaminant that produces developmental neurotoxicity associated with deficits in cognitive function, locomotor development, and sexual behavior. The molecular mechanisms underlying these neurotoxic actions have not been determined. However, TCDD interacts with the aryl hydrocarbon receptor (AhR) to exert toxicity in other tissues. The AhR is a transcription factor that regulates the expression of regulatory molecules that play critical roles in cellular development. Thus, it is conceivable that TCDD disrupts normal brain development through binding to the AhR. Although the precise anatomical regions and cell types targeted by TCDD during brain development have not been identified, preliminary results indicate that AhR is expressed by pluripotent neuroepithelial stem cells (NSC) and cerebellar granule cell progenitors (CGNP). Therefore, these precursor cells, among others, might be important sites of action for AhR-mediated TCDD neurotoxicity. Based on these observations, it is hypothesized that TCDD binds to AhR and interferes with precursor cell development. These signaling events disrupt the normal genetic programs required for differentiation and thereby produce neurotoxicity. This exploratory proposal is designed to identify critical developmental periods in which CNS precursor cells are vulnerable to TCDD exposure. Accordingly, the studies proposed in this application will determine whether TCDD, through interaction with the AhR, interferes with the development of NSC, CGNP, and lineage-restricted precursor cells by modifying gene expression and precursor cell function. Results of the proposed research have significant implications for understanding the risks of TCDD exposure during pregnancy, and offer new approaches to the analysis of TCDD toxicity in the developing central nervous system. ? ?
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