The ubiquitous and persistent environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been linked to developmental neurotoxicity in humans and experimental animals. TCDD, the most potent dioxin, mediates toxicity via binding to the aryl hydrocarbon receptor (AhR), a ligand-activated member of the bHLH/PAS transcription factor superfamily. These transcription factors serve as environmental sensors and transducers of physiological signals, particularly during development. The endogenous functions of AhR remain unknown. Certain bHLH/PAS proteins have been implicated in the regulation of cell fate determination, proliferation, and differentiation during neurogenesis. Therefore, it is conceivable that AhR plays similar roles. TCDD, through its high affinity binding and activation of the AhR, causes numerous biochemical and pathological abnormalities, particularly following developmental exposure. Deficits in cognitive function, locomotor development, and sexual behavior are some of the most sensitive endpoints associated with perinatal exposure to dioxin-like chemicals. However, the regional, cellular, and gene targets of AhR-mediated TCDD neurotoxicity remain unclear. Our laboratory has determined that cerebellar granule neuron precursors (GNPs) express high levels of transcriptionally active AhR during a critical period of cerebellar neurogenesis. The proposed studies are an extension of our previous work toward understanding the neurotoxic impact of AhR activation by TCDD in GNPs during cerebellar development. One approach will explore the manner in which inappropriate AhR activation by TCDD disrupts cerebellar neurogenesis. A second strategy will investigate the developmental role of AhR by defining the effects of AhR deletion on GNP maturation in mutant mice. Behavioral correlates of cerebellar function will be assessed in both of these models. Our preliminary studies demonstrate striking effects of TCDD on GNP proliferation, early differentiation, survival, and also on gene expression patterns associated with those processes. We have additional evidence that cerebellar growth is abnormal in AhR-/- mice. Together, these observations raise the intriguing hypothesis that TCDD disrupts cerebellar maturation by impeding AhR actions during GNP development. The primary hypothesis of the proposed studies is that AhR intrinsically controls the balance between GNP proliferation, differentiation, and apoptosis during cerebellar development. It is postulated that AhR alters cell cycle regulation, transcription factor activity, and programmed cell death by modulating gene expression in immature GNPs. Consequently, TCDD exposure disrupts endogenous AhR-mediated spatiotemporal gene profiles associated with the proper formation of cerebellar cytoarchitecture, which, in turn, adversely impacts behavioral function. The findings from this research will be important to further our understanding of transcriptional and cell cycle regulation during GNP differentiation, which may lead to the identification of factors that contribute to the anatomical and functional deficits following exposure to dioxins.

Public Health Relevance

The results from these studies will be important for understanding the adverse effects of dioxin and related chemicals on brain development. Dioxins have been associated with neurological deficits in children who have been exposed during the perinatal period. Moreover, the observations from these studies will offer insight into the cognitive and motor impairments that arise following exposure to dioxin, which is a widespread environmental contaminant.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES016357-04
Application #
8230729
Study Section
Special Emphasis Panel (ZRG1-IFCN-A (02))
Program Officer
Kirshner, Annette G
Project Start
2009-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
4
Fiscal Year
2012
Total Cost
$340,454
Indirect Cost
$107,338
Name
University of Rochester
Department
Public Health & Prev Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Dever, Daniel P; Opanashuk, Lisa A (2012) The aryl hydrocarbon receptor contributes to the proliferation of human medulloblastoma cells. Mol Pharmacol 81:669-78
Latchney, Sarah E; Lioy, Daniel T; Henry, Ellen C et al. (2011) Neural precursor cell proliferation is disrupted through activation of the aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Stem Cells Dev 20:313-26
Fox, Donald A; Opanashuk, Lisa; Zharkovsky, Aleksander et al. (2010) Gene-chemical interactions in the developing mammalian nervous system: Effects on proliferation, neurogenesis and differentiation. Neurotoxicology 31:589-97