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ToxSci Advance Access published online on November 10, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfi031
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received August 13, 2004
Accepted November 3, 2004

Neurotoxicology

Aryl Hydrocarbon Receptor Expression and Activity in Cerebellar Granule Neuroblasts: Implications for Development and Dioxin Neurotoxicity

Mary A. Williamson 1, Thomas A. Gasiewicz 1, and Lisa A. Opanashuk 1*

1 Department of Environmental Medicine, 575 Elmwood Avenue, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

* To whom correspondence should be addressed.
Lisa A. Opanashuk, E-mail: Lisa_Opanashuk{at}urmc.rochester.edu


  Abstract

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent teratogen that produces neurobehavioral abnormalities associated with both cognitive and locomotor systems, yet the precise regional and cellular targets of developmental neurotoxicity remain largely unknown. Most, if not all, TCDD-induced pathology is mediated via binding to the aryl hydrocarbon receptor (AhR), a ligand activated transcription factor that belongs to the basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) superfamily. Upon ligand binding, AhR translocates to the nucleus, dimerizes with the AhR nuclear translocator protein (Arnt), and regulates transcription by interaction with dioxin response elements (DREs) in target genes, most notably specific cytochrome P450 (CYP) family members. To assess whether developing cerebellar granule neuroblasts are potential direct targets for TCDD toxicity, AhR expression and transcriptional activity were examined. AhR and Arnt proteins were present in mouse cerebellum from birth throughout postnatal development. AhR protein levels peaked between postnatal day (PND) 3-10, a critical period for granule neuroblast growth and maturation. Transcriptionally active AhR was detected in immature cerebellar granule cells in a transgenic dioxin-responsive lacZ mouse model following acute TCDD exposure. AhR and Arnt were also expressed in cerebellar granule neuroblast cultures. AhR localized to the nucleus in granule cells 15 minutes following TCDD treatment. TCCD elicited time and concentration dependent increases in CYP1A1 and1B1 mRNA and protein levels. Moreover, TCDD treatment reduced both thymidine incorporation and granule neuroblast survival in a concentration-dependent manner. These data suggest that 1) granule neuroblasts are direct targets for developmental AhR mediated TCDD neurotoxicity and 2) TCDD exposure may disrupt granule cell neurogenesis.

Keywords: neurogenesis; bHLH/PAS; Arnt; CYP 1A1/1B1; dioxin.
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