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

Nov 13, 2004Toxicological sciences : an official journal of the Society of Toxicology

Aryl hydrocarbon receptor levels and function in developing cerebellar nerve cells: possible effects on brain development and dioxin toxicity

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Abstract

AhR protein levels in cerebellar granule neuroblasts peaked between postnatal day 3-10.

AhR and Arnt proteins are present in the mouse cerebellum from birth through postnatal development.
Transcriptionally active AhR was detected in immature cerebellar granule cells after acute TCDD exposure.
AhR localized to the nucleus of granule cells within 15 minutes of TCDD treatment.
TCDD exposure led to time-dependent and concentration-dependent increases in CYP1A1 and CYP1B1 mRNA and protein levels.
TCDD treatment reduced thymidine incorporation and granule neuroblast survival in a concentration-dependent manner.
Granule neuroblasts may be direct targets for developmental AhR-mediated TCDD neurotoxicity.

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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 after acute TCDD exposure. AhR and Arnt were also expressed in cerebellar granule neuroblast cultures. AhR localized to the nucleus in granule cells 15 min after TCDD treatment. TCCD elicited time-dependent and concentration-dependent increases in CYP1A1 and 1B1 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.

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

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