ToxSci Advance Access originally published online on January 27, 2008
Toxicological Sciences 2008 103(1):125-136; doi:10.1093/toxsci/kfn017
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2,3,7,8-Tetracholorodibenzo-p-Dioxin Exposure Disrupts Granule Neuron Precursor Maturation in the Developing Mouse Cerebellum
Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642
2 To whom correspondence should be addressed at Box EHSC Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY 14642. Fax: (585) 276-0453. E-mail: Lisa_Opanashuk{at}urmc.rochester.edu.
Received September 29, 2007; accepted January 21, 2008
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Abstract |
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The widespread environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been linked to developmental neurotoxicity associated with abnormal cerebellar maturation in both humans and rodents. TCDD mediates toxicity via binding to the aryl hydrocarbon receptor (AhR), a transcription factor that regulates the expression of xenobiotic metabolizing enzymes and growth regulatory molecules. Our previous studies demonstrated that cerebellar granule neuron precursor cells (GNPs) express transcriptionally active AhR during critical developmental periods. TCDD exposure also impaired GNP proliferation and survival in vitro. Therefore, this study tested the hypothesis that TCDD exposure disrupts cerebellar development by interfering with GNP differentiation. In vivo experiments indicated that TCDD exposure on postnatal day (PND) 6 resulted in increased expression of a mitotic marker and increased thickness of the external granule layer (EGL) on PND10. Expression of the early differentiation marker TAG-1 was also more pronounced in postmitotic, premigratory granule neurons of the EGL, and increased apoptosis of GNPs was observed. On PND21, expression of the late GNP differentiation marker GABAA
6 receptor (GABARA6) and total estimated cell numbers were both reduced following exposure on PND6. Studies in unexposed adult AhR–/– mice revealed lower GABARA6 levels and DNA content. In vitro studies showed elevated expression of the early differentiation marker p27/Kip1 and the GABARA6 in GNPs following TCDD exposure, and the expression patterns of proteins related to granule cell neurite outgrowth, βIII-tubulin and polysialic acid neural cell adhesion molecule, were consistent with enhanced neuroblast differentiation. Together, our data suggest that TCDD disrupts a normal physiological role of AhR, resulting in compromised GNP maturation and neuroblast survival, which impacts final cell number in the cerebellum.
Key Words: neurogenesis; neurotoxicity; neural progenitor; differentiation; TCDD; cell cycle.
Loretta L. Collins and Mary A. Williamson contributed equally to this work.
1 Present address: Department of Hospital Laboratories, University of Massachusetts Memorial Hospital, Worcester, MA 01605.
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