Document Detail

Neural precursor cell proliferation is disrupted through activation of the aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-p-dioxin.
MedLine Citation:
PMID:  20486776     Owner:  NLM     Status:  MEDLINE    
Neurogenesis involves the proliferation of multipotent neuroepithelial stem cells followed by differentiation into lineage-restricted neural precursor cells (NPCs) during the embryonic period. Interestingly, these progenitor cells express robust levels of the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that regulates expression of genes important for growth regulation, and xenobiotic metabolism. Upon binding 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a pervasive environmental contaminant and potent AhR ligand, AhR, is activated and disrupts gene expression patterns to produce cellular toxicity. Because of its widespread distribution in the brain during critical proliferative phases of neurogenesis, it is conceivable that AhR participates in NPC expansion. Therefore, this study tested the hypothesis that AhR activation by TCDD disrupts signaling events that regulate NPC proliferation. The C17.2 NPC line served as a model system to (1) assess whether NPCs are targets for TCDD-induced neurotoxicity and (2) characterize the effects of TCDD on NPC proliferation. We demonstrated that C17.2 NPCs express an intact AhR signaling pathway that becomes transcriptionally active after TCDD exposure. (3)H-thymidine and alamar blue reduction assays indicated that TCDD suppresses NPC proliferation in a concentration-dependent manner without the loss of cell viability. Cell cycle distribution analysis by flow cytometry revealed that TCDD-induced growth arrest results from an impaired G1 to S cell cycle transition. Moreover, TCDD exposure altered p27( kip1) and cyclin D1 cell cycle regulatory protein expression levels consistent with a G1 phase arrest. Initial studies in primary NPCs isolated from the ventral forebrain of embryonic mice demonstrated that TCDD reduced cell proliferation through a G1 phase arrest, corroborating our findings in the C17.2 cell line. Together, these observations suggest that the inappropriate or sustained activation of AhR by TCDD during neurogenesis can interfere with signaling pathways that regulate neuroepithelial stem cell/NPC proliferation, which could adversely impact final cell number in the brain and lead to functional impairments.
Sarah E Latchney; Daniel T Lioy; Ellen C Henry; Thomas A Gasiewicz; Frederick G Strathmann; Margot Mayer-Pröschel; Lisa A Opanashuk
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-08-31
Journal Detail:
Title:  Stem cells and development     Volume:  20     ISSN:  1557-8534     ISO Abbreviation:  Stem Cells Dev.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-01-24     Completed Date:  2011-06-24     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  101197107     Medline TA:  Stem Cells Dev     Country:  United States    
Other Details:
Languages:  eng     Pagination:  313-26     Citation Subset:  IM    
Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
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MeSH Terms
Cell Cycle / drug effects
Cell Cycle Proteins / genetics,  metabolism
Cell Proliferation / drug effects*
Cell Survival / drug effects
Cells, Cultured
DNA Replication / drug effects
Embryo, Mammalian
Gene Expression Regulation, Developmental / drug effects
Mice, Inbred C57BL
Mitogens / pharmacology
Neural Stem Cells / cytology,  drug effects*
Neurons / cytology,  drug effects*
Prosencephalon / cytology
Receptors, Aryl Hydrocarbon / agonists*,  metabolism
Tetrachlorodibenzodioxin / pharmacology*
Tumor Cells, Cultured
Grant Support
Reg. No./Substance:
0/Cell Cycle Proteins; 0/Mitogens; 0/Receptors, Aryl Hydrocarbon; 1746-01-6/Tetrachlorodibenzodioxin

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