Document Detail

Does mechanism matter? Unrelated neurotoxicants converge on cell cycle and apoptosis during neurodifferentiation.
MedLine Citation:
PMID:  22546817     Owner:  NLM     Status:  MEDLINE    
Mechanistically unrelated developmental neurotoxicants often produce neural cell loss culminating in similar functional and behavioral outcomes. We compared an organophosphate pesticide (diazinon), an organochlorine pesticide (dieldrin) and a metal (Ni(2+)) for effects on the genes regulating cell cycle and apoptosis in differentiating PC12 cells, an in vitro model of neuronal development. Each agent was introduced at 30μM for 24 or 72h, treatments devoid of cytotoxicity. Using microarrays, we examined the mRNAs encoding nearly 400 genes involved in each of the biological processes. All three agents targeted both the cell cycle and apoptosis pathways, evidenced by significant transcriptional changes in 40-45% of the cell cycle-related genes and 30-40% of the apoptosis-related genes. There was also a high degree of overlap as to which specific genes were affected by the diverse agents, with 80 cell cycle genes and 56 apoptosis genes common to all three. Concordance analysis, which assesses stringent matching of the direction, magnitude and timing of the transcriptional changes, showed highly significant correlations for pairwise comparisons of all the agents, for both cell cycle and apoptosis. Our results show that otherwise disparate developmental neurotoxicants converge on common cellular pathways governing the acquisition and programmed death of neural cells, providing a specific link to cell deficits. Our studies suggest that identifying the initial mechanism of action of a developmental neurotoxicant may be strategically less important than focusing on the pathways that converge on common final outcomes such as cell loss.
Theodore A Slotkin; Frederic J Seidler
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural     Date:  2012-04-24
Journal Detail:
Title:  Neurotoxicology and teratology     Volume:  34     ISSN:  1872-9738     ISO Abbreviation:  Neurotoxicol Teratol     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-24     Completed Date:  2013-05-22     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  8709538     Medline TA:  Neurotoxicol Teratol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  395-402     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC, USA.
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MeSH Terms
Apoptosis / drug effects*,  physiology
Cell Cycle / drug effects*,  physiology
Cell Differentiation / drug effects,  physiology
Diazinon / toxicity*
Dieldrin / toxicity*
Insecticides / toxicity
Neurogenesis / drug effects,  physiology
Neurons / cytology,  drug effects*,  physiology
Nickel / toxicity*
PC12 Cells
Grant Support
Reg. No./Substance:
0/Insecticides; 333-41-5/Diazinon; 60-57-1/Dieldrin; 7440-02-0/Nickel

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