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Developmental cholinotoxicants: nicotine and chlorpyrifos.
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MedLine Citation:
PMID:  10229709     Owner:  NLM     Status:  MEDLINE    
The stimulation of cholinergic receptors in target cells during a critical developmental period provides signals that influence cell replication and differentiation. Accordingly, environmental agents that promote cholinergic activity evoke neurodevelopmental damage because of the inappropriate timing or intensity of stimulation. Nicotine evokes mitotic arrest in brain cells possessing high concentrations of nicotinic cholinergic receptors. In addition, the cholinergic overstimulation programs the expression of genes that evoke apoptosis and delayed cell loss. Effects of cholinesterase inhibitors exhibit many similarities to those of nicotine. Chlorpyrifos administered to developing rats in doses that do not evoke signs of overt toxicity decreased DNA synthesis and caused shortfalls in cell numbers in brain regions enriched in cholinergic innervation. In embryo cultures, chlorpyrifos also evoked apoptosis during neurulation. However, chlorpyrifos also evokes noncholinergic disruption of cell development by interfering with cell signaling via adenylyl cyclase, leading to widespread disruption that is not limited to cholinergic systems. We have tested this hypothesis in vitro with PC12 cells, which lack the enzymes necessary to produce chlorpyrifos oxon, the metabolite that inhibits cholinesterase. Chlorpyrifos inhibited DNA synthesis in undifferentiated PC12 cells, which have relatively few cholinergic receptors. Furthermore, chlorpyrifos was more effective than nicotine and its effects were not blocked by cholinergic antagonists. When cells were allowed to differentiate in the presence of chlorpyrifos, cell replication was inhibited even more profoundly and cell acquisition was arrested. At higher concentrations, chlorpyrifos also inhibited neuritic outgrowth. Thus, chlorpyrifos elicits damage by both noncholinergic and cholinergic mechanisms extending from early stages of neural cell replication through late stages of axonogenesis and terminal differentiation. Accordingly, the window of developmental vulnerability to chlorpyrifos is likely to extend from the embryonic period into postnatal life.
T A Slotkin
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Environmental health perspectives     Volume:  107 Suppl 1     ISSN:  0091-6765     ISO Abbreviation:  Environ. Health Perspect.     Publication Date:  1999 Feb 
Date Detail:
Created Date:  2000-07-27     Completed Date:  2000-07-27     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  0330411     Medline TA:  Environ Health Perspect     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  71-80     Citation Subset:  IM    
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
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MeSH Terms
Brain / drug effects*
Chlorpyrifos / toxicity*
Cholinesterase Inhibitors / toxicity*
DNA / biosynthesis
Insecticides / toxicity*
Neurotransmitter Agents / physiology
Nicotine / toxicity*
PC12 Cells
Parasympathetic Nervous System / drug effects*
Reg. No./Substance:
0/Cholinesterase Inhibitors; 0/Insecticides; 0/Neurotransmitter Agents; 2921-88-2/Chlorpyrifos; 54-11-5/Nicotine; 9007-49-2/DNA

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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Journal Information
Journal ID (nlm-ta): Environ Health Perspect
ISSN: 0091-6765
Article Information
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Print publication date: Month: 2 Year: 1999
Volume: 107 Issue: Suppl 1
First Page: 71 Last Page: 80
ID: 1566354
PubMed Id: 10229709
Publisher Item Identifier: sc271_5_1835

Developmental cholinotoxicants: nicotine and chlorpyrifos.
T A Slotkin
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.

Article Categories:
  • Research Article

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