Document Detail

Induction of the cell cycle regulatory gene p21 (Waf1, Cip1) following methylmercury exposure in vitro and in vivo.
MedLine Citation:
PMID:  10373404     Owner:  NLM     Status:  MEDLINE    
Methylmercury (MeHg) is recognized as a significant environmental hazard, particularly to the development of the nervous system. To study the molecular mechanisms underlying cell cycle inhibition by MeHg, we assessed the involvement of p21 (Waf1, Cip1), a cell cycle regulatory gene implicated in the G1 and G2 phases of cell cycle arrest, in primary embryonic cells and adult mice following MeHg exposure. Previous literature has supported the association of increased p21 expression with chondrocyte differentiation. In support of this finding, we observed an increasing p21 expression during limb bud (LB), but not midbrain central nervous system (CNS) cell differentiation. Both embryonic LB and CNS cells responded to MeHg exposure with a concentration-dependent increase in p21 mRNA. In the parallel adult study, C57BL/6 female mice were chronically exposed to 10 ppm MeHg via drinking water for 4 weeks. While there was limited or absent induction of Gadd45, Gadd153, and the gamma-glutamylcysteine synthetase catalytic subunit, p21 was markedly induced in the brain, kidney, and liver tissues in most of the animals that showed MeHg-induced behavioral toxicity such as hyperactivity and tremor. Furthermore, the induction of p21 mRNA was accompanied by an increase in p21 protein level. The results indicate that the activation of cell cycle regulatory genes may be one mechanism by which MeHg interferes with the cell cycle in adult and developing organisms. Continued examination of the molecular mechanisms underlying cell cycle inhibition may potentially lead to utilization of this mechanistic information to characterize the effects of MeHg exposure in vivo.
Y C Ou; S A Thompson; R A Ponce; J Schroeder; T J Kavanagh; E M Faustman
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Toxicology and applied pharmacology     Volume:  157     ISSN:  0041-008X     ISO Abbreviation:  Toxicol. Appl. Pharmacol.     Publication Date:  1999 Jun 
Date Detail:
Created Date:  1999-07-12     Completed Date:  1999-07-12     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0416575     Medline TA:  Toxicol Appl Pharmacol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  203-12     Citation Subset:  IM    
Copyright Information:
Copyright 1999 Academic Press.
Department of Environmental Health, University of Washington, Seattle, Washington 98195, USA.
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MeSH Terms
Blotting, Northern
Blotting, Western
Cell Cycle / drug effects,  genetics
Cell Differentiation / drug effects
Cell Survival / drug effects
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p21
Cyclins / genetics*
Extremities / embryology
Gene Expression Regulation*
Mesencephalon / cytology,  embryology
Methylmercury Compounds / toxicity*
Mice, Inbred C57BL
Organ Specificity
Precipitin Tests
Rats, Sprague-Dawley
Grant Support
Reg. No./Substance:
0/Cdkn1a protein, mouse; 0/Cdkn1a protein, rat; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/Methylmercury Compounds; 1184-57-2/methylmercury hydroxide

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