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Marine toxin okadaic acid induces aneuploidy in CHO-K1 cells in presence of rat liver postmitochondrial fraction, revealed by cytokinesis-block micronucleus assay coupled to FISH.

Abstract
Okadaic acid (OA), a major polyether toxin involved in diarrhetic shellfish poisoning (DSP), is a potent tumor promoter in rodent skin and glandular stomach and a specific inhibitor of the serine/threonine protein phosphatases PP1 and PP2A. A previous study, which used the cytokinesis-block micronucleus (CBMN) assay in CHO-K1 cells, showed that OA induced chromosome damage in the presence of a rat liver metabolic activation system (S9). To support OA biotransformation by S9, the same test system was performed, and DNA damage induced by OA was measured with and without metabolic activation as well as in the presence of heat-inactivated S9 fraction. The results showed that only in the presence of active S9 did OA significantly increased the frequency of micronucleated binucleated (MNBN) cells. After a 4-h treatment a 2- to 5-fold increase of MNBN cells was observed at 30 nM and at 50 nM of OA. However, without S9 or in the presence of heat-inactivated S9, OA did not induce any chromosome damage. We concluded that OA can be metabolically activated in vitro into metabolites that are more genotoxic. The CBMN assay coupled with fluorescence in situ hybridization (FISH) using a DNA probe for centromere detection was performed to discriminate between clastogenic (chromosome breakage) and aneugenic (chromosome loss) effects. FISH analysis showed that OA metabolites increased in a dose-dependent manner in centromere positive micronuclei (CEN+): 60% of CEN+ at 30 nM and 75% of CEN+ at 50 nM of OA. The uptake of OA into CHO-K1 cells and the biotransformation of the toxin are discussed.
AuthorsLudovic Le Hégarat, Valérie Fessard, Jean Michel Poul, Sylviane Dragacci, Pascal Sanders
JournalEnvironmental toxicology (Environ Toxicol) Vol. 19 Issue 2 Pg. 123-8 (Apr 2004) ISSN: 1520-4081 [Print] United States
PMID15037998 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright 2004 Wiley Periodicals, Inc. Environ Toxicol 19: 123-128, 2004
Chemical References
  • Okadaic Acid
Topics
  • Analysis of Variance
  • Aneuploidy
  • Animals
  • CHO Cells
  • Cell Division (drug effects)
  • Chromosome Breakage
  • Chromosome Deletion
  • Cricetinae
  • Cricetulus
  • DNA Damage (drug effects)
  • Dose-Response Relationship, Drug
  • In Situ Hybridization, Fluorescence
  • Liver (chemistry)
  • Micronuclei, Chromosome-Defective (drug effects)
  • Micronucleus Tests
  • Okadaic Acid (pharmacokinetics, toxicity)
  • Rats
  • Rats, Sprague-Dawley

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