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Lack of DNA damage induction by okadaic acid, a marine toxin, in the CHO-Hprt and the in vitro UDS assays.
Mutat Res. 2004 Dec 12; 564(2):139-47.MR

Abstract

Okadaic acid (OA) is a marine toxin produced by dinoflagellates and responsible for human intoxications. OA is a specific inhibitor of serine/threonine protein phosphatases PP1 and PP2A and a potent tumor promoter in mouse skin and rat glandular stomach. In a previous study, we demonstrated that OA induced aneuploidy in CHO-K1 cells using the cytokinesis-block micronucleus (CBMN) assay coupled to FISH and concluded that OA was not a direct mutagen. As some previous in vitro mutagenicity studies had given positive results with OA, we decided to perform two additional in vitro mutagenicity assays in accordance with the OECD guidelines: (i) the CHO/Hprt test, which provides end points about locus-specific gene mutation; (ii) the in vitro unscheduled DNA synthesis (UDS) assay in rat hepatocytes, which measures [(3)H]thymidine incorporation into DNA undergoing excision repair. In the CHO/Hprt assay, there was no significant increase in the number of mutants for doses ranging from 5 to 5000 nM in the presence or absence of rat liver S9 fraction. In the in vitro UDS assay, OA did not induce primary DNA damages in rat hepatocytes following 18 h exposure at concentrations between 1.32 and 100 nM. As OA could affect the DNA repair systems via the inhibition of protein phosphatases, its effects on the repair kinetic of 2AAF-induced DNA damage were also investigated with the UDS assay. The results showed that OA did not interact with the DNA-repair process involved in in vitro UDS in rat hepatocytes. We concluded that OA failed to induce direct DNA damage but acted principally by altering the chromosome number, which could contribute to its carcinogenic effect.

Authors+Show Affiliations

AFSSA, Laboratoire d'Etudes et de Recherches sur les Médicaments Vétérinaires et les Désinfectants, Unité de Toxicologie Alimentaire, B.P. 90203, 35302 Fougères Cedex, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

15507378

Citation

Le Hégarat, Ludovic, et al. "Lack of DNA Damage Induction By Okadaic Acid, a Marine Toxin, in the CHO-Hprt and the in Vitro UDS Assays." Mutation Research, vol. 564, no. 2, 2004, pp. 139-47.
Le Hégarat L, Nesslany F, Mourot A, et al. Lack of DNA damage induction by okadaic acid, a marine toxin, in the CHO-Hprt and the in vitro UDS assays. Mutat Res. 2004;564(2):139-47.
Le Hégarat, L., Nesslany, F., Mourot, A., Marzin, D., & Fessard, V. (2004). Lack of DNA damage induction by okadaic acid, a marine toxin, in the CHO-Hprt and the in vitro UDS assays. Mutation Research, 564(2), 139-47.
Le Hégarat L, et al. Lack of DNA Damage Induction By Okadaic Acid, a Marine Toxin, in the CHO-Hprt and the in Vitro UDS Assays. Mutat Res. 2004 Dec 12;564(2):139-47. PubMed PMID: 15507378.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lack of DNA damage induction by okadaic acid, a marine toxin, in the CHO-Hprt and the in vitro UDS assays. AU - Le Hégarat,Ludovic, AU - Nesslany,Fabrice, AU - Mourot,Annick, AU - Marzin,Daniel, AU - Fessard,Valérie, PY - 2004/03/02/received PY - 2004/07/26/revised PY - 2004/08/10/accepted PY - 2004/10/28/pubmed PY - 2005/1/22/medline PY - 2004/10/28/entrez SP - 139 EP - 47 JF - Mutation research JO - Mutat Res VL - 564 IS - 2 N2 - Okadaic acid (OA) is a marine toxin produced by dinoflagellates and responsible for human intoxications. OA is a specific inhibitor of serine/threonine protein phosphatases PP1 and PP2A and a potent tumor promoter in mouse skin and rat glandular stomach. In a previous study, we demonstrated that OA induced aneuploidy in CHO-K1 cells using the cytokinesis-block micronucleus (CBMN) assay coupled to FISH and concluded that OA was not a direct mutagen. As some previous in vitro mutagenicity studies had given positive results with OA, we decided to perform two additional in vitro mutagenicity assays in accordance with the OECD guidelines: (i) the CHO/Hprt test, which provides end points about locus-specific gene mutation; (ii) the in vitro unscheduled DNA synthesis (UDS) assay in rat hepatocytes, which measures [(3)H]thymidine incorporation into DNA undergoing excision repair. In the CHO/Hprt assay, there was no significant increase in the number of mutants for doses ranging from 5 to 5000 nM in the presence or absence of rat liver S9 fraction. In the in vitro UDS assay, OA did not induce primary DNA damages in rat hepatocytes following 18 h exposure at concentrations between 1.32 and 100 nM. As OA could affect the DNA repair systems via the inhibition of protein phosphatases, its effects on the repair kinetic of 2AAF-induced DNA damage were also investigated with the UDS assay. The results showed that OA did not interact with the DNA-repair process involved in in vitro UDS in rat hepatocytes. We concluded that OA failed to induce direct DNA damage but acted principally by altering the chromosome number, which could contribute to its carcinogenic effect. SN - 0027-5107 UR - https://www.unboundmedicine.com/medline/citation/15507378/Lack_of_DNA_damage_induction_by_okadaic_acid_a_marine_toxin_in_the_CHO_Hprt_and_the_in_vitro_UDS_assays_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1383-5718(04)00212-8 DB - PRIME DP - Unbound Medicine ER -