Assessment of genotoxicity induced by 7,12-dimethylbenz(a)anthracene or diethylnitrosamine in the Pig-a, micronucleus and Comet assays integrated into 28-day repeat dose studies
| Autor: | Ljubica Krsmanovic, Michelle Klug Laforce, Madhav Paranjpe, Sandra Springer, Samual Atta-Safoh, Kathleen Szabo, Fekado Debelie, Jing Shi, Mirna Arevalo, Shannon W. Bruce, Jamie E. Sly, Tawney Kelly |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Erythrocytes Reticulocytes Time Factors Epidemiology DNA damage Endpoint Determination Health Toxicology and Mutagenesis 9 10-Dimethyl-1 2-benzanthracene DMBA Mutagen CD59 Antigens Gene mutation medicine.disease_cause Risk Assessment Rats Sprague-Dawley chemistry.chemical_compound Bone Marrow medicine Animals Diethylnitrosamine Genetics (clinical) Micronucleus Tests Dose-Response Relationship Drug Chemistry Mutagenicity Tests 7 12-Dimethylbenz[a]anthracene Membrane Proteins Reproducibility of Results Reference Standards Flow Cytometry Molecular biology Rats Comet assay Liver Data Interpretation Statistical Calibration Mutation Comet Assay Micronucleus Laboratories Genotoxicity Mutagens |
| Zdroj: | Environmental and molecular mutagenesis. 52(9) |
| ISSN: | 1098-2280 |
| Popis: | As part of the Stage 3 of the Pig-a international trial, we evaluated 7,12-dimethylbenz(a)anthracene (DMBA) for induction of Pig-a gene mutation using a 28-day repeat dose study design in Sprague-Dawley rats. In the same study, chromosomal damage in peripheral blood and primary DNA damage in liver were also investigated by the micronucleus (MN) assay and the Comet assay, respectively. In agreement with previously published data (Dertinger et al., [2010]: Toxicol Sci 115:401-411), DMBA induced dose-dependent increases of CD59-negative erythrocytes/reticulocytes and micronucleated reticulocytes (MN-RETs). However, there was no significant increase in DNA damage in the liver cells when tested up to 10 mg/kg/day, which appears to be below the maximum tolerated dose. When tested up to 200 mg/kg/day in a follow-up 3 dose study, DMBA was positive in the liver Comet assay. Additionally, we evaluated diethylnitrosamine (DEN), a known mutagen/hepatocarcinogen, for induction of Pig-a mutation, MN and DNA damage in a 28-day study. DEN produced negative results in both the Pig-a mutation assay and the MN assay, but induced dose-dependent increases of DNA damage in the liver and blood Comet assay. In summary, our results demonstrated that the Pig-a mutation assay can be effectively integrated into repeat dose studies and the data are highly reproducible between different laboratories. Also, integration of multiple genotoxicity endpoints into the same study not only provides a comprehensive evaluation of the genotoxic potential of test chemicals, but also reduces the number of animals needed for testing, especially when more than one in vivo genotoxicity tests are required. |
| Databáze: | OpenAIRE |
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