3Rs friendly study designs facilitate rat liver and blood micronucleus assays andPig‐agene mutation assessments: Proof‐of‐concept with 13 reference chemicals
| العنوان: | 3Rs friendly study designs facilitate rat liver and blood micronucleus assays andPig‐agene mutation assessments: Proof‐of‐concept with 13 reference chemicals |
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| المؤلفون: | Priyanka Singh, Amanda Drake, Stephen D. Dertinger, Svetlana L. Avlasevich, Jeffrey C. Bemis, Dorothea K. Torous, Sumee Khanal, Christopher Kirby, James T. MacGregor |
| المصدر: | Environ Mol Mutagen |
| بيانات النشر: | Wiley, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Male, Epidemiology, Health, Toxicology and Mutagenesis, Mutagen, 010501 environmental sciences, Pharmacology, Gene mutation, medicine.disease_cause, 01 natural sciences, Article, Flow cytometry, 03 medical and health sciences, In vivo, medicine, Animals, Micronuclei, Chromosome-Defective, Genetics (clinical), 030304 developmental biology, 0105 earth and related environmental sciences, Cisplatin, 0303 health sciences, Micronucleus Tests, medicine.diagnostic_test, business.industry, Membrane Proteins, Rats, Vinblastine, Liver, Research Design, Female, Micronucleus, business, Genotoxicity, DNA Damage, Mutagens, medicine.drug |
| الوصف: | Regulatory guidance documents stress the value of assessing the most appropriate endpoints in multiple tissues when evaluating the in vivo genotoxic potential of chemicals. However, conducting several independent studies to evaluate multiple endpoints and/or tissue compartments is resource intensive. Furthermore, when dependent on visual detection, conventional approaches for scoring genotoxicity endpoints can be slow, tedious, and less objective than the ideal. To address these issues with current practices we attempted to (1) devise resource sparing treatment and harvest schedules that are compatible with liver and blood micronucleus endpoints, as well as the Pig-a gene mutation assay, and (2) utilize flow cytometry-based methods to score each of these genotoxicity biomarkers. Proof-of-principle experiments were performed with 4-week-old male and female Crl:CD(SD) rats exposed to aristolochic acids I/II, benzo[a]pyrene, cisplatin, cyclophosphamide, diethylnitrosamine, 1,2-dimethylhydrazine, dimethylnitrosamine, 2,6-dinitrotoluene, hydroxyurea, melphalan, temozolomide, quinoline, or vinblastine. These 13 chemicals were each tested in two treatment regimens: one 3-day exposure cycle, and three 3-day exposure cycles. Each exposure, blood collection, and liver harvest was accomplished during a standard Monday-Friday workweek. Key findings are that even these well-studied, relatively potent genotoxicants were not active in both tissues and all assays (indeed only cisplatin was clearly positive in all three assays); and whereas the sensitivity of the Pig-a assay clearly benefitted from three versus one treatment cycle, micronucleus assays yielded qualitatively similar results across both study designs. Collectively, these results suggest it is possible to significantly reduce animal and other resource requirements while improving assessments of in vivo genotoxicity potential by simultaneously evaluating three endpoints and two important tissue compartments using fit-for-purpose study designs in conjunction with flow cytometric scoring approaches. Environ. Mol. Mutagen., 60:704-739, 2019. © 2019 Wiley Periodicals, Inc. |
| تدمد: | 1098-2280 0893-6692 |
| DOI: | 10.1002/em.22312 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3c10cfab09b1a5e3ba897d24f3ba219e https://doi.org/10.1002/em.22312 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....3c10cfab09b1a5e3ba897d24f3ba219e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10982280 08936692 |
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| DOI: | 10.1002/em.22312 |