Dose and temporal evaluation of ethylene oxide-induced mutagenicity in the lungs of male big blue mice following inhalation exposure to carcinogenic concentrations
| Autor: | Meagan B. Myers, Ying Chen, Sharon D. Shelton, Nigel P. Moore, Karen L. McKim, Bruce C. Allen, Martha M. Moore, Lynne T. Haber, B. Bhaskar Gollapudi, Barbara L. Parsons, Mugimane G. Manjanatha |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Inhalation exposure Inhalation Epidemiology Chemistry Health Toxicology and Mutagenesis Mutant Mutagen Pharmacology medicine.disease_cause In vitro Toxicology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine In vivo 030220 oncology & carcinogenesis medicine Bioassay Genetics (clinical) Carcinogen |
| Zdroj: | Environmental and Molecular Mutagenesis. 58:122-134 |
| ISSN: | 0893-6692 |
| DOI: | 10.1002/em.22080 |
| Popis: | Ethylene oxide (EO) is a direct acting alkylating agent; in vitro and in vivo studies indicate that it is both a mutagen and a carcinogen. However, it remains unclear whether the mode of action (MOA) for cancer for EO is a mutagenic MOA, specifically via point mutation. To investigate the MOA for EO-induced mouse lung tumors, male Big Blue (BB) B6C3F1 mice (10/group) were exposed to EO by inhalation, 6 hr/day, 5 days/week for 4 (0, 10, 50, 100, or 200 ppm EO), 8, or 12 weeks (0, 100, or 200 ppm EO). Lung DNA samples were analyzed for cII mutant frequency (MF) at 4, 8 and 12 weeks of exposure; the mutation spectrum was analyzed for mutants from control and 200 ppm EO treatments. Although EO-induced cII MFs were 1.5- to 2.7-fold higher than the concurrent controls at 4 weeks, statistically significant increases in the cII MF were found only after 8 and 12 weeks of exposure and only at 200 ppm EO (P ≤ 0.05), which is twice the highest concentration used in the cancer bioassay. Consistent with the positive response, DNA sequencing of cII mutants showed a significant shift in the mutational spectra between control and 200 ppm EO following 8 and 12 week exposures (P ≤ 0.035), but not at 4 weeks. Thus, EO mutagenic activity in vivo was relatively weak and required higher than tumorigenic concentrations and longer than 4 weeks exposure durations. These data do not follow the classical patterns for a MOA mediated by point mutations. Environ. Mol. Mutagen. 58:122-134, 2017. © 2017 Wiley Periodicals, Inc. |
| Databáze: | OpenAIRE |
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