期刊
TOXICOLOGICAL SCIENCES
卷 136, 期 1, 页码 26-38出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kft190
关键词
mode of action; risk assessment; reactive oxygen species; oxidative stress; cII mutation frequency; dose response
类别
资金
- Ethylene Oxide and Derivatives Producers' Association
- Lower Olefins Sector Group of Cefic
- European Chemical Industry Association
- Cooperative Research and Development Agreement between Toxicology Excellence for Risk Assessment and National Center for Toxicological Research
Ethylene oxide (EO) is a genotoxicant and a mouse lung carcinogen, but whether EO is carcinogenic through a mutagenic mode of action remains unclear. To investigate this question, 8-week-old male Big Blue B6C3F(1) mice (10 mice/group) were exposed to EO by inhalationu6h/day, 5 days/week for 4 weeks (0, 10, 50, 100, or 200 ppm EO) and 8 or 12 weeks (0, 100, or 200 ppm EO). Lung DNA samples were analyzed for levels of 3 K-ras codon 12 mutations (GGTGAT, GGTGTT, and GGTTGT) using ACB-PCR. No measureable level of K-ras codon 12 TGT mutation was detected (ie, all lung mutant fractions [MFs] 10(5)). Four weeks of inhalation of 100 ppm EO caused a significant increase in K-ras codon 12 GGTGTT MF relative to controls, whereas 50, 100, and 200 ppm EO caused significant increases in K-ras codon 12 GGTGAT MF. In addition, significant inverse correlations were observed between K-ras codon 12 GGTGTT MF and cII mutant frequency in the lungs of the same mice exposed to 50, 100, or 200 ppm EO for 4 weeks. Surprisingly, 8 weeks of exposure to 100 and 200 ppm EO caused significant decreases in K-ras MFs relative to controls. Thus, the changes in K-ras MF as a function of cumulative EO dose were nonmonotonic and were consistent with EO causing early amplification of preexisting K-ras mutations, rather than induction of K-ras mutation through genotoxicity at codon 12. The possibility that these changes reflect K-ras mutant cell selection under varying degrees of oxidative stress is discussed.
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