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Toxicol Sci 2013 Nov;136(1):26-38

Temporal Changes in K-ras Mutant Fraction in Lung Tissue of Big Blue B6C3F1 Mice Exposed to Ethylene Oxide.

Parsons BL, Manjanatha MG, Myers MB, McKim KL, Shelton S, Wang Y, Gollapudi BB, Moore NP, Haber LT, Moore MM


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 B6C3F1 mice (10 /group) were exposed to EO by inhalation, six hours/day, five days/week for four (0, 10, 50, 100, or 200 ppm EO), eight or twelve weeks (0, 100, or 200 ppm EO). Lung DNA samples were analyzed for levels of three K-ras codon 12 mutations (GGT-->GAT, GGT-->GTT, and GGT-->TGT) using ACB-PCR. No measureable level of K-ras codon 12 TGT mutation was detected (i.e., all lung MFs GTT mutant fraction (MF) relative to controls, whereas 50, 100, and 200 ppm EO caused significant increases in K-ras codon 12 GGT-->GAT MF. In addition, significant inverse correlations were observed between K-ras codon 12 GGT-->GTT MF and cII mutant frequency in the lungs of the same mice exposed to 100 or 200 ppm EO for four weeks. Surprisingly, eight 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 non-monotonic, and were consistent with EO causing early amplification of pre-existing 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.

Category: Journal Article
PubMed ID: #24029818 DOI: 10.1093/toxsci/kft190
Includes FDA Authors from Scientific Area(s): Toxicological Research
Entry Created: 2013-09-14 Entry Last Modified: 2014-01-03