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Predominant K-ras Codon 12 G A Transition in Chemically Induced Lung Neoplasms in B6C3F1 Mice

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Hue-Hua L. Hong

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Colleen H. Anna

Environmental Toxicology Program and Environmental Carcinogenesis Program, Research Triangle Park, North Carolina 27709, USA

June K. Dunnick

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Theodora R. Devereux

Environmental Toxicology Program and Environmental Carcinogenesis Program, Research Triangle Park, North Carolina 27709, USA

Robert C. Sills

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Yongbaek Kim

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA, kim16{at}niehs.nih.gov

Based on long-term toxicity and carcinogencity studies in B6C3F1 mice conducted by the National Toxicology Program, 2,2-Bis(bromomethyl)-1,3-propanediol (BMP) and tetranitromethane (TNM) have been identified as carcinogens. Following 2 yr of exposure to 312, 625, or 1,250 ppm BMP in feed, or exposure to 0.5 or 2 ppm TNM by inhalation, increased incidences of lung neoplasms were observed in B6C3F1 mice at all exposure concentrations compared to unexposed mice. The present study characterizes genetic alterations in the K-ras protooncogene in BMP- and TNM-induced lung neoplasms, respectively, and compares the findings to spontaneous lung neoplasms from corresponding control mice. The frequencies of the K-ras mutations were 57% (29/51) in BMP-induced lung neoplasms compared to 15% (3/20) in lung neoplasms from dosed feed control mice, and 54% (14/26) in TNM-induced lung neoplasms compared to 60% (3/5) in lung neoplasms from inhalation control mice. G A transitions at the second base of the K-ras codon 12 (GGT GAT) were the most frequent pattern of K-ras mutations identified in BMP-induced (20/29) and TNM-induced lung neoplasms (13/14), which differed from the mutational patterns identified in the lung neoplasms from unexposed control mice. These results indicate that mutations in the K-ras gene are involved in B6C3F1 lung carcinogenesis following BMP- and TNM-exposure, and the high frequency and specificity of the ras mutation profile in lung neoplasms (G A transition) may be due to in vivo genotoxicity by the parent compounds or their metabolites.

Key Words: 2,2-Bis(bromomethyl)-1,3-propanediol • tetranitromethane • alveolar bronchiolar adenoma • alveolar bronchiolar carcinoma • K-ras mutations • K-ras codon 12 G A transition • B6C3F1 mouse.

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