Predominant K-ras codon 12 G --> A transition in chemically induced lung neoplasms in B6C3F1 mice.
Based on long-term toxicity and carcinogenicity 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.
Ton
Thai-Vu T
TV
National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Hong
Hue-Hua L
HH
Anna
Colleen H
CH
Dunnick
June K
JK
Devereux
Theodora R
TR
Sills
Robert C
RC
Kim
Yongbaek
Y
D000818:Animals; D003062:Codon / Q000235:genetics; D004247:DNA / Q000032:analysis; D004252:DNA Mutational Analysis; D004032:Diet; D004305:Dose-Response Relationship, Drug; D005260:Female; D005411:Flame Retardants / Q000633:toxicity; D011905:Genes, ras / Q000235:genetics*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D020125:Mutation, Missense; D016877:Oxidants / Q000633:toxicity; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011409:Propylene Glycols / Q000633:toxicity; D013774:Tetranitromethane / Q000633:toxicity
D003062:Codon; D005411:Flame Retardants; D016877:Oxidants; D011409:Propylene Glycols; C060080:2,2-bis(bromomethyl)-1,3-propanediol; D004247:DNA; D013774:Tetranitromethane