ras proto-oncogene activation in dichloroacetic acid-, trichloroethylene- and tetrachloroethylene-induced liver tumors in B6C3F1 mice.
The frequency and mutation spectra of proto-oncogene activation in hepatocellular neoplasms induced by tetrachloroethylene, trichloroethylene and dichloroacetic acid were examined to help define the molecular basis for their carcinogenicity. H-ras codon 61 activation was not significantly different among dichloroacetic acid- and trichloroethylene-induced and combined historical and concurrent control hepatocellular tumors (62%, 51% and 69% respectively). The mutation spectra of H-ras codon 61 mutations showed a significant decrease in AAA and increase in CTA mutations for dichloroacetic acid- and trichloroethylene-induced tumors when compared to combined controls. The H-ras codon 61 mutation frequency for tetrachloroethylene-induced tumors was significantly lower (24%) than that of combined controls and also that of the two other chemicals. Mutations at codons 13 and 117 plus a second exon insert contributed 4% to the total H-ras frequencies for trichloroethylene and tetrachloroethylene. There was also a higher incidence of K-ras activation (13%) in tetrachloroethylene-induced tumors than in the other chemically induced or control tumors. Four liver tumors were found to contain insertions of additional bases within the second exon of K- or H-ras. These findings suggest that exposure to dichloroacetic acid, trichloroethylene and tetrachloroethylene provides a selective growth advantage to spontaneously occurring mutations in codon 61 of H-ras and, at the same time, is responsible for a small number of unique molecular lesions suggestive of either a random genotoxic mode of action or a non-specific result of secondary DNA damage. However, the absence of ras activation in many of the liver neoplasms suggests that alternative mechanisms are also important in B6C3F1 mouse hepatocarcinogenesis.
Anna
C H
CH
Environmental Carcinogenesis Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Maronpot
R R
RR
Pereira
M A
MA
Foley
J F
JF
Malarkey
D E
DE
Anderson
M W
MW
D000818:Animals; D001483:Base Sequence; D015197:Carcinogenicity Tests; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003062:Codon; D003999:Dichloroacetic Acid / Q000633:toxicity*; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D011905:Genes, ras / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D013750:Tetrachloroethylene / Q000633:toxicity*; D014241:Trichloroethylene / Q000633:toxicity*
D003062:Codon; D014241:Trichloroethylene; D003999:Dichloroacetic Acid; D013750:Tetrachloroethylene