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.
Environmental Carcinogenesis Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
C H
CH
Anna
R R
RR
Maronpot
M A
MA
Pereira
J F
JF
Foley
D E
DE
Malarkey
M W
MW
Anderson
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