Ras oncogene activation during hepatocarcinogenesis in B6C3F1 male mice by dichloroacetic and trichloroacetic acids.
Dichloroacetic (DCA) and trichloroacetic (TCA) acids, two major by-products formed during chlorine disinfection of drinking water, increase the incidence of tumors in B6C3F1 mice by 6- and 3-fold respectively. In order to understand better the mechanism by which these two compounds induce liver tumors, the incidence and spectrum of mutations in the K- and H-ras proto-oncogenes in these tumors were analyzed. DNA from spontaneous, DCA- and TCA-induced liver tumor from B6C3F1 male mice was evaluated for point mutations in exons 1, 2 and 3 of the two genes by single-stranded conformation polymorphism. Results demonstrated a similar incidence of mutations for exon 2 of H-ras in spontaneous carcinomas (58%), and in carcinomas induced by DCA 3.5 g/l (50%), 1.0 g/l (48%) and TCA 4.5 g/l (45%). Only four showed mutations in the other exons of Hras or in K-ras. Sequence analysis of spontaneous tumor samples with second exon H-ras mutations revealed a change in codon 61 from CAA to AAA in 80% and CAA to CGA in 20% of tumors. In contrast, tumors with H-ras mutations from DCA-treated mice revealed a H-61 change from CAA to AAA in 21% at 3.5 g/l and 16% at 1.0 g/l. CAA to CGA was observed in 50% of tumors from mice given DCA 3.5 or 1.0 g/l, and CAA to CTA was present in 29% and 34% of the two dosage groups respectively. Interestingly, TCA showed the same mutational spectrum as the spontaneous liver tumors. The data indicates that induction of liver carcinoma by DCA and TCA involves activation of the H-ras proto-oncogene at a frequency similar to that observed in spontaneous tumors. However, the mechanism(s) for including hepatocellular carcinoma does not appear to be identical for DCA and TCA.
Ferreira-Gonzalez
A
A
Department of Pathology, George Washington University, Washington, DC 20037.
DeAngelo
A B
AB
Nasim
S
S
Garrett
C T
CT
D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity*; D017931:DNA Primers; D003999:Dichloroacetic Acid / Q000633:toxicity*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D011905:Genes, ras; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D017354:Point Mutation; D014238:Trichloroacetic Acid / Q000633:toxicity*
D002273:Carcinogens; D017931:DNA Primers; D014238:Trichloroacetic Acid; D003999:Dichloroacetic Acid