Analysis of renal cell transformation following exposure to trichloroethene in vivo and its metabolite S-(dichlorovinyl)-L-cysteine in vitro.
Trichloroethene (TCE) is classified as a potential human carcinogen although there is a significant debate regarding the mechanism of TCE induced renal tumor formation. This controversy stems in part from the extremely high doses of TCE required to induce renal tumors and the potential contribution of the associated nephrotoxicity to tumorigenesis. We have used Eker rats, which are uniquely susceptible to renal carcinogens, to determine if exposures to TCE in vivo or exposure to its metabolite S-(dichlorovinyl)-L-cysteine (DCVC) in vitro can transform kidney epithelial cells in the absence of cytotoxicity. Treatment with TCE (0, 100, 250, 500, 1000 mg/kg bw by gavage, 5 days a week) for 13 weeks resulted in a significant increase in cell proliferation in kidney tubule cells, but did not enhance formation of preneoplastic lesions or tumor incidence in Eker rat kidneys as compared to controls. In vitro, concentrations of DCVC, which reduced cell survival to 50%, were able to transform rat kidney epithelial cells. However, no carcinogen-specific mutations were identified in the VHL or Tsc-2 tumor suppressor genes in the transformants. Taken together, the inability of TCE to enhance formation of preneoplastic changes or neoplasia and the absence of carcinogen-specific alteration of genes accepted to be critical for renal tumor development suggest that TCE mediated carcinogenicity may occur secondary to continuous toxic injury and sustained regenerative cell proliferation.
Mally
Angela
A
Department of Toxicology, University of Würzburg, Versbacher Str. 9, 97078 Würzburg, Germany. Mally@toxi.uni-wuerzburg.de
Walker
Cheryl L
CL
Everitt
Jeffrey I
JI
Dekant
Wolfgang
W
Vamvakas
Spiros
S
D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens; D002292:Carcinoma, Renal Cell / Q000139:chemically induced* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D003545:Cysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D015972:Gene Expression Regulation, Neoplastic; D007668:Kidney / Q000166:cytology*; D007672:Kidney Cortex / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology; D007680:Kidney Neoplasms / Q000139:chemically induced* / Q000235:genetics; D019656:Loss of Heterozygosity; D008297:Male; D011230:Precancerous Conditions / Q000139:chemically induced / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012997:Solvents / Q000633:toxicity*; D014241:Trichloroethylene / Q000633:toxicity*
D002273:Carcinogens; D012997:Solvents; D014241:Trichloroethylene; C039961:S-(1,2-dichlorovinyl)cysteine; D004247:DNA; D003545:Cysteine