DISSIMILAR CHARACTERISTICS OF N-METHYL-N-NITROSOUREA-INITIATED FOCI AND TUMORS PROMOTED BY DICHLOROACETIC ACID OR TRICHLOROACETIC-ACID IN THE LIVER OF FEMALE B6C3F1 MICE
Jr. Latendresse et Ma. Pereira, DISSIMILAR CHARACTERISTICS OF N-METHYL-N-NITROSOUREA-INITIATED FOCI AND TUMORS PROMOTED BY DICHLOROACETIC ACID OR TRICHLOROACETIC-ACID IN THE LIVER OF FEMALE B6C3F1 MICE, Toxicologic pathology, 25(5), 1997, pp. 433-440
Dichloroacetic acid (DCA) and trichloroacetic acid (TCA) are metabolit
es of the industrial solvent and environmental contaminant trichloroet
hylene (TCE), as well as contaminants of chlorinated drinking water. H
uman exposure to these chemicals is of concern as all three have been
shown to increase liver tumor incidence in mice. Differences in dose-r
esponse curves, progression to cancer, and postexposure regression of
lesions suggest that TCA and DCA work through different mechanisms. Th
e purpose of this study was to further characterize the proliferative
hepatocellular lesions promoted by TCP, and DCA using biomarkers of ce
ll growth, differentiation, and metabolism in liver sections to better
delineate the distinctions in the mechanism of the two chloroacetates
. Fifteen-day-old female mice were initiated with 25 mg/kg N-methyl-N-
nitrosourea. The initiated mice were administered DCA or TCA (20.0 mmo
l/L) in drinking water from age 49 days until euthanasia at age 413 da
ys. The pathologic assessment showed that the foci of altered hepatocy
tes and tumors occurring in the animals promoted with DCA were eosinop
hilic and positive immunohistochemically for TGF-alpha, c-jun, c-myc,
CYP 2E1, CYP 4A1, and glutathione S-transferase-pi (GST-pi). The DCA l
esions also were essentially negative for c-fos and TGF-beta, but nont
umor hepatocytes were consistently TGF-beta-positive. In contrast, tum
ors promoted by TCA were predominantly basophilic, lacked GST-pi, and
stained variably; usually, more than 50% of the turner hepatocytes wer
e essentially negative for the other biomarkers. This study demonstrat
es some striking differences in certain molecular biomarkers of cell g
rowth, differentiation, and metabolism between DCA and TCA. The result
s also suggest some potential growth signal transduction pathways that
may contribute to the DCA promotion of tumors, further support the pr
emise that these two chloroacetates promote hepatocarcinogenes is in d
ifferent ways, and provide a rational basis for a similar comparison w
ith TCE. Such a comparison should give some insight as to whether DCA,
TCA, or both are playing a significant role in the murine liver carci
nogenesis of the parent compound, TCE.