HALOACETATE-INDUCED OXIDATIVE DAMAGE TO DNA IN THE LIVER OF MALE B6C3F1 MICE

Brominated and chlorinated haloacetates (HAs) are by-products of drink ing water disinfection. Dichloroacetate (DCA) and trichloroacetate (TC A) are hepatocarcinogenic in rodents, but the brominated analogs have received little study. Prior work has indicated that acute doses of th e brominated derivatives are more potent inducers of oxidative stress and increase the 8-hydroxydeoxyguanosine (8-OH-dG) content of the nucl ear DNA in the liver. Since, DCA and TCA are also known as weak peroxi some proliferators, the present study was intended to determine whethe r this activity might be exacerbated by peroxisomal proliferation. Cla ssical responses to peroxisome proliferators, cyanide-insensitive acyl -CoA oxidase activity and increased 12-hydroxylation of lauric acid, w ere elevated in a dose-related manner in mice maintained on TCA and cl ofibric acid (positive control), but not with DCA, dibromoacetate (DBA ) or bromochloroacetate (BCA). Administration of the HAs in drinking w ater to male B6C3F1 mice for periods from 3 to 10 weeks resulted in do se-related increases in 8-OH-dG in nuclear DNA of the liver with DBA a nd BCA, but not with TCA or DCA. These findings indicate that oxidativ e damage induced by the haloacetates is, at least in part, independent of peroxisome proliferation. In addition, these data suggest that oxi dative damage to DNA may play a more important role in the chronic tox icology of brominated compared to the chlorinated haloacetates.