Haloacetate-induced oxidative damage to DNA in the liver of male B6C3F1 mice.
Brominated and chlorinated haloacetates (HAs) are by-products of drinking water disinfection. Dichloroacetate (DCA) and trichloroacetate (TCA) are hepatocarcinogenic in rodents, but the brominated analogs have received little study. Prior work has indicated that acute doses of the brominated derivatives are more potent inducers of oxidative stress and increase the 8-hydroxydeoxyguanosine (8-OH-dG) content of the nuclear DNA in the liver. Since, DCA and TCA are also known as weak peroxisome proliferators, the present study was intended to determine whether this activity might be exacerbated by peroxisomal proliferation. Classical responses to peroxisome proliferators, cyanide-insensitive acyl-CoA oxidase activity and increased 12-hydroxylation of lauric acid, were elevated in a dose-related manner in mice maintained on TCA and clofibric acid (positive control), but not with DCA, dibromoacetate (DBA) or bromochloroacetate (BCA). Administration of the HAs in drinking water to male B6C3F1 mice for periods from 3 to 10 weeks resulted in dose-related increases in 8-OH-dG in nuclear DNA of the liver with DBA and BCA, but not with TCA or DCA. These findings indicate that oxidative damage induced by the haloacetates is, at least in part, independent of peroxisome proliferation. In addition, these data suggest that oxidative damage to DNA may play a more important role in the chronic toxicology of brominated compared to the chlorinated haloacetates.
Parrish
J M
JM
Pharmacology/Toxicology Graduate Program, Washington State University, Pullman, USA.
Austin
E W
EW
Stevens
D K
DK
Kinder
D H
DH
Bull
R J
RJ
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000085:Acetates / Q000008:administration & dosage / Q000633:toxicity*; D042962:Acyl-CoA Oxidase; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D002995:Clofibric Acid / Q000378:metabolism / Q000633:toxicity; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D003999:Dichloroacetic Acid / Q000008:administration & dosage / Q000633:toxicity; D004326:Drinking; D005618:Fresh Water; D006900:Hydroxylation; D007850:Lauric Acids / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008830:Microbodies / Q000187:drug effects / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000378:metabolism; D012015:Reference Standards; D014874:Water Pollutants, Chemical / Q000633:toxicity
D000085:Acetates; D007850:Lauric Acids; D014874:Water Pollutants, Chemical; C030358:lauric acid; D002995:Clofibric Acid; C016274:bromoacetate; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003577:Cytochrome P-450 Enzyme System; D003999:Dichloroacetic Acid; C099813:bromochloroacetic acid; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D042926:Cytochrome P-450 CYP4A; D042962:Acyl-CoA Oxidase; D003849:Deoxyguanosine