ToxSci Advance Access published online on September 1, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh266
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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1 Department of Pathology, Medical College of Ohio, 3055 Arlington Avenue, Toledo, OH 43614-5806, USA
* To whom correspondence should be addressed. E-mail: tao-2{at}medctr.osu.edu.
Dibromoacetic acid (DBA) is a drinking water disinfection by-product. Its analogues, dichloroacetic acid (DCA) and trichloroacetic acid (TCA) are liver carcinogens in rodents. We evaluated the ability of DBA to cause DNA hypomethylation, glycogen accumulation, and peroxisome proliferation that are activities previously reported for the two other haloacetic acids. Female B6C3F1 mice and male Fischer 344 rats were administered 0, 1000 and 2000 mg/L DBA in drinking water. The animals were euthanized after 2, 4, 7 and 28 days of exposure. DBA caused a dose and time dependent decrease of 20 - 46% in the 5-methylcytosine content of DNA. Hypomethylation of the c-myc gene was observed in mice after 7-days of DBA-exposure. Methylation of 24 CpG sites in the insulin-like growth factor 2 (IGF-II) gene was reduced from 80.2±9.2% to 18.8±12.9% by 2,000 mg/L DBA for 28-days. mRNA expression of the c-myc and IGF-II genes in mouse liver was increased by DBA. A dose-dependent increase in the mRNA expression of the c-myc gene was also observed in rats. In both mice and rats, DBA caused dose-dependent accumulation of glycogen and an increase of peroxisomal lauroyl-CoA oxidase activity. Hence, DBA, similar to DCA and TCA, induced hypomethylation of DNA and of the c-myc and IGF-II genes, increased mRNA expression of both genes, and caused peroxisome proliferation. Similar to DCA, DBA also induced glycogen accumulation. These results indicate that DBA shares biochemical and molecular activities in common with DCA and/or TCA suggesting that it might also be a liver carcinogen.
Accepted August 4, 2004
Carcinogenicity
Effect of Dibromoacetic Acid on DNA Methylation, Glycogen Accumulation, and Peroxisome Proliferation in Mouse and Rat Liver
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