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ToxSci Advance Access published online on July 13, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi257
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received March 11, 2005
Accepted July 7, 2005

Carcinogenicity

DNA Hypomethylation Induced by Drinking Water Disinfection By-Products in Mouse and Rat Kidney

Lianhui Tao 1*, Wei Wang 1, Long Li 2, Paula K. Kramer 2, and Michael A. Pereira 1

1 Department of Internal Medicine, Division of Hematology and Oncology, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43210, USA
2 Department of Pathology, Medical College of Ohio, 3055 Arlington Avenue, Toledo, OH 43614, USA

* To whom correspondence should be addressed.
Lianhui Tao, E-mail: tao-2{at}medctr.osu.edu


  Abstract

Bromodichloromethane (BDCM), chloroform, dibromoacetic acid (DBA), dichloroacetic acid (DCA) and trichloroacetic acid (TCA) are chlorine disinfection by-products (DBPs) found in drinking water, that have indicated renal carcinogenic and/or tumor promoting activity. We have reported that the DBPs caused DNA hypomethylation in mouse liver, which correlated with their carcinogenic and tumor promoting activity. In this study, we determined their ability to cause renal DNA hypomethylation. B6C3F1 mice were administered DCA or TCA concurrently with/without chloroform in their drinking water for seven days. In male, but not female mouse kidney, DCA, TCA and to a lesser extent chloroform decreased the methylation of DNA and the c-myc gene. Co-administering chloroform increased only DCA but not TCA-induced DNA hypomethylation. DBA and BDCM caused renal DNA hypomethylation in both male B6C3F1 mice and Fischer 344 rats. We have reported that in mouse liver, methionine prevented DCA and TCA-induced hypomethylation of the c-myc gene. To determine whether it would also prevent hypomethylation in the kidneys, male mice were administered methionine in their diet concurrently with DCA or TCA in their drinking water. Methionine prevented both DCA and TCA-induced hypomethylation of the c-myc gene. The ability of the DBPs to cause hypomethylation of DNA and of the c-myc gene correlated with their carcinogenic and tumor promoting activity in mouse and rat kidney, that should be taken into consideration as part of their risk assessment. That methionine prevents DCA and TCA-induced hypomethylation of the c-myc gene would suggest it could prevent their carcinogenic activity in the kidney.


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