Molecular biomarkers of oxidative stress associated with bromate carcinogenicity

• Published in: Toxicology (Amsterdam) 2006-04, Vol.221 (2), p.158-165
• Main Authors: Delker, Don, Hatch, Gary, Allen, James, Crissman, Bobby, George, Michael, Geter, David, Kilburn, Steve, Moore, Tanya, Nelson, Gail, Roop, Barbara, Slade, Ralph, Swank, Adam, Ward, William, DeAngelo, Anthony
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers, Tumor - genetics; Bromates - toxicity; Carcinogens - toxicity; Dose-Response Relationship, Drug; Epithelium - drug effects; Epithelium - metabolism; Epithelium - pathology; Gene expression; Gene Expression - drug effects; Gene Expression Profiling; Glutathione metabolism; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Male; Molecular biomarkers; Neoplasms - chemically induced; Neoplasms - metabolism; Neoplasms - pathology; Oligonucleotide Array Sequence Analysis; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - genetics; Oxygen-18; Potassium bromate; Rats; Rats, Inbred F344; Risk assessment; RNA, Messenger - genetics; Threshold; Thyroid Gland - drug effects; Thyroid Gland - metabolism; Thyroid Gland - pathology; Tissue oxidation
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2005.12.011

Potassium bromate (KBrO 3) is a chemical oxidizing agent found in drinking water as a disinfection byproduct of surface water ozonation. Chronic exposures to KBrO 3 cause renal cell tumors in rats, hamsters and mice and thyroid and testicular mesothelial tumors in rats. Experimental evidence indicates that bromate mediates toxicological effects via the induction of oxidative stress. To investigate the contribution of oxidative stress in KBrO 3-induced cancer, male F344 rats were administered KBrO 3 in their drinking water at multiple concentrations for 2–100 weeks. Gene expression analyses were performed on kidney, thyroid and mesothelial cell RNA. Families of mRNA transcripts differentially expressed with respect to bromate treatment included multiple cancer, cell death, ion transport and oxidative stress genes. Multiple glutathione metabolism genes were up-regulated in kidney following carcinogenic (400 mg/L) but not non-carcinogenic (20 mg/L) bromate exposures. 8-Oxodeoxyguanosine glycosylase ( Ogg1) mRNA was up-regulated in response to bromate treatment in kidney but not thyroid. A dramatic decrease in global gene expression changes was observed following 1 mg/L compared to 20 mg/L bromate exposures. In a separate study oxygen-18 ( 18O) labeled KBrO 3 was administered to male rats by oral gavage and tissues were analyzed for 18O deposition. Tissue enrichment of 18O was observed at 5 and 24 h post-KBr 18O 3 exposure with the highest enrichment occurring in the liver followed by the kidney, thyroid and testes. The kidney dose response observed was biphasic showing similar statistical increases in 18O deposition between 0.25 and 50 mg/L (equivalent dose) KBr 18O 3 followed by a much greater increase above 50 mg/L. These results suggest that carcinogenic doses of potassium bromate require attainment of a threshold at which oxidation of tissues occurs and that gene expression profiles may be predictive of these physiological changes in renal homeostasis.