title: Molecular biomarkers of oxidative stress associated with bromate carcinogenicity.
abstract: Potassium bromate (KBrO3) is a chemical oxidizing agent found in drinking water as a disinfection byproduct of surface water ozonation. Chronic exposures to KBrO3 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 KBrO3-induced cancer, male F344 rats were administered KBrO3 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 1mg/L compared to 20 mg/L bromate exposures. In a separate study oxygen-18 (18O) labeled KBrO3 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-KBr18O3 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) KBr18O3 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.
authors.affiliation: Environmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA. delker.don@epa.gov
authors.forename: Don
authors.initials: D
authors.lastname: Delker
authors.forename: Gary
authors.initials: G
authors.lastname: Hatch
authors.forename: James
authors.initials: J
authors.lastname: Allen
authors.forename: Bobby
authors.initials: B
authors.lastname: Crissman
authors.forename: Michael
authors.initials: M
authors.lastname: George
authors.forename: David
authors.initials: D
authors.lastname: Geter
authors.forename: Steve
authors.initials: S
authors.lastname: Kilburn
authors.forename: Tanya
authors.initials: T
authors.lastname: Moore
authors.forename: Gail
authors.initials: G
authors.lastname: Nelson
authors.forename: Barbara
authors.initials: B
authors.lastname: Roop
authors.forename: Ralph
authors.initials: R
authors.lastname: Slade
authors.forename: Adam
authors.initials: A
authors.lastname: Swank
authors.forename: William
authors.initials: W
authors.lastname: Ward
authors.forename: Anthony
authors.initials: A
authors.lastname: DeAngelo
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D001959:Bromates / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009369:Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D001959:Bromates; D002273:Carcinogens; D012333:RNA, Messenger; C019536:potassium bromate