title: Oxidative DNA damage from potassium bromate exposure in Long-Evans rats is not enhanced by a mixture of drinking water disinfection by-products.
abstract: Public drinking water treated with chemical disinfectants contains a complex mixture of disinfection by-products (DBPs) for which the relative toxicity of the mixtures needs to be characterized to accurately assess risk. Potassium bromate (KBrO(3)) is a by-product from ozonation of high-bromide surface water for production of drinking water and is a rodent carcinogen that produces thyroid, mesothelial, and renal tumors. The proposed mechanism of KBrO(3) renal carcinogenesis involves the formation of 8-oxoguanine (8-oxoG), a promutagenic base lesion in DNA typically removed through base excision repair (BER). In this study, male Long-Evans rats were exposed via drinking water to carcinogenic concentrations of KBrO(3) (0.4 g/L), 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (0.07 g/L), chloroform (1.8 g/L), bromodichloromethane (0.7 g/L), or a mixture of all these chemicals at the same concentrations for 3 weeks. Half of one kidney was processed for microscopic examination, and the remaining kidney was frozen for isolation of genomic DNA. Levels of 8-oxoG were measured using HPLC with electrochemical detection in DNA samples incubated with formamidopyrimidine-DNA glycosylase. Aldehydic lesions (e.g. abasic sites) in DNA samples were quantitated using an aldehyde-reactive probe slot-blot assay. Treatment with KBrO(3) produced a measurable increase of 8-oxoG in the kidney, and this effect was greater than that produced by treatment with the DBP mixture. No other single chemical treatment caused measurable increases of 8-oxoG. The mixture effect on the amount of 8-oxoG observed in this study suggests an interaction between chemicals that reduced the generation of oxidative DNA damage. No increases in abasic sites were observed with treatment, but a decrease was apparent in the rats treated with the DBP mixture. These data are consistent with previous studies where chronic exposure to this chemical mixture in drinking water resulted in a less than additive carcinogenic response in Tsc2 mutant Long-Evans rats.
authors.affiliation: Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: McDorman
authors.forename: Brian F
authors.initials: BF
authors.lastname: Pachkowski
authors.forename: Jun
authors.initials: J
authors.lastname: Nakamura
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wolf
authors.forename: James A
authors.initials: JA
authors.lastname: Swenberg
mesh_terms: D000818:Animals; D001959:Bromates / Q000378:metabolism / Q000633:toxicity*; D002725:Chloroform / Q000378:metabolism / Q000633:toxicity; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage; D004202:Disinfectants / Q000737:chemistry / Q000633:toxicity*; D005663:Furans / Q000378:metabolism / Q000633:toxicity; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006651:Histocytochemistry; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D008297:Male; D018384:Oxidative Stress; D051381:Rats; D020318:Rats, Long-Evans; D011922:Rats, Mutant Strains; D022882:Trihalomethanes / Q000378:metabolism / Q000633:toxicity; D018508:Water Purification / Q000379:methods*; D014881:Water Supply
chemical_list: D001959:Bromates; D004202:Disinfectants; D005663:Furans; D022882:Trihalomethanes; C019536:potassium bromate; C024829:8-hydroxyguanine; D006147:Guanine; C054121:3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone; C025191:bromodichloromethane; D002725:Chloroform; D004247:DNA