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OXIDATIVE DNA DAMAGE AND REPAIR IN RATS TREATED WITH POTASSIUM BROMATE AND A MIXTUE OF DRINKING WATER DISINFECTION BY-PRODUCTS
Citation:
McDorman, K. S., B. Pachkowski, G W. Knapp, J. Nakamura, D C. Wolf, AND J. A. Swenberg. OXIDATIVE DNA DAMAGE AND REPAIR IN RATS TREATED WITH POTASSIUM BROMATE AND A MIXTUE OF DRINKING WATER DISINFECTION BY-PRODUCTS. Presented at Society of Toxicologic Pathologists annual meeting, Denver, CO, 06/3-6/2002.
Description:
Oxidative DNA Damage and Repair in Rats Treated with Potassium Bromate and a Mixture of Drinking Water Disinfection By-Products
Public drinking water treated with chemical disint'ectants contains a complex mixture of disinfection by-products (D BPs). There is a need for mechanistic data to aid in the evaluation of simple and complex mixtures of D BPs to characterize the relative toxicity of the mixtures, evaluate interactions between mixture components, and accurately assess risk. Potassium bromate (KBrO3) is a by-product from ozonation of high-bromide surface water for production of drinking water. KBrO3 is a rodent carcinogen that produces thyroid, mesothelial, and renal tumors. The proposed mechanism of KBrO3 renal carcinogenesis involves the formation of 8-oxoguanine (8oxoG), 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 KBrO3 (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 for 3 weeks. Half of one kidney was processed for microscopic examination, and the remaining kidney tissue was frozen for isolation of genomic DNA and total RNA. Levels of 8oxoG were measured using HPLC with electrochemical detection in DNA samples incubated with formamidopyrimidine (fapy)-DNA glycosylase. Aldehydic lesions (e.g., abasic sites) in DNA samples were quantitated using an aldehyde-reactive probe slot-blot assay. Expression levels of key enzymes in the base excision repair pathway were measured using quantitative real-time reverse transcription-PCR (QRT RT -PCR). Treatment with KBrO3 produced measurable increases of 8oxoG 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 SoxoG. No increases in abasic sites were observed with treatment, but a significant decrease was apparent in the rats treated with the DBP mixture, suggesting enhanced BER. However, the expression levels of BER genes analyzed by QRT RT -PCR were not significantly higher than control. Even though the promutagenic DNA lesion 8oxoG was demonstrated to accumulate in tissue, an associated induction of repair enzyme expression was not observed. These data suggest that repair of SoxoG may occur through alternate pathways or that a higher level of DNA damage is required before enhanced gene expression is detectable.
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