McDorman Kevin S, Pachkowski Brian F, Nakamura Jun, Wolf Douglas C, Swenberg James A
Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC 27599, USA.
Chem Biol Interact. 2005 Apr 15;152(2-3):107-17. doi: 10.1016/j.cbi.2005.02.003.
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.
经化学消毒剂处理的公共饮用水含有复杂的消毒副产物（DBPs）混合物，需要对该混合物的相对毒性进行表征，以便准确评估风险。溴酸钾（KBrO₃）是高溴化物地表水臭氧氧化生产饮用水过程中产生的副产物，是一种啮齿动物致癌物，可引发甲状腺、间皮和肾脏肿瘤。KBrO₃肾脏致癌的推测机制涉及8-氧代鸟嘌呤（8-oxoG）的形成，8-oxoG是DNA中一种通常通过碱基切除修复（BER）去除的促诱变碱基损伤。在本研究中，雄性Long-Evans大鼠通过饮用水接触致癌浓度的KBrO₃（0.4 g/L）、3-氯-4-（二氯甲基）-5-羟基-2（5H）-呋喃酮（0.07 g/L）、氯仿（1.8 g/L）、溴二氯甲烷（0.7 g/L），或所有这些化学物质以相同浓度混合的混合物，持续3周。一侧肾脏的一半用于显微镜检查，另一半肾脏冷冻用于分离基因组DNA。使用高效液相色谱-电化学检测法，在与甲酰胺嘧啶-DNA糖基化酶孵育的DNA样品中测量8-oxoG的水平。使用醛反应探针斑点杂交测定法定量DNA样品中的醛类损伤（如无碱基位点）。KBrO₃处理使肾脏中8-oxoG的含量有可测量的增加，且这种效应大于DBP混合物处理所产生的效应。其他单一化学处理均未导致8-oxoG含量有可测量的增加。本研究中观察到的混合物对8-oxoG含量的影响表明，化学物质之间存在相互作用，减少了氧化性DNA损伤的产生。处理后未观察到无碱基位点增加，但在DBP混合物处理的大鼠中明显减少。这些数据与之前的研究一致，即在饮用水中慢性接触这种化学混合物会导致Tsc2突变的Long-Evans大鼠产生小于相加的致癌反应。
