Mechanisms of chemically induced renal carcinogenesis in the laboratory rodent
Mechanisms of chemically induced renal carcinogenesis in the laboratory rodent
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DOI：
10.1177/019262339802600112
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发表时间：
1998-01-01
影响因子：
1.5
通讯作者：
Hard, GC
中科院分区：
文献类型：
--
作者：
Hard, GC
在大鼠和小鼠中进行的经典肾脏致癌物的实验室研究，以及在国家毒理学计划致癌性生物测定中证明对肾脏呈阳性的一些化学品的研究调查，已经证明存在一系列不同的啮齿动物肾脏致癌机制。作为研究肾肿瘤发病机制的实验模型的经典致癌物，如亚硝胺，具有遗传毒性，并直接与DNA相互作用，形成具有致突变潜力的DNA加合物。与此相反，溴酸钾和次氮基三乙酸铁（Fe-NTA），也是有效的肾脏致癌物，似乎会引起间接损伤的DNA介导的氧化应激。许多非遗传毒性化学品与啮齿类动物的表观遗传性肾肿瘤诱导有关，这些化学品的活性往往涉及在整个暴露期间长期刺激细胞增殖。这种作用模式反映了持续的再生反应，要么是由于对小管细胞的直接化学毒性（如氯仿），要么是由于与溶酶体过载相关的间接细胞毒性（如给予d-柠檬烯和四氯乙烯等化学品导致的雄性大鼠中α（2u）-球蛋白蓄积）。对苯二酚肾癌发生的组织病理学性质表明，大鼠肾小管肿瘤形成的另一个表观遗传途径可能是通过化学介导的年龄相关性自发性肾脏疾病慢性进行性肾病的恶化及其相互作用。这些不同的机制途径对诱导的癌症过程的性质有影响，涉及肿瘤发生率、潜伏期、恶性程度和性别倾向。
Laboratory studies with classical renal carcinogens in the rat and mouse, as well as research investigation with some of the chemicals proving positive for the kidney in National Toxicology Program carcinogenicity bioassays, have demonstrated the existence of a range of diverse mechanisms underlying rodent kidney carcinogenesis. The classical carcinogens used as experimental models for studying renal tumor pathogenesis, such as the nitrosamines, are genotoxic and interact directly with DNA, forming DNA adducts with mutagenic potential. In contrast, potassium bromate and ferric nitrilotriacetate (Fe-NTA), also effective renal carcinogens, appear to cause indirect damage to DNA mediated by oxidative stress. A number of nongenotoxic chemicals are associated with epigenetic renal tumor induction in rodents, and the activity of these tends to involve prolonged stimulation of cell proliferation throughout the duration of exposure. This mode of action reflects a sustained regenerative response, either due to direct chemical toxicity to the tubule cells, as with chloroform, or to indirect cytotoxicity associated with lysosomal overload, as in alpha(2u)-globulin accumulation in male rats resulting from the administration of such chemicals as d-limonene and tetrachloroethylene. The histopathologic nature of hydroquinone renal carcinogenesis suggests that an additional epigenetic pathway to renal tubule tumor formation in rats may be through chemical-mediated exacerbation of, and interaction with, the age-related spontaneous renal disease, chronic progressive nephropathy. These various mechanistic pathways have implications for the nature of the induced cancer process with respect to tumor incidence, latency, malignancy, and sex predisposition.