Mechanisms of Chemically Induced Renal Carcinogenesis in the Laboratory Rodent

Abstract

ABSTRAC~ in theLaboratory 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 femc 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 dircct chemical toxicity to the tubule cells, as with chloroform, or to indirect cytotoxicity associated with lysosomal overload, as in a,,-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 chemicalmediated 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.

Prediction of rodent nongenotoxic carcinogenesis: evaluation of biochemical and tissue changes in rodents following exposure to nine nongenotoxic NTP carcinogens.

“…During the early stages of this simulation, we evaluated a range of acute/subacute markers of presumed nongenotoxic rodent carcinogenesis. The markers used in this study have been reported by others for the rodent liver (27,28,30,31,41), kidney (9,26,33,39,40), and thyroid gland (9,37,38). The results of the study for individual markers are shown schematically in Figure 1.…”

Invited Review: A Contemporary Overview of Chronic Progressive Nephropathy in the Laboratory Rat, and Its Significance for Human Risk Assessment

“…Because of the substantial cell turnover that typifies CPN tubules (Figure 3), it is not surprising that an association with the occasional development of atypical tubule hyperplasia, a precursor of renal tubule tumor (Hard et al, 1995), has been recorded (Blatherwick and Medlar, 1937;Foley et al, 1964;Peter et al, 1986;Hard et al, 1995). Consequently, there is an increasing awareness that CPN can be a risk factor for the spontaneous development of renal tubule tumors in rats (Figure 4), particularly in the male (Lipsky and Trump, 1988;Hard, 1998). Furthermore, evidence is emerging that certain chemicals can interact with CPN to increase the incidence of CPN-related proliferative lesions (Hard et al, 1997;Lynch et al, 1998;Hard, 2002).…”

The Effect of Chronic Progressive Nephropathy on the Incidence of Renal Tubule Cell Neoplasms in Control Male F344 Rats

“…The question of a relationship between CPN and proliferative lesions of the renal tubules including RTCN has been discussed with no de nitive answer (12)(13)(14). The suggestion of a relationship is supported by data that have measured either the level of DNA synthesis or cell proliferation rates in animals with CPN (15,16) or from studies where chemicals which enhance the severity of CPN result in a greater number of RTCN (14,17,18).…”

“…These chemicals are often associated with enhancing CPN severity. Some studies suggest that increased cell proliferation within foci of CPN secondary to chemical toxicity may increase the risk for RTCN development (13,20). Clearly chemical toxicity and increased cell proliferation may not be the only factors that contribute to a renal tumor response (22,23).…”