Lack of oxidative DNA damage or initiation of carcinogenesis in the kidneys of male F344 rats given subchronic exposure to p-dichlorobenzene (pDCB) at a carcinogenic dose.
p-Dichlorobenzene (pDCB) is a male rat kidney carcinogen believed to act through alpha2u-globulin nephropathy. Recent data on metabolism, however, suggest a potential for generating oxidative stress. To examine possible mechanisms of kidney carcinogenesis, pDCB was studied for ability to produce 8-oxodeoxyguanosine (8-oxodG) in kidney nuclear DNA and for initiating activity in a two-stage renal carcinogenesis model. F344 male rats were given pDCB by intragastric instillation, 5 days/week for 13 weeks at 300 mg/kg per day, which is a carcinogenic dose with chronic administration. To assess initiation after exposure, trisodium nitrilotriacetic acid (NTA), a kidney tumor promoter was given in the drinking water at 1,000 ppm for 39 weeks. At the end of the exposure segment, pDCB did not produce an increase of 8-oxodG levels in the kidney nuclear DNA in contrast to potassium bromate (KBrO3). Following NTA promotion, no neoplastic lesions occurred in rats given pDCB, although diethylnitrosamine carcinogenesis was enhanced. Thus, pDCB did not produce oxidative DNA damage in the rat kidney or effect initiation of kidney carcinogenesis. These data suggest that oxidative stress is not involved in pDCB-induced renal carcinogenesis. The alpha2u-globulin-mediated chronic nephropathy probably acts as a promoter, not an initiation of renal carcinogenesis. Accordingly, pDCB is assessed to have no cancer hazard to humans who are not susceptible to the alpha2u-globulin nephropathy.
Umemura
T
T
Division of Toxicology, Biological Safety Research Center, National Institute of Health Sciences, Tokyo, Japan. umemura@nihs.go.jp
Kodama
Y
Y
Kurokawa
Y
Y
Williams
G M
GM
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000230:Adenocarcinoma / Q000139:chemically induced / Q000473:pathology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002722:Chlorobenzenes / Q000633:toxicity*; D003537:Cystadenoma / Q000139:chemically induced / Q000473:pathology; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D006965:Hyperplasia / Q000139:chemically induced / Q000473:pathology; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D002722:Chlorobenzenes; D004273:DNA, Neoplasm; D000080242:8-Hydroxy-2'-Deoxyguanosine; C018511:4-dichlorobenzene; D003849:Deoxyguanosine