Oxidative DNA damage and cell proliferation in kidneys of male and female rats during 13-weeks exposure to potassium bromate (KBrO3).
It has been assumed that oxidative damage, including formation of 8-hydroxydeoxyguanosine (8-OHdG) adducts in kidney DNA due to potassium bromate (KBrO3), a renal carcinogen to both sexes of rats, is involved in its mechanisms of tumor induction. However, despite the presumed existence of a repair enzyme(s) for 8-OHdG, there have been no reports demonstrating the changes in adduct levels during medium- or long-term exposure. To elucidate the actual kinetics regarding this parameter during the early stages of KBrO3 carcinogenesis, we measured 8-OHdG levels in kidney DNA together with cell proliferation in renal tubules in both sexes of rats receiving KBrO3 at a dose of 500 ppm in the drinking water for 1, 2, 3, 4, and 13 weeks. Rapid elevation of 8-OHdG levels was noted in treated male rats which persisted until the end of the experiment. Increased cell proliferation in the proximal convoluted tubules was also observed throughout the experimental period, concomitant with alpha2mu-globulin accumulation. Increase in 8-OHdG levels in treated females first became apparent 3 weeks after the start of exposure, with cell proliferation only elevated at the 13-week time point. The present study, employing the same route and dose of KBrO3 known to cause tumors, strongly suggested the requirement of persistent increase of 8-OHdG for neoplastic conversion. Moreover, a clear sex difference in susceptibility to generation of oxidative stress in kidney DNA was found, in addition to alpha2mu-globulin-dependent variation in cell proliferation in the renal tubules.
Umemura
T
T
Division of Toxicology, Biological Safety Research Center, National Institute of Health Sciences, Tokyo, Japan.
Takagi
A
A
Sai
K
K
Hasegawa
R
R
Kurokawa
Y
Y
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D015415:Biomarkers; D001959:Bromates / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D005260:Female; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344
D015415:Biomarkers; D001959:Bromates; D002273:Carcinogens; C019536:potassium bromate; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine