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-hy droxydeoxyguanosine (8-OHdG) adducts in kidney DNA due to potassium br omate (KBrO3), a renal carcinogen to both sexes of rats, is involved i n its mechanisms of tumor induction. However, despite the presumed exi stence of a repair enzyme(s) for 8-OHdG, there have been no reports de monstrating the changes in adduct levels during medium-or long-term ex posure. To elucidate the actual kinetics regarding this parameter duri ng the early stages of KBrO3 carcinogenesis, we measured 8-OHdG levels in kidney DNA together with cell proliferation in renal tubules in bo th 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 n as noted in treated male rats which persisted until the end of the exp eriment. Increased cell proliferation in the proximal convoluted tubul es was also observed throughout the experimental period, concomitant w ith alpha(2 mu)-globulin accumulation. Increase in 8-OHdG levels in tr eated females first became apparent 3 weeks after the start of exposur e, with cell proliferation only elevated at the 13-week time point. Th e present study, employing the same route and dose of KBrO3 known to c ause 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 alpha(2 mu)-globulin-dependent variation in cel l proliferation in the renal tubules.