NICKEL(II)-MEDIATED OXIDATIVE DNA-BASE DAMAGE IN RENAL AND HEPATIC CHROMATIN OF PREGNANT RATS AND THEIR FETUSES - POSSIBLE RELEVANCE TO CARCINOGENESIS

DNA base damage was studied in renal and hepatic chromatin of nickel(II)-injected pregnant female F344/NCr rats and their fetuses under conditions leading to initiation of sodium barbital-promotable renal tumors, but not liver tumors, in the male offspring. Pregnant rats were given a total of 90 or 180 mumol of nickel(II) acetate/kg body wt in a single ip dose on day 17 or in 2 or 4 ip doses between days 12 and 18 of gestation. Control rats received 180 mumol of sodium acetate/kg body wt. The animals were killed 24 or 48 h after the last injection. Chromatin was isolated from livers and kidneys from both adults and fetuses and analyzed by gas chromatography/mass spectrometry with selected ion monitoring. Eleven products derived from the purine and pyrimidine bases in DNA bases were identified and quantified. These were the following: 5-hydroxy-5-methylhydantoin,5-hydroxyhydantoin,5-(hydroxymethyl)uracil,cytosine glycol, thymine glycol, 5,6-dihydroxycytosine, 4,6-diamino-5-formamidopyrimidine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine,8-hydroxyadenine, 2-hydroxyadenine, and 8-hydroxyguanine (8-OH-Gua). Nickel(II) exposure increased the content of these products, especially those derived from purines, in both renal and hepatic chromatin of pregnant rats. The major difference between these two organs was the content of 8-OH-Gua, which increased greatly in the kidney but remained unchanged in the liver. In the corresponding fetal organs, the relative increases in 8-OH-Gua were comparable to the findings in adults. Fetal kidney DNA was relatively higher in pyrimidine-derived products (especially thymine glycol and 5-hydroxyhydantoin) and lower in purine-derived products (except for 8-OH-Gua) than fetal hepatic DNA. No consistent dose effect of nickel(II) on the amounts of the DNA base products recovered from either organ was observed in either the dams or their fetuses. The products determined were typical hydroxyl radical-produced derivatives of DNA bases, suggesting a role for hydroxyl radical in the induction of their formation by nickel(II). Some of these base products have been shown previously to be promutagenic. Therefore, the present results indicate possible involvement of oxidative DNA base damage in the mechanism of nickel(II) carcinogenesis in the rat kidney. The prevalence of 8-OH-Gua in the kidney but not in the liver is consistent with the hypothesis that 8-OH-Gua is a tumor-initiating lesion in that organ. However, the complexity of the observed response to nickel(II) does not exclude possible roles for other DNA base products elevated by nickel(II) treatment, especially thymine glycol and 5-hydroxyhydantoin, in nickel(II)-induced carcinogenesis in the kidney.