Nickel(II)-mediated oxidative DNA base damage in renal and hepatic chromatin of pregnant rats and their fetuses. Possible relevance to carcinogenesis

Abstract

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-dihydroxycystosine, 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Ni(II) Specifically Cleaves the C-Terminal Tail of the Major Variant of Histone H2A and Forms an Oxidative Damage-Mediating Complex with the Cleaved-Off Octapeptide

“…These results also provide evidence that the squareplanar complex of Ni(II) with the cutoff end of the tail can catalyze oxidative damage to DNA and proteins via Fenton-like mechanisms, and thus produce genotoxic effects. This, in turn, mechanistically supports our previous reports of Ni(II)-induced oxidative DNA damage in vivo under conditions leading to carcinogenesis (2,3,(49)(50)(51)(52)(53)(54). In conclusion, the observed interactions of Ni(II) with the C-terminal tail of histone H2A may provide a dual mechanism of Ni(II)-induced carcinogenesis, embracing both genotoxic (initiation) and epigenetic (promotion and progression of tumors) pathways.…”

Ni(II) Specifically Cleaves the C-Terminal Tail of the Major Variant of Histone H2A and Forms an Oxidative Damage-Mediating Complex with the Cleaved-Off Octapeptide

“…These results also provide evidence that the squareplanar complex of Ni(II) with the cutoff end of the tail can catalyze oxidative damage to DNA and proteins via Fenton-like mechanisms, and thus produce genotoxic effects. This, in turn, mechanistically supports our previous reports of Ni(II)-induced oxidative DNA damage in vivo under conditions leading to carcinogenesis (2,3,(49)(50)(51)(52)(53)(54). In conclusion, the observed interactions of Ni(II) with the C-terminal tail of histone H2A may provide a dual mechanism of Ni(II)-induced carcinogenesis, embracing both genotoxic (initiation) and epigenetic (promotion and progression of tumors) pathways.…”

Enhancement by L-histidine of nickel(II)-induced DNA-protein cross-linking and oxidative DNA base damage in the rat kidney

“…This agrees with the relatively slow kinetics of Ni(II)mediated oxidative attack on chromatin previously observed in vitro (6). Surprisingly enough, unlike in our preceding in vitro studies (5,7), NiAcet alone tested in the present study did not produce any significant oxidative renal DNA base damage. The difference was most likely due to a much lower dose of Ni(II) used in this study (20 µ /kg body wt vs 90-95 µ /kg body wt employed before) to match the dose of NiHis.…”

“…Conclusion. The results of this work confirm and widen our previous observations indicating that modification of nuclear DNA in kidneys of animals exposed to Ni(II) is consistent with oxygen-derived radical activity (4,5,7). Also, the present in vivo study confirms our former in vitro findings about His enhancement of Ni(II)-mediated oxidative damage to DNA bases and extends this enhancement on the formation of DNA-protein cross-links.…”

Oxidative DNA Base Damage in Renal, Hepatic, and Pulmonary Chromatin of Rats after Intraperitoneal Injection of Cobalt(II) Acetate

“…The DNA base products identified and measured in the present study are, like those reported in our previous publications (6,10,11), characteristic for oxidative DNA damage (reviewed in refs 29 and 30). To our knowledge, the ability of Co(II) acetate to mediate such damage in vivo is shown here for the first time.…”

Ni(II) Specifically Cleaves the C-Terminal Tail of the Major Variant of Histone H2A and Forms an Oxidative Damage-Mediating Complex with the Cleaved-Off Octapeptide

“…These results also provide evidence that the squareplanar complex of Ni(II) with the cutoff end of the tail can catalyze oxidative damage to DNA and proteins via Fenton-like mechanisms, and thus produce genotoxic effects. This, in turn, mechanistically supports our previous reports of Ni(II)-induced oxidative DNA damage in vivo under conditions leading to carcinogenesis (2,3,(49)(50)(51)(52)(53)(54). In conclusion, the observed interactions of Ni(II) with the C-terminal tail of histone H2A may provide a dual mechanism of Ni(II)-induced carcinogenesis, embracing both genotoxic (initiation) and epigenetic (promotion and progression of tumors) pathways.…”

Enhancement by L-histidine of nickel(II)-induced DNA-protein cross-linking and oxidative DNA base damage in the rat kidney

“…This agrees with the relatively slow kinetics of Ni(II)mediated oxidative attack on chromatin previously observed in vitro (6). Surprisingly enough, unlike in our preceding in vitro studies (5,7), NiAcet alone tested in the present study did not produce any significant oxidative renal DNA base damage. The difference was most likely due to a much lower dose of Ni(II) used in this study (20 µ /kg body wt vs 90-95 µ /kg body wt employed before) to match the dose of NiHis.…”

“…Conclusion. The results of this work confirm and widen our previous observations indicating that modification of nuclear DNA in kidneys of animals exposed to Ni(II) is consistent with oxygen-derived radical activity (4,5,7). Also, the present in vivo study confirms our former in vitro findings about His enhancement of Ni(II)-mediated oxidative damage to DNA bases and extends this enhancement on the formation of DNA-protein cross-links.…”

Oxidative DNA Base Damage in Renal, Hepatic, and Pulmonary Chromatin of Rats after Intraperitoneal Injection of Cobalt(II) Acetate

“…The DNA base products identified and measured in the present study are, like those reported in our previous publications (6,10,11), characteristic for oxidative DNA damage (reviewed in refs 29 and 30). To our knowledge, the ability of Co(II) acetate to mediate such damage in vivo is shown here for the first time.…”

Ni(II) Specifically Cleaves the C-Terminal Tail of the Major Variant of Histone H2A and Forms an Oxidative Damage-Mediating Complex with the Cleaved-Off Octapeptide

“…These results also provide evidence that the squareplanar complex of Ni(II) with the cutoff end of the tail can catalyze oxidative damage to DNA and proteins via Fenton-like mechanisms, and thus produce genotoxic effects. This, in turn, mechanistically supports our previous reports of Ni(II)-induced oxidative DNA damage in vivo under conditions leading to carcinogenesis (2,3,(49)(50)(51)(52)(53)(54). In conclusion, the observed interactions of Ni(II) with the C-terminal tail of histone H2A may provide a dual mechanism of Ni(II)-induced carcinogenesis, embracing both genotoxic (initiation) and epigenetic (promotion and progression of tumors) pathways.…”

Enhancement by L-histidine of nickel(II)-induced DNA-protein cross-linking and oxidative DNA base damage in the rat kidney

“…This agrees with the relatively slow kinetics of Ni(II)mediated oxidative attack on chromatin previously observed in vitro (6). Surprisingly enough, unlike in our preceding in vitro studies (5,7), NiAcet alone tested in the present study did not produce any significant oxidative renal DNA base damage. The difference was most likely due to a much lower dose of Ni(II) used in this study (20 µ /kg body wt vs 90-95 µ /kg body wt employed before) to match the dose of NiHis.…”

“…Conclusion. The results of this work confirm and widen our previous observations indicating that modification of nuclear DNA in kidneys of animals exposed to Ni(II) is consistent with oxygen-derived radical activity (4,5,7). Also, the present in vivo study confirms our former in vitro findings about His enhancement of Ni(II)-mediated oxidative damage to DNA bases and extends this enhancement on the formation of DNA-protein cross-links.…”

Oxidative DNA Base Damage in Renal, Hepatic, and Pulmonary Chromatin of Rats after Intraperitoneal Injection of Cobalt(II) Acetate

“…The DNA base products identified and measured in the present study are, like those reported in our previous publications (6,10,11), characteristic for oxidative DNA damage (reviewed in refs 29 and 30). To our knowledge, the ability of Co(II) acetate to mediate such damage in vivo is shown here for the first time.…”