Bulky DNA-adduct formation induced by Ni(II) in vitro and in vivo as assayed by 32P-postlabeling |
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| Affiliation: | 1. Division of Toxicology, Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA;2. Shell Research Ltd., Sittingbourne Research Centre, Sittingbourne, Kent ME9 8AG, UK;1. Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran;2. Center for Childhood Cancer Research, Children’s Hospital of Philadelphia (CHOP), Philadelphia, PA 19104, USA;3. Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran;4. Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran;1. Key Laboratory of Cenozoic Geology and Environment, Institute of Geology and Geophysics, Chinese Academy of Sciences, Beijing, 100029, China;2. Innovation Academy for Earth Science, Chinese Academy of Sciences, Beijing, 100029, China;3. Center for Excellence in Life and Paleoenvironment, Chinese Academy of Sciences, Beijing, 100044, China;4. Yunnan Key Laboratory of Plateau Geographical Processes and Environmental Change, School of Tourism and Geographical Sciences, Yunnan Normal University, Kunming, 650500, China;5. College of Earth and Planetary Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China;6. Center for Excellence in Tibetan Plateau Earth Science, Chinese Academy of Sciences, Beijing, 100101, China;7. Centre for Ecological and Evolutionary Synthesis (CEES), Department of Biosciences, University of Oslo, Blindern, N-0316, Oslo, Norway;1. Physics of Ice, Climate and Earth (PICE), Niels Bohr Institute, University of Copenhagen, Tagensvej 16, Copenhagen N, 2200, Denmark;2. Oceans Graduate School, The University of Western Australia, M470, Perth, WA, 6009, Australia;3. Department of Environmental Sciences, Informatics and Statistics, University Ca’ Foscari of Venice, via Torino 155, 30172, Venice, Italy;4. Institute of Polar Sciences, National Research Council of Italy, via Torino 155, 30172, Venice, Italy;5. Department of Atmospheric Chemistry and Climate, Institute of Physical Chemistry Rocasolano, CSIC. Serrano 119, 28006, Madrid, Spain;6. Institute of Atmospheric Sciences and Climate, National Research Council of Italy, SPLecce - Monteroni Km 1.2 -73100, Lecce, Italy |
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| Abstract: | Various small oxidation products (e.g. 8-hydroxydeoxyguanosine) can be induced in DNA by nickel compounds. In this study, the 32P-postlabeling assay was applied to determine whether Ni(II) compounds are able to induce bulky DNA-adduct formation in vitro and in vivo. In vitro studies detected two major and several minor adducts in DNA incubated with NiCl2 and H2O2 at 37°C for 1 h. Formation of the two major adducts increased with incubation time (0–24 h) and NiCl2 concentration (0–800 μM). Adduct levels were greatly reduced by hydroxyl free-radical scavengers, i.e. 0.4 M sodium formate or 0.05 M p-nitrosodimethylaniline, and by a singlet oxygen scavenger, 0.05 M sodium azide. The in vitro effects of NiCl2 on DNA were significantly enhanced by (1) addition of 3 mM ascorbic acid, (2) replacement of H2O with D2O in the reaction, and (3) prior denaturation of DNA. Adduct formation presumably involved a Fenton-type reaction, in which DNA crosslinks may arise by reaction with hydroxyl free radicals and singlet oxygen.For in vivo studies, male 6–8 wk old B6C3F1 mice were used. In untreated mice, several I-compounds (putative indigenous DNA modifications that increase with age) were detected in liver, kidney, and lung. Two of these spots (1 and 2) were chromatographically identical to the two major spots induced by Ni(II) in vitro. The intensities of spots 1 and 2 in kidney and of some other spots in liver and lung were increased 1 and 2 h after i.p. injection with a single dose of 170 μmoles/kg NiAc2. The effects of NiAc2 were reduced or undetectable in the three tissues 24 h after treatment. These observations indicate the capacity of Ni(II) to induce and modulate bulky DNA modifications both in vitro and in vivo. |
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