Oxidative DNA damage in cultured cells and rat lungs by carcinogenic nickel compounds.
DNA damage in cultured cells and in lungs of rats induced by nickel compounds was investigated to clarify the mechanism of nickel carcinogenesis. DNA strand breaks in cultured cells exposed to nickel compounds were measured by using a pulsed field gel electrophoresis technique. Among nickel compounds (Ni(3)S(2), NiO (black), NiO (green), and NiSO(4)), only Ni(3)S(2), which is highly carcinogenic, induced lesions of both double- and single-stranded DNA in cultured human cells (Raji and HeLa cells). Treatment of cultured HeLa cells with Ni(3)S(2) (10 microg/ml) induced a 1.5-fold increase in 8-hydroxy-2'-deoxyguanosine (8-OH-dG) compared with control, whereas NiO (black), NiO (green), and NiSO(4) did not enhance the generation of 8-OH-dG. Intratracheal instillation of Ni(3)S(2), NiO(black), and NiO(green) to Wistar rats increased 8-OH-dG in the lungs significantly. NiSO(4) induced a smaller but significant increase in 8-OH-dG. Histological studies showed that all the nickel compounds used induced inflammation in lungs of the rats. Nitric oxide (NO) generation in phagocytic cells induced by Ni(3)S(2), NiO(black), and NiO(green) was examined using macrophage cell line RAW 264.7 cells. NO generation in RAW 264.7 cells stimulated with lipopolysaccharide was enhanced by all nickel particles. Two mechanisms for nickel-induced oxidative DNA damage have been proposed as follows: all the nickel compounds used induced indirect damage through inflammation, and Ni(3)S(2) also showed direct oxidative DNA damage through H(2)O(2) formation. This double action may explain relatively high carcinogenic risk of Ni(3)S(2).
Kawanishi
S
S
Department of Hygiene, Mie University School of Medicine, Mie, Japan. kawanisi@doc.medic.mie-u.ac.jp
Inoue
S
S
Oikawa
S
S
Yamashita
N
N
Toyokuni
S
S
Kawanishi
M
M
Nishino
K
K
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002417:Cattle; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D016521:Electrophoresis, Gel, Pulsed-Field; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009532:Nickel / Q000633:toxicity*; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar
D002273:Carcinogens; D009532:Nickel; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine