Relative susceptibilities of C57BL/6, (C57BL/6 x C3H/He)F1, and C3H/He mice to acute toxicity and carcinogenicity of nickel subsulfide.
The aim of this study was to compare susceptibility of mice of different strains to the toxicity and carcinogenicity of nickel subsulfide (Ni3S2), a water insoluble compound suspected to damage cells through oxidative mechanisms. Groups of 30 male mice of each strain, C57BL/6 (C57BL), (C57BL x C3H/He)F1 (B6C3F1), and C3H/He (C3H), were injected with single doses of 0.5-10 mg of Ni3S2/site into the thigh muscle and observed for up to 78 weeks. The highest Ni3S2 dose was lethal within 1 week to C57BL (93%) > B6C3F1 (80%) > C3H (53%) mice. The most susceptible C57BL mice also had the most severe necrotic/inflammatory kidney damage, compared with that in the other mice. The final incidence of local sarcomas at the 5 mg Ni3S2 dose was: C3H (97%) > B6C3F1 (76%) > C57BL (40% of mice at risk, i.e. those surviving at least 25 week; P < 0.05 or better as compared to the incidence in C3H mice). The relatively highest acute toxicity of Ni3S2 in C57BL mice observed in the present study, concurred with the weakest antioxidant response to systemic water-soluble nickel(II), resulting in reduction in glutathione (GSH) level and increased lipid peroxidation (LPO) in their kidneys and livers, two main targets of acute nickel toxicity, reported by us previously (Toxicol. Lett. 1991, 57, 269; ibid. 1991, 58, 121). Ni3S2 deposited in the muscle, therefore, constitutes a source of soluble nickel that can reach and damage distant organs. THe strongest tumor response in C3H mice relative to other strains did, in turn, concur with the lowest base levels of GSH and highest LPO in their muscle, the target for Ni3S2 carcinogenesis. Thus, the acute toxicity and carcinogenicity of Ni3S2 and Ni3S2-derived soluble nickel(II) in mice seem to depend, at least in part, on antioxidant capacity of target organs, which varies among different strains.
Rodriguez
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Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center, Maryland 21702, USA. kasprkaz@fcrfv2.ncifcrf.gov
Misra
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Diwan
B A
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Riggs
C W
CW
Kasprzak
K S
KS
D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000032:analysis; D007273:Injections, Intramuscular; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019042:Muscle Neoplasms / Q000139:chemically induced; D009369:Neoplasms / Q000139:chemically induced; D009532:Nickel / Q000008:administration & dosage / Q000633:toxicity*; D012509:Sarcoma / Q000139:chemically induced; D013045:Species Specificity; D015996:Survival Rate
D002273:Carcinogens; D009532:Nickel; D005978:Glutathione; C017557:nickel subsulfide