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Metallothionein-I/II Double Knockout Mice Are No More Sensitive to the Carcinogenic Effects of Nickel Subsulfide than Wild-Type Mice

Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA

Kazimierz S. Kasprzak

Metals Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, Maryland, USA

Bhalchandra A. Diwan

Basic Research Program, SAIC-Frederick, National Cancer Institute at Frederick, Frederick, Maryland, USA

Correspondence: Address correspondence to Michael Waalkes, NCI at NIEHS, 111 Alexander Drive, P.O. Box 12233, MD F0-09, Research Triangle Park, NC 27709, USA. E-mail:waalkes{at}niehs.nih.gov

Metallothionein (MT) is a high-affinity metal-binding protein thought to mitigate the toxicity of various metals. MT may limit the toxicity of a metal by direct binding or through action as an antioxidant for metals that generate reactive oxygen species. Nickel compounds have carcinogenic potential in humans and animals, possibly by production of oxidative stress. The impact of MT deficiency on the carcinogenic effects of nickel is unknown. Thus, groups (n = 25) of male MT-I/II double knockout (MT-null) or MT wild-type (WT) mice were exposed to a single treatment of nickel (0.5 or 1.0 mg Ni₃S₂/site, intramuscularly, [i.m.], into both hind legs), or left untreated (control) and observed over the next 104 weeks. There were no differences in the incidence of spontaneous tumors in MT-null and WT mice. Nickel induced injection site fibrosarcomas in a dose-related fashion to a similar extent in both WT and MT-null mice. Nickel-treatment had no effect on total lung tumor incidence, although some phenotypic-specific differences occurred in the proportion of benign and malignant pulmonary tumors. Overall, MT-null mice appear no more sensitive to the carcinogenic effects of nickel than WT mice. Thus, poor MT production does not appear to be a predisposing factor for nickel carcinogenesis.

Key Words: Carcinogenesis • Metallothionein Deficient • Mice • Nickel • Sarcoma

International Journal of Toxicology, Vol. 24, No. 4, 215-220 (2005)
DOI: 10.1080/10915810591000668


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