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Metallic nickel particles induce cell apoptosis through a caspase-8/AIF-mediated cytochrome c-independent pathway.

Zhao-J; Bowman-L; Zhang-X; Shi-X; Castranova-V; Ding-M
Toxicologist 2009 Mar; 108(1):61
Numerous studies have described the pathogenic and carcinogenic effects of nickel compounds, but little has been published on the biologic effects of metallic nickel. The present study investigates metallic nickel particle-induced apoptosis and the signal pathways involved in this process in JB6 cells. Using MTT the assay, we found that metallic nickel nanoparticles (80 nm) exhibited higher cytotoxicity than fine particles (3 mu M). Both metallic nickel nano- and fine particles induced JB6 cell apoptosis in a dose-dependent manner. Western-blot analysis showed an upregulation of proapoptotic factors, including Fas, FADD, caspase-8, DR3 and BID, following exposure to metallic nickel particles. Metallic nickel particles showed only a very slight activation of caspase-3, -6 and -9. IP western blot analysis demonstrated the formation of the Fas-related death-inducing signaling complex (DISC) during the apoptotic process. Furthermore, during this process, lamin A, beta-actin and PARP were cleaved. Moreover, we found that apoptosis-inducing factor (AIF) was upregulated and released from mitochondria into cytoplasm in nickel- treated cells. However, no cytochrome c release from mitochondria into the cytoplasm was found in nickel-treated cells. In addition, activation of anti-apoptotic factors, including phospho-Akt and Bcl-2, was detected. In conclusion, we report for the first time that metallic nickel nanoparticles caused higher cytotoxicity and apoptotic induction than fine particles in JB6 cells. Apoptotic cell death induced by metallic nickel particles in JB6 cells is through a caspase-8/AIF-mediated cytochrome c-independent pathway. Activation of Bcl-2 and Akt may play an importment role in preventing cytochrome c release from mitochondria into the cytoplasm and may also be important in the carcinogenicity of metallic nickel particles. The data obtained from this study will be of benefit for elucidating the pathogenic and carcinogenic potential of metallic nickel particles.
Airborne-dusts; Airborne-particles; Biological-effects; Biological-function; Biological-systems; Biological-transport; Cell-biology; Cell-damage; Cell-function; Cell-metabolism; Cellular-reactions; Dose-response; Dosimetry; Exposure-assessment; Exposure-levels; Exposure-methods; Metal-poisoning; Metallic-dusts; Molecular-biology; Particle-aerodynamics; Particulate-dust; Particulates; Pulmonary-clearance; Statistical-analysis; Toxic-effects; Nanotechnology; Author Keywords: metals; in vitro study; cytotoxicity; pathogenicity; carcinogenicity
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The Toxicologist. Society of Toxicology 48th Annual Meeting and ToxExpo, March 15-19, 2009, Baltimore, Maryland