Size-dependent effects of tungsten carbide - cobalt particles on oxygen radical production and activation of cell signaling pathways in murine epidermal cells.
Ding-M; Kisin-ER; Zhao-J; Bowman-L; Lu-Y; Jiang-B; Leonard-S; Vallyathan-V; Castranova-V; Murray-AR; Fadeel-B; Shvedova-AA
Toxicol Appl Pharmacol 2009 Dec; 241(3):260-268
Hard metal or cemented carbide consists of a mixture of tungsten carbide (WC) (85%) and metallic cobalt (Co) (5-15%). WC--Co is considered to be potentially carcinogenic to humans. However, no comparison of the adverse effects of nano-sized WC--Co particles is available to date. In the present study, we compared the ability of nano- and fine-sized WC--Co particles to form free radicals and propensity to activate the transcription factors, AP-1 and NF-kappaB, along with stimulation of mitogen-activated protein kinase (MAPK) signaling pathways in a mouse epidermal cell line (JB6 P+). Our results demonstrated that nano-WC--Co generated a higher level of hydroxyl radicals, induced greater oxidative stress, as evidenced by a decrease of GSH levels, and caused faster JB6 P+ cell growth/proliferation than observed after exposure of cells to fine WC--Co. In addition, nano-WC--Co activated AP-1 and NF-kappaB more efficiently in JB6+/+ cells as compared to fine WC--Co. Experiments using AP-1-luciferase reporter transgenic mice confirmed the activation of AP-1 by nano-WC--Co. Nano- and fine-sized WC--Co particles also stimulated MAPKs, including ERKs, p38, and JNKs with significantly higher potency of nano-WC--Co. Finally, co-incubation of the JB6+/+ cells with N-acetyl-cysteine decreased AP-1 activation and phosphorylation of ERKs, p38 kinase, and JNKs, thus suggesting that oxidative stress is involved in WC--Co-induced toxicity and AP-1 activation.
Metals; Carcinogens; Free-radicals; Nanotechnology;
Author Keywords: Skin; Cancer; Signaling pathway; Transcription factor; Nanoparticles; Tungsten carbide--cobalt
A.A. Shvedova, Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA
7440-48-4; 7440-33-7; 11130-73-7
Toxicology and Applied Pharmacology
University of Pittsburgh at Pittsburgh