title: Size-dependent effects of tungsten carbide-cobalt particles on oxygen radical production and activation of cell signaling pathways in murine epidermal cells.
abstract: 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.
authors.affiliation: Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ding
authors.forename: E R
authors.initials: ER
authors.lastname: Kisin
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.forename: L
authors.initials: L
authors.lastname: Bowman
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.forename: B
authors.initials: B
authors.lastname: Jiang
authors.forename: S
authors.initials: S
authors.lastname: Leonard
authors.forename: V
authors.initials: V
authors.lastname: Vallyathan
authors.forename: V
authors.initials: V
authors.lastname: Castranova
authors.forename: A R
authors.initials: AR
authors.lastname: Murray
authors.forename: B
authors.initials: B
authors.lastname: Fadeel
authors.forename: A A
authors.initials: AA
authors.lastname: Shvedova
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003035:Cobalt / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D004789:Enzyme Activation / Q000187:drug effects; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D007150:Immunohistochemistry; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000096:biosynthesis; D053758:Nanoparticles; D010316:Particle Size; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013438:Sulfhydryl Compounds / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000096:biosynthesis; D017973:Tungsten Compounds / Q000633:toxicity*
chemical_list: D007202:Indicators and Reagents; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D018808:Transcription Factor AP-1; D017973:Tungsten Compounds; C002802:tungsten carbide; D003035:Cobalt; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione