Cobalt-mediated generation of reactive oxygen species and its possible mechanism
Introduction
Cobalt (Co) is an essential trace element for mammalian nutrition. It is toxic and carcinogenic at higher concentrations 1, 2, 3, 4. The International Agency for Research on Cancer has classified this metal as possibly carcinogenic to humans [5]. Occupational exposure to hard metals, including Co, causes “hard metal diseases”, such as cancer and asthma [6]. As stated in the National Occupational Research Agenda (NORA), investigation on occupational diseases caused by exposure to metals, such as cobalt, chromium and tungsten, is a NORA mission and appears on the National Toxicology Program priority list [6].
In epidemiological studies, workers exposed to cobalt in an electrochemical plant producing cobalt and workers exposed to cobalt-containing hard metal compounds exhibited significantly enhanced risk for lung cancer 7, 8, 9. In laboratory studies Co(II) caused direct induction of DNA damage 10, 11, DNA-protein crosslinking, and sister-chromatid exchange [1]. Besides the direct induction of DNA damage, Co(II) has been reported to interfere with DNA repair processes 1, 11. Co(II) enhances the frequency of UV induced mutations and sister-chromatid exchanges in V79 Chinese hamster cells [12]. Co(II) compounds have been shown to have a carcinogenic effects in animal studies 1, 13. Cobalt itself causes little or no DNA damage in vitro although Co(II) can bind to DNA [14]. While the mechanisms of cobalt-induced toxicity and carcinogenicity remains to be elucidated, cobalt-mediated free radical reactions have been suggested to be involved 10, 15. Co(II) alone does not efficiently generate hydroxyl radicals (⋅OH) from H2O2. However, in the presence of nitrilotriacetic acid as a chelating agent, Hanna et al. [16]have reported the formation of ⋅OH radical from H2O2 by Co(II). Although nitrilotriacetic acid may not be a significant ligand for Co(II) in cells exposed to this cation, this study does suggest that the reactivity of Co(II) toward H2O2 could be enhanced by proper chelation. In a recent study [15], we have shown that Co(II) can generate ⋅OH and lipid hydroperoxide-derived free radicals from H2O2 and model lipid hydroperoxides in the presence of biologically relevant ligands, such as glutathione and anserine. The cobalt-mediated radical generation from these reactions was suggested to be involved in the mechanism of Co(II)-related toxicity and carcinogenicity 11, 15.
At present, most of the studies concerning the cobalt-mediated free radical generation have focused on Co(II). There is only limited study of free radical generation mediated by cobalt metal [17]. The goal of the present study is to investigate the possible free radical generation by cobalt metal and elucidate possible mechanisms of generation.
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Materials
Cobalt metal powder (trade name, Xtra Fine Cobalt) was obtained from Newcomer Products (Latrobe, PA). The material is used as the metal binder in the industrial production of WC–Co hard metals. Xtra Fine Cobalt was analyzed at 99.3 purity of Co (O2, 0.6%; Ni, 0.1%; C, 0.3%; Na, 0.2%; Si, 0.01%; Ca, 0.01%; Mg, 0.01%; Mn, 0.01%; Cu, 0.01%; Fe, 0.01%; Mg, 0.01%). The range of particle size is 0.1–1.5 μm. Cobalt suspension, instead of solution, is used.
Diethylenetriaminepentaacetic acid (DTPA),
Results
Fig. 1 contains the scanning electron microscope image of cobalt particles. As shown by this figure, the particle sizes are distributed in the range of 0.1–1.5 μm. Fig. 2 shows a typical ESR spectrum obtained from an aqueous solution of 10 mg/ml cobalt particles at pH 7.4. The spectrum is centered at g=2.0065, which indicates oxygen involvement. Computer stimulation shows that the hyperfine splittings are aN=7.1 G and aH=4.2, where aN and aH denote hyperfine splitting constants of nitroxyl
Discussion
The results obtained in the present study show that reaction of metallic Co in aqueous suspension with dissolved oxygen is able to generate a strong oxidant as shown by the formation of DMPOX. According to Rosen and Rauckman [19], the DMPOX signal is indirect evidence for peroxy radical (ROO⋅) generation and its trapping by DMPO. While further studies are required to elucidate the detailed mechanism, the steps outlined in Fig. 7 may best explain the pathways of DMPOX formation.
When SOD was
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