Abstract
The molecular responses of macrophages to copper-based nanoparticles have been investigated via a combination of proteomic and biochemical approaches, using the RAW264.7 cell line as a model. Both metallic copper and copper oxide nanoparticles have been tested, with copper ion and zirconium oxide nanoparticles used as controls. Proteomic analysis highlighted changes in proteins implicated in oxidative stress responses (superoxide dismutases and peroxiredoxins), glutathione biosynthesis, the actomyosin cytoskeleton, and mitochondrial proteins (especially oxidative phosphorylation complex subunits). Validation studies employing functional analyses showed that the increases in glutathione biosynthesis and in mitochondrial complexes observed in the proteomic screen were critical to cell survival upon stress with copper-based nanoparticles; pharmacological inhibition of these two pathways enhanced cell vulnerability to copper-based nanoparticles, but not to copper ions. Furthermore, functional analyses using primary macrophages derived from bone marrow showed a decrease in reduced glutathione levels, a decrease in the mitochondrial transmembrane potential, and inhibition of phagocytosis and of lipopolysaccharide-induced nitric oxide production. However, only a fraction of these effects could be obtained with copper ions. In conclusion, this study showed that macrophage functions are significantly altered by copper-based nanoparticles. Also highlighted are the cellular pathways modulated by cells for survival and the exemplified cross-toxicities that can occur between copper-based nanoparticles and pharmacological agents.
Highlights
Manufactured nanoparticles are more and more widely used in more and more consumer products, ranging from personal care products to tyres and concrete
Copper and copper oxide nanoparticles could be dispersed to a microaggregate size of ca. 250 nm
All of the undesirable phenomena were prevented when the copper and copper oxide nanoparticles were coated with polyvinylpyrrolidone (PVP) prior to dilution in the cell culture medium
Summary
Manufactured nanoparticles are more and more widely used in more and more consumer products, ranging from personal care products to tyres and concrete. Metals and metal oxides represent an important part of the total production and are used in water treatment, as antibacterials, in antifouling paints or in microelectronics. These wide uses pose in turn the problem of the toxicological evaluation of the toxicity of these nanoparticles [1, 2], and especially of the long-term effects that often do not come from simple cell mortality but from altered cellular functions. A few exceptions exist, e.g. on carbon-based nanoparticles [19] and on titanium dioxide [20, 21]
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