  Two different zinc oxide nanoparticles, as well as zinc ions, are used to
study the cellular responses of the RAW 264 macrophage cell line. A proteomic
screen is used to provide a wide view of the molecular effects of zinc, and the
most prominent results are cross-validated by targeted studies. Furthermore,
the alteration of important macrophage functions (e.g. phagocytosis) by zinc is
also investigated. The intracellular dissolution/uptake of zinc is also studied
to further characterize zinc toxicity. Zinc oxide nanoparticles dissolve
readily in the cells, leading to high intracellular zinc concentrations, mostly
as protein-bound zinc. The proteomic screen reveals a rather weak response in
the oxidative stress response pathway, but a strong response both in the
central metabolism and in the proteasomal protein degradation pathway. Targeted
experiments confirm that carbohydrate catabolism and proteasome are critical
determinants of sensitivity to zinc, which also induces DNA damage. Conversely,
glutathione levels and phagocytosis appear unaffected at moderately toxic zinc
concentrations.
