Metal Ion Release of Manufactured Metal Oxide Nanoparticles Is Involved in the Allergic Response to Inhaled Ovalbumin in Mice

The aim of the present study was to establish the mechanism of the allergy aggravation effect. Our previous study showed that soluble ZnO nanoparticles caused allergy aggravation, but insoluble TiO2 and SiO2 nanoparticles did not induce an allergic response. Metal ion release is associated with the cytotoxicity of manufactured nanoparticles; however, the role of metal ion release in allergy aggravation remains to be elucidated. Therefore, we examined the allergy aggravation potential of several soluble manufactured nanoparticles (ZnO, CuO, NiO, MgO, and CaCO3). These nanoparticles were administered to mouse lungs by pharyngeal aspiration and subsequently, the mice inhaled ovalbumin (OVA). We also compared the properties of soluble NiO nanoparticles with insoluble micro-scale NiO particles. NiO nanoparticles markedly increased the levels of OVAspecific immunoglobulin (Ig) E but micro-scale NiO particles did not. Among the nanoparticles (ZnO, CuO, MgO, and CaCO3), ZnO induced increase of OVA-specific IgE level. CuO showed tendency to increase OVA-specific IgE; however, no significant difference was observed. Additionally, ZnO and NiO nanoparticles enhanced expression of a gene related to inflammation (Cxcl2), heavy metal detox (metallothionein 2), and oxidative stress (heme oxygenase-1). Gene expression of arginase1, which is enhanced by T helper 2 cytokine, was remarkably enhanced in mice administered ZnO and NiO particles. These effects were not observed in mice administered MgO and CaCO3 nanoparticles. In conclusion, the solubility and type of metal ion released from the nanoparticles influence the allergy aggravation effect. The results showed that the release of Zn2+ and Ni2+ aggravated the allergic reaction.