Silicon dioxide nanoparticles induce insulin resistance through endoplasmic reticulum stress and generation of reactive oxygen species

BACKGROUND: Silicon dioxide nanoparticles (SiO(2) NPs) are one of the most widely utilized NPs in various food sectors. However, the potential endocrine toxicity of SiO(2) NPs has not been characterized. RESULTS: In the present study, mice were orally administered a series of doses of SiO(2) NPs. All doses of SiO(2) NPs were absorbed into the blood, liver, and pancreas of the mice. Administration of 100 mg/kg bw (body weight) of SiO(2) NPs significantly increased blood glucose levels in mice. However, the same dose of SiO(2) fine-particles (FPs) did not result in altered blood glucose. Whole-genome analysis showed that SiO(2) NPs affected the expression of genes associated with reactive oxygen species (ROS) production and endoplasmic reticulum (ER) stress. In addition, we showed that SiO(2) NPs activated xenobiotic metabolism, resulting in ER stress. Endoplasmic reticulum stress resulted in increased ROS production, which activated the NF-κB pathway leading to expression of inflammatory cytokines. Increased inflammatory cytokine expression resulted in serine phosphorylation of IRS1, which induced insulin resistance (IR). Furthermore these inflammatory cytokines activated the MAPK pathway, which further promoted the serine phosphorylation of IRS1. Insulin resistance resulted in elevated blood glucose. The ER stress inhibitor 4-phenylbutyric acid (4-PBA) inhibited SiO(2) NP-induced ROS production. The ROS scavenger N-acetylcysteine (NAC) did not affect SiO(2) NP-induced ER stress, but inhibited SiO(2) NP-induced activation of the NF-κB and MAPK pathways, expression of inflammatory cytokines, SiO(2) NP-induced serine phosphorylation of IRS1, and SiO2 NP-induced elevations of blood glucose. CONCLUSION: Silicon dioxide NPs induced IR through ER stress and generation of ROS, but SiO(2) FPs did not. Therefore, lifelong exposure of humans to SiO(2) NPs may result in detrimental effects on blood glucose. The results of this study strongly suggested that non-nanoformed SiO(2) should be used as food additives.