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

Abstract

Background Silicon dioxide nanoparticles (SiO2 NPs) are one of the most widely utilized NPs in various food sectors. However, the potential endocrine toxicity of SiO2 NPs has not been characterized. Results In the present study, mice were orally administered a series of doses of SiO2 NPs. All doses of SiO2 NPs were absorbed into the blood, liver, and pancreas of the mice. Administration of 100 mg/kg bw (body weight) of SiO2 NPs significantly increased blood glucose levels in mice. However, the same dose of SiO2 fine-particles (FPs) did not result in altered blood glucose. Whole-genome analysis showed that SiO2 NPs affected the expression of genes associated with reactive oxygen species (ROS) production and endoplasmic reticulum (ER) stress. In addition, we showed that SiO2 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 SiO2 NP-induced ROS production. The ROS scavenger N-acetylcysteine (NAC) did not affect SiO2 NP-induced ER stress, but inhibited SiO2 NP-induced activation of the NF-κB and MAPK pathways, expression of inflammatory cytokines, SiO2 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 SiO2 FPs did not. Therefore, lifelong exposure of humans to SiO2 NPs may result in detrimental effects on blood glucose. The results of this study strongly suggested that non-nanoformed SiO2 should be used as food additives.

Metformin increases tauroursodeoxycholic acid levels to improve insulin resistance in diet-induced obese mice

“…This is reminiscent of the expression pattern of Nrf2, a crucial stress regulator to reduce the ROS, which is a key factor in sensitizing insulin signaling 55–57 . It has also been confirmed that up-regulation of the Nrf2 expression both by genetic manipulation and pharmacological interference, can significantly decrease the content of ROS and ameliorate IR and T2D 58,59 . In the mice supplement with metformin, the significant up-regulation in the expression of Nrf2 and its downstream target genes ( Gclc , Cat and Ho-1 ) occurred, which further alleviated IR and over-oxidation.…”

Issues currently complicating the risk assessment of synthetic amorphous silica (SAS) nanoparticles after oral exposure

“…It is not clear whether the SAS used by Liang et al (2018) and Yun et al (2015) is compliant with the E 551 specifications. Three recent studies using relatively low dose levels (from 2 up to 200 mg/kg bw/d), however, did report effects, including effects on the liver (Boudard et al 2019;Hu et al 2019;Tassinari et al 2020). The study by Boudard et al (2019) demonstrated that chronic exposure (18 months) of mice to 4.8 mg/kg bw/d precipitated SAS (NM-200) via the drinking water triggered renal and liver inflammation accompanied by amyloidosis in kidney glomeruli and in perivascular regions.…”

“…on liver and kidney (Boudard et al 2019;Boudard et al 2020). A subchronic study using relatively low dose levels was performed by Hu et al (2019), in which mice were treated for 18 weeks with different doses pyrogenic or colloidal silica particles (both NPs and MPs) focusing on endocrine effects and blood glucose levels. Exposure to 100 mg/kg bw/d (the only tested dose) of pyrogenic NPs resulted in lowered superoxide dismutase (SOD) and glutathione (GSH) levels and increased malonyl dialdehyde (MDA) levels after 7 weeks in serum and in the liver, indicating reactive oxygen species (ROS) generation in the liver.…”

Endoplasmic Reticulum Stress Provocation by Different Nanoparticles: An Innovative Approach to Manage the Cancer and Other Common Diseases

“…Recently, it has been reported in human hepatoma cells that SiO 2 -NPs promote oxidative stress through the ER stress [218], and leads to the induction of TNF-α and activates MAPK pathways [219]. SiO 2 -NPs induced ER stress also leads to the activation of NF-κB, leading to the expression of interferons [220]. It has been further reported that SiO 2 -NPs persuade the expression of MAP kinase regulated transcription factors like CYMC and CJUN [219].…”