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. 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. 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.

中文翻译：

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二氧化硅纳米颗粒通过内质网应激和活性氧的产生诱导胰岛素抵抗。

二氧化硅纳米颗粒（SiO2 NPs）是各种食品领域中使用最广泛的NPs之一。但是，SiO2 NPs的潜在内分泌毒性尚未得到表征。在本研究中，给小鼠口服了一系列剂量的SiO2 NPs。所有剂量的SiO2 NPs都被吸收到小鼠的血液，肝脏和胰腺中。给予100 mg / kg bw（体重）的SiO2 NPs会显着增加小鼠的血糖水平。但是，相同剂量的SiO2微粒（FPs）不会导致血糖改变。全基因组分析表明，SiO2 NPs影响与活性氧（ROS）产生和内质网（ER）胁迫相关的基因的表达。此外，我们表明SiO2 NPs激活异种生物代谢，从而导致内质网应激。内质网应激导致ROS产生增加，从而激活NF-κB通路，导致炎症性细胞因子的表达。炎性细胞因子表达增加导致IRS1的丝氨酸磷酸化，从而诱导胰岛素抵抗（IR）。此外，这些炎性细胞因子激活了MAPK途径，从而进一步促进了IRS1的丝氨酸磷酸化。胰岛素抵抗导致血糖升高。ER应力抑制剂4-苯基丁酸（4-PBA）抑制SiO2 NP诱导的ROS产生。ROS清除剂N-乙酰半胱氨酸（NAC）不会影响SiO2 NP诱导的内质网应激，但会抑制SiO2 NP诱导的NF-κB和MAPK途径活化，炎性细胞因子的表达，SiO2 NP诱导的IRS1丝氨酸磷酸化，以及SiO2 NP引起的血糖升高。二氧化硅NPs通过ER应力和ROS的产生诱导IR，但是SiO2 FPs没有。因此，人类终生暴露于SiO2 NPs可能会对血糖产生不利影响。这项研究的结果强烈建议应使用非纳米形式的SiO2作为食品添加剂。