Titanium dioxide nanoparticles (TiO₂ NPs) constitute the top five NPs in use today. In this study, oral administration of 50, 100, and 200 mg/kg body weight (b.w.) TiO₂ NPs increases plasma glucose in mice, whereas 10 and 20 mg/kg b.w. TiO₂ NPs did not. RNA sequencing (RNA-seq) technology was used to investigate genome-wide effects of TiO₂ NPs. Clustering analysis of the RNA-seq data showed the most significantly enriched gene ontology terms and KEGG pathways related to the endoplasmic reticulum (ER) and ER stress. Molecular biology verification showed that 50 mg/kg b.w. and higher doses TiO₂ NPs activated a xenobiotic biodegradation response and increased expression of cytochrome P450 family genes in mouse livers, thus inducing ER stress in mice. ER stress-activated MAPK and NF-κB pathways and induced an inflammation response, resulting in phosphorylation of the insulin receptor substrate 1 and, consequently, insulin resistance. This was the main mechanism by which TiO₂ NPs increased plasma glucose in mice. Meanwhile, ER stress disturbed the monooxygenase system, and thus generated reactive oxygen species (ROS). Relief of ER stress with 4-phenylbutyric acid inhibited all the above effects of TiO₂ NPs, including the generation of ROS. Therefore, TiO₂ NP-induced ER stress was a decisive factor with a central role in plasma glucose disturbance in mice.

中文翻译：

---

RNA测序分析表明，二氧化钛纳米颗粒可诱导内质网应激，这在介导小鼠血浆葡萄糖中起着重要作用

二氧化钛纳米颗粒（TiO ₂ NP）构成了当今使用的前五种NP。在这项研究中，口服50、100和200 mg / kg体重（bw）的TiO ₂ NPs可增加小鼠的血浆葡萄糖，而10和20 mg / kg bw的TiO ₂ NPs则不会。RNA测序（RNA-seq）技术用于研究TiO ₂ NP的全基因组效应。RNA-seq数据的聚类分析显示，与内质网（ER）和ER应激相关的基因本体术语和KEGG途径最丰富。分子生物学验证表明，50 mg / kg bw和更高剂量的TiO ₂ NPs激活异种生物降解反应并增加细胞色素P450的表达小鼠肝脏中的家族基因，从而在小鼠中诱导内质网应激。内质网应激激活MAPK和NF-κB通路并引起炎症反应，导致胰岛素受体底物1磷酸化，进而导致胰岛素抵抗。这是TiO ₂ NPs增加小鼠血浆葡萄糖的主要机制。同时，内质网应激扰乱了单加氧酶系统，从而产生了活性氧（ROS）。用4-苯基丁酸缓解ER应力可抑制TiO ₂ NP的所有上述作用，包括ROS的产生。因此，TiO ₂ NP诱导的内质网应激是决定因素，在小鼠血浆葡萄糖紊乱中起着核心作用。