RNA sequencing analysis shows that titanium dioxide nanoparticles induce endoplasmic reticulum stress, which has a central role in mediating plasma glucose in mice

Abstract

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.

Keywords:

• Titanium dioxide nanoparticles
• RNA sequencing
• endoplasmic reticulum stress
• plasma glucose
• mice

Disclosure statement

The authors declare there are no competing financial interests.

Additional information

Funding

This work was supported by funds of the National Natural Science Foundation of China (Grant No. 21677044, 31271593), the Open Project of State Key Laboratory of Urban Water Resource and Environment of Harbin Institute of Technology (Grant No. ES201115, ES201512), the National Funds for Creative Research Group of China (Grant No. 51121062), and the Fundamental Research Funds for the Central Universities (Grant No. HIT. NSRIF. 201669).