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Nanotoxicology. 2019 Sep 13:1-18. doi: 10.1080/17435390.2019.1663288. [Epub ahead of print]

Molecular mechanisms underlying zinc oxide nanoparticle induced insulin resistance in mice.

Author information

1
School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology , Harbin , China.
2
Faculty of Education, Wakayama University , Wakayama , Japan.
3
State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology , Harbin , China.
4
The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University , Guangzhou , China.
5
School of Life Sciences, Guangzhou University , Guangzhou , China.

Abstract

Zinc oxide nanoparticles (ZnO NPs) represent an important class of commercially applied materials. Recently, adverse effects of ZnO NPs were found in humans and animals following ingestion, although the effects on endocrine system disease remain unclear. In this study, ZnO NPs were orally administered to mice, and at doses of 25 mg/kg bw (body weight) ZnO NPs and above, plasma glucose increased significantly. The genome-wide effects of ZnO NPs were then investigated using RNA-sequencing technology. In the cluster analysis, the most significantly enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways concerned membranes and their close association with endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation. Biochemical and gene and protein expression analyses revealed that ZnO NPs activated a xenobiotic biodegradation response and increased the expression of cytochrome P450 (CYP) enzymes in mice livers, leading to ER stress. The ER stress increased ROS generation. The high levels of ROS activated the MAPK and NF-κB pathways and induced an inflammation response, resulting in the phosphorylation of insulin receptor substrate 1. Thus, the insulin resistance that developed was the primary mechanism for the increase in the plasma glucose of mice treated orally with ZnO NPs.

KEYWORDS:

RNA-sequencing; Zinc oxide nanoparticles; endoplasmic reticulum stress; mice; plasma glucose

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