title: Titanium dioxide nanoparticles increase plasma glucose via reactive oxygen species-induced insulin resistance in mice.
abstract: There have been few reports about the possible toxic effects of titanium dioxide (TiO2 ) nanoparticles on the endocrine system. We explored the endocrine effects of oral administration to mice of anatase TiO2 nanoparticles (0, 64 and 320 mg kg(-1) body weight per day to control, low-dose and high-dose groups, respectively, 7 days per week for 14 weeks). TiO2 nanoparticles were characterized by scanning and transmission electron microscopy (TEM) and dynamic light scattering (DLS), and their physiological distribution was investigated by inductively coupled plasma. Biochemical analyzes included plasma glucose, insulin, heart blood triglycerides (TG), free fatty acid (FFA), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6 and reactive oxygen species (ROS)-related markers (total SOD, GSH and MDA). Phosphorylation of IRS1, Akt, JNK1, and p38 MAPK were analyzed by western blotting. Increased titanium levels were found in the liver, spleen, small intestine, kidney and pancreas. Biochemical analyzes showed that plasma glucose significantly increased whereas there was no difference in plasma insulin secretion. Increased ROS levels were found in serum and the liver, as evidenced by reduced total SOD activity and GSH level and increased MDA content. Western blotting showed that oral administration of TiO2 nanoparticles induced insulin resistance (IR) in mouse liver, shown by increased phosphorylation of IRS1 (Ser307) and reduced phosphorylation of Akt (Ser473). The pathway by which TiO2 nanoparticles increase ROS-induced IR were included in the inflammatory response and phosphokinase, as shown by increased serum levels of TNF-α and IL-6 and increased phosphorylation of JNK1 and p38 MAPK in liver. These results show that oral administration of TiO2 nanoparticles increases ROS, resulting in IR and increasing plasma glucose in mice.
authors.affiliation: School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Hu
authors.affiliation: School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Guo
authors.affiliation: School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China.
authors.forename: Changlin
authors.initials: C
authors.lastname: Wang
authors.affiliation: Key Laboratory of Pu-erh Tea Science of Ministry of Education, Yunnan Research Center for Advanced Tea Processing, Yunnan Agricultural University, Kunming, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Ma
authors.affiliation: School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China.
authors.forename: Hongjuan
authors.initials: H
authors.lastname: He
authors.affiliation: Faculty of Education, Wakayama University, Wakayama, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Oh
authors.affiliation: State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Feng
authors.affiliation: School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.affiliation: School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Gu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D004435:Eating / Q000187:drug effects; D007333:Insulin Resistance; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D053768:Metal Nanoparticles / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR; D010316:Particle Size; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014018:Tissue Distribution; D014025:Titanium / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D001786:Blood Glucose; D016207:Cytokines; D008055:Lipids; D017382:Reactive Oxygen Species; C009495:titanium dioxide; D014025:Titanium
keywords: IR; ROS; TiO2 nanoparticles; insulin; plasma glucose