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.

Effects of aluminum, copper, and titanium nanoparticles onsome blood parameters in Wistar rats

“…The TOS levels in TiO 2 -exposed rats were also increased in the present study, but this was not statistically significant. In recent years, there has been considerable evidence in the literature on ROS increase and antioxidant system failure following TiO 2 , CuO, ZnO, and Al 2 O 3 exposures of rats (Sha et al, 2011;Yu et al, 2014;Hu et al, 2015;Lei et al, 2015), supporting the present data, which showed the TOS increase in the serum.…”

Mechanisms of titanium dioxide nanoparticle‐induced oxidative stress and modulation of plasma glucose in mice

“…A theoretical framework study comparing redox potentials of the relevant intracellular reactions with NP energy band structure showed that harmful oxide NPs possess band energy levels comparable to redox potentials of these biological reactions, leading to generation of ROS . Earlier research by our group focusing on the toxic effects of TiO 2 NPs on the endocrine system in mice demonstrated that oral administration of these NPs leads to increased plasma glucose levels . Moreover, generation of ROS appeared to be the predominant mechanism underlying the TiO 2 NP‐mediated increase in plasma glucose and consequent toxic effects .…”

“…8 Earlier research by our group focusing on the toxic effects of TiO 2 NPs on the endocrine system in mice demonstrated that oral administration of these NPs leads to increased plasma glucose levels. 9,10 Moreover, generation of ROS appeared to be the predominant mechanism underlying the TiO 2 NP-mediated increase in plasma glucose and consequent toxic effects. 10 Notably, inhibition of ROS in TiO 2 NP-treated mice with resveratrol (Res) and vitamin E (Ve) resulted in suppression of plasma glucose levels in mice.…”

“…9,10 Moreover, generation of ROS appeared to be the predominant mechanism underlying the TiO 2 NP-mediated increase in plasma glucose and consequent toxic effects. 10 Notably, inhibition of ROS in TiO 2 NP-treated mice with resveratrol (Res) and vitamin E (Ve) resulted in suppression of plasma glucose levels in mice. 11 Recent usage of RNA sequencing (RNA-seq) technology to establish the toxicity mechanisms of TiO 2 NPs led to the unexpected finding that oral administration of these NPs not only promotes ROS levels in mice but also induces endoplasmic reticulum (ER) stress.…”

Investigation on the mechanism of non‐photocatalytically TiO2‐induced reactive oxygen species and its significance on cell cycle and morphology

“…However, recent studies suggest that it also poses adverse biological and environmental toxicity depending on the size, surface area, charge and media interactions (Donaldson et al, 2001;Nel et al, 2006;Oberdoester, 2010;Oberdorster et al, 2005). The potential of TiO 2 in the production of reactive oxygen species (ROS) and proinflammatory responses in cells were reported earlier (Hu et al, 2015;Meena et al, 2015). They are also found to cause a neurological lesion Ze et al, 2014).…”