Neurotoxicity and gene‐expressed profile in brain‐injured mice caused by exposure to titanium dioxide nanoparticles

Abstract

Titanium dioxide nanoparticles (TiO2 NPs) are widely used in toothpastes, sunscreens, and products for cosmetic purpose that the human use daily. Although the neurotoxicity induced by TiO2 NPs has been demonstrated, very little is known about the molecular mechanisms underlying the brain cognition and behavioral injury. In this study, mice were exposed to 2.5, 5, and 10 mg/kg body weight (BW) TiO2 NPs by nasal administration for 90 consecutive days, respectively, and their brains' injuries and brain gene-expressed profile were investigated. Our findings showed that TiO2 NPs could be translocated and accumulated in brain, led to oxidative stress, overproliferation of all glial cells, tissue necrosis as well as hippocampal cell apoptosis. Furthermore, microarray data showed significant alterations in the expression of 249 known function genes, including 113 genes upregulation and 136 genes downregulation following exposure to 10 mg/kg BW TiO2 NPs, which were associated with oxidative stress, immune response, apoptosis, memory and learning, brain development, signal transduction, metabolic process, DNA repair, response to stimulus, and cellular process. Especially, significant increases in Col1a1, serine/threonine-protein kinase 1, Ctnnb1, cysteine-serine-rich nuclear protein-1, Ddit4, Cyp2e1, and Krev interaction trapped protein 1 (Krit1) expressions and great decreases in DA receptor D2, Neu1, Fc receptor-like molecules, and Dhcr7 expressions following long-term exposure to TiO2 NPs resulted in neurogenic disease states in mice. Therefore, these genes may be potential biomarkers of brain toxicity caused by TiO2 NPs exposure, and the application of TiO2 NPs should be carried out cautiously.

Effect of chromium disilicide and titanium nitride nanoparticles on the expression of NAMPT, E2F8, FAS, TBX3, IL13RA2, and UPS7 genes in mouse liver

“…It is well known that proteins enco ding by E2F8 and USP7 genes have variable properties and can contribute to regulation of cell proliferation and apoptosis [18,25,26]. It is possible that our results can reflect the genotoxic effect of titanium nitride and chromium disilicide nanoparticles and are mostly consistent with data Ze et al [2] and Alarifi et al [8] as well as with our previous data [28,29].…”

“…Ultrafine titanium dioxide nanoparticles is widely used in the number of applications, including white pigment in paint, ceramics, food packaging material, food additive, cosmetic creams, toothpastes, and component of surgical implants [1]. However, long-term exposure to titanium dioxide nanoparticles led to accumulation of these nanoparticles in brain, oxidative stress, over-prolife ration of all glial cells, tissue necrosis as well as hippocampal cell apoptosis, resulted in neurogenic disea se states in mice [2]. Significant changes in brain gene expressions were also founded: significant increases in collagen A1 (COL1A1), serine/threonine-protein kinase 1 (AKT1), catenin β1 (CTNNB1), cysteine and serine rich nuclear protein 1 (CSRNP1), DDIT4 (DNA Damage Inducible Transcript 4), cytochrome P450 family 2 subfamily E member 1 (CYP2E1), and Krev interaction trapped protein 1 (KRIT1) expressions and great decreases in dopamine receptor D2 (DRD2), neuraminidase 1 (NEU1), Fc receptor-like A (FCRLA), and 7-dehydrocholesterol reductase (DHCR7) expressions [2].…”

“…For titanium dioxide nanoparticles, which are widely used in the number of applications, including cosmetic creams, toothpastes, and component of surgical implants, it was shown that long-term exposure to these nanoparticles led to accumulation of these nanoparticles in brain, over-proliferation of glial cells and significant changes in brain gene expressions as well as to neurogenic disease states in mice [1,2]. At the same time, the genotoxicity of titanium nitride nanoparticles, which have favorable properties and used for coronary stents, syringe needles, and the coating of orthopedic implant as well as in dental medicine for improving long-term implants [4][5][6][7], did not studied yet.…”

Application of dental nanomaterials: potential toxicity to the central nervous system

“…Their results indicated that TiO 2 NPs could transfer through the BBB and thereafter induce an injury to the brain by the activation of oxidative stress responses. In another toxicity study of TiO 2 NPs in mice performed by Ze et al 71 TiO 2 NPs were translocated and accumulated in the brain through nasal administration, and this led to an oxidative stress and a series of pathological changes, such as an overproliferation of the glial cells and hippocampal cell apoptosis. The authors further noted some significant changes in genes that may be potential biomarkers of brain toxicity.…”

Toxic effects of the interaction of titanium dioxide nanoparticles with chemicals or physical factors

“…11 Moreover, a recent study showed oxidative stress in mice brain as well as overproliferation of all glial cells. 12 These occurred in mice that were exposed to 2.5 mg/kg, 5 mg/kg, and 10 mg/kg body weight TiO 2 NPs through nasal administration for 90 days. The toxicokinetics ( Figure 1) and toxic effects of TiO 2 NPs [13][14][15] alone have been well documented in many in vivo and in vitro studies, but reviews of the effects (or toxicities) of the interaction of TiO 2 NPs with other chemicals or physical factors are currently unavailable.…”