Molecular mechanism of DNA damage induced by titanium dioxide nanoparticles in toll-like receptor 3 or 4 expressing human hepatocarcinoma cell lines

Abstract

BackgroundTitanium dioxide nanoparticles (TiO2 NPs) are widely used in the biological sciences. The increasing use of TiO2 NPs increases the risk of humans and the environment being exposed to NPs. We previously showed that toll-like receptors (TLRs) play an important role in the interactions between NPs and cells. Our previous results indicated that TLR4 increased the DNA damage response induced by TiO2 NPs, due to enhanced NP uptake into the cytoplasm, whereas TLR3 expression decreased the DNA damage response induced by TiO2 NPs because of NP retention in the endosome. In this study, we explored the molecular mechanism of the DNA damage response induced by TiO2 NPs using TLR3 or TLR4 transfected cells. We examined the effect of TLR3 or TLR4 over-expression on oxidative stress and the effect of DNA damage induced by TiO2 NPs on gene expression levels.ResultsOur results showed evidence for elevated oxidative stress, including the generation of reactive oxygen species (ROS), with increased hydrogen peroxide levels, decreased glutathione peroxidase, and reduced glutathione and activated caspase-3 levels in cells exposed for 48 h to 10 μg/ml TiO2 NPs. These effects were enhanced by TLR4 and reduced by TLR3 over-expression. Seventeen genes related to DNA double-strand breaks and apoptosis were induced, particularly IP6K3 and ATM.ConclusionOur results indicated that TiO2 NPs induced ROS, and the above molecules are implicated in the genotoxicity induced by TiO2 NPs.

Thioesterase-mediated control of cellular calcium homeostasis enables hepatic ER stress

“…To explore this possibility, we measured hydrogen peroxide concentrations in the mouse livers (39). Although hydrogen peroxide accumulation was reduced by 27% in high-fat-fed Pctp -/-mice, the absence of Them2 expression had no effect, irrespective of diet (Supplemental Figure 11, A and B).…”

Cytotoxic and inflammatory responses of TiO2 nanoparticles on human peripheral blood mononuclear cells

“…Therefore, TiO 2 ‐NPs at concentrations ≥25 μg ml −1 could induce apoptosis via this pathway and might shift to necrosis in high concentrations of TiO 2 ‐NP exposure. Apoptosis through the mitochondrial pathway by TiO 2 ‐NP induction has also been reported in various cells such as human hepatocarcinoma (El‐Said et al ., ) and bronchial epithelial cell lines (Hussain et al ., ). The significant increases of PI+ cells were detected after treating PBMCs with TiO 2 ‐NPs at concentrations 125–500 μg ml −1 but not at 25 μg ml −1 .…”

Comparison of Oxidative Stresses Mediated by Different Crystalline Forms and Surface Modification of Titanium Dioxide Nanoparticles

“…In previous study, we demonstrated that an increased DNA damage response is mediated by the anatase crystalline form compared to rutile and mixed forms [20] and that PEG-TiO 2 NPs showed a reduction in DNA damage responses compared to TiO 2 NPs [21]. We also showed that TiO 2 NPs induced ROS, which are implicated in the genotoxicity induced by TiO 2 NPs [22]. However, the molecular mechanism of the DNA damage induced by the different crystalline forms of TiO 2 NPs is unknown.…”