title: Molecular mechanism of DNA damage induced by titanium dioxide nanoparticles in toll-like receptor 3 or 4 expressing human hepatocarcinoma cell lines.
abstract: BACKGROUND
  Titanium 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.
  
  
  RESULTS
  Our 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.
  
  
  CONCLUSIONS
  Our results indicated that TiO2 NPs induced ROS, and the above molecules are implicated in the genotoxicity induced by TiO2 NPs.
authors.affiliation: Cell-Material Interaction Group, Biomaterial Unit, Nano-Bio Field, Interaction Center for Material Nanoarchitectonics (MANA), National Institute for Materials Science (NIMS), Tsukuba, Japan. SAMYELSAIDALI.Karim@nims.go.jp.|Department of Chemistry, Faculty of Science, Tanta University, Tanta, Egypt. SAMYELSAIDALI.Karim@nims.go.jp.
authors.forename: Karim Samy
authors.initials: KS
authors.lastname: El-Said
authors.affiliation: Department of Chemistry, Faculty of Science, Tanta University, Tanta, Egypt. ehab_1964@hotmail.com.
authors.forename: Ehab Mostafa
authors.initials: EM
authors.lastname: Ali
authors.affiliation: Biotechnology Group, TOTO Ltd. Research Institute, Honson 2-8-1, Chigasaki, Kanagawa, 253-8577, Japan. koki.kanehira@jp.toto.com.
authors.forename: Koki
authors.initials: K
authors.lastname: Kanehira
authors.affiliation: Cell-Material Interaction Group, Biomaterial Unit, Nano-Bio Field, Interaction Center for Material Nanoarchitectonics (MANA), National Institute for Materials Science (NIMS), Tsukuba, Japan. taniguchi.akiyoshi@nims.go.jp.|Graduate School of Advanced Science and Engineering, Waseda University, Shinjuku, Japan. taniguchi.akiyoshi@nims.go.jp.|National Institute for Materials Science (NIMS), 1-1 Namiki, Tsukuba, Ibaraki, 305-0044, Japan. taniguchi.akiyoshi@nims.go.jp.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Taniguchi
mesh_terms: D004249:DNA Damage / Q000187:drug effects* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014025:Titanium / Q000633:toxicity*; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; C009495:titanium dioxide; D006861:Hydrogen Peroxide; D014025:Titanium; D005979:Glutathione Peroxidase; D005978:Glutathione