title: Titanium dioxide (TiO2) nanoparticles induce JB6 cell apoptosis through activation of the caspase-8/Bid and mitochondrial pathways.
abstract: Titanium dioxide (TiO(2)), a commercially important material, is used in a wide variety of products. Although TiO(2) is generally regarded as nontoxic, the cytotoxicity, pathogenicity, and carcinogenicity of TiO(2) nanoparticles have been recently recognized. The present study investigated TiO(2) nanoparticle-induced cell apoptosis and molecular mechanisms involved in this process in a mouse epidermal (JB6) cell line. Using the 3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay, TiO(2) nanoparticles were found to exhibit higher cytotoxicity than fine particles. YO-PRO-1 iodide (YP) staining demonstrated that both TiO(2) nanoparticles and fine particles induced cell death through apoptosis. The signaling pathways involved in TiO(2) particle-induced apoptosis were investigated. Western-blot analysis showed an activation of caspase-8, Bid, BAX, and caspase-3 and a decrease of Bcl-2 in JB6 cells treated with TiO(2) particles. Time-dependent poly(ADP)ribose polymerase (PARP) cleavage induced by TiO(2) nanoparticles was observed. TiO(2) particles also induced cytochrome c release from mitochondria to cytosol. Further studies demonstrated that TiO(2) nanoparticles induced significant changes in mitochondrial membrane permeability, suggesting the involvement of mitochondria in the apoptotic process. In conclusion, evidence indicated that TiO(2) nanoparticles exhibit higher cytotoxicity and apoptotic induction compared to fine particles in JB6 cells. Caspase-8/Bid and mitochondrial signaling may play a major role in TiO(2) nanoparticle-induced apoptosis involving the intrinsic mitochondrial pathway. Unraveling the complex mechanisms associated with these events may provide further insights into TiO(2) nanoparticle-induced pathogenicity and potential to induce carcinogenicity.
authors.affiliation: Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia, USA.
authors.forename: Jinshun
authors.initials: J
authors.lastname: Zhao
authors.forename: Linda
authors.initials: L
authors.lastname: Bowman
authors.forename: Xingdong
authors.initials: X
authors.lastname: Zhang
authors.forename: Val
authors.initials: V
authors.lastname: Vallyathan
authors.forename: Shih-Houng
authors.initials: SH
authors.lastname: Young
authors.forename: Vincent
authors.initials: V
authors.lastname: Castranova
authors.forename: Min
authors.initials: M
authors.lastname: Ding
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D000078404:Epidermal Cells; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000187:drug effects; D053758:Nanoparticles / Q000633:toxicity*; D009336:Necrosis / Q000139:chemically induced; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D014025:Titanium / Q000633:toxicity*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494827:Bax protein, mouse; C494815:Bid protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C009495:titanium dioxide; D045304:Cytochromes c; D014025:Titanium; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C505526:Casp8 protein, mouse; D053148:Caspase 3; D053181:Caspase 8