title: A mixture of anatase and rutile TiO₂ nanoparticles induces histamine secretion in mast cells.
abstract: BACKGROUND
  Histamine released from mast cells, through complex interactions involving the binding of IgE to FcεRI receptors and the subsequent intracellular Ca²⁺ signaling, can mediate many allergic/inflammatory responses. The possibility of titanium dioxide nanoparticles (TiO₂ NPs), a nanomaterial pervasively used in nanotechnology and pharmaceutical industries, to directly induce histamine secretion without prior allergen sensitization has remained uncertain.
  
  
  RESULTS
  TiO₂ NP exposure increased both histamine secretion and cytosolic Ca²⁺ concentration ([Ca²⁺]C) in a dose dependent manner in rat RBL-2H3 mast cells. The increase in intracellular Ca²⁺ levels resulted primarily from an extracellular Ca²⁺ influx via membrane L-type Ca²⁺ channels. Unspecific Ca²⁺ entry via TiO₂ NP-instigated membrane disruption was demonstrated with the intracellular leakage of a fluorescent calcein dye. Oxidative stress induced by TiO₂ NPs also contributed to cytosolic Ca²⁺ signaling. The PLC-IP₃-IP₃ receptor pathways and endoplasmic reticulum (ER) were responsible for the sustained elevation of [Ca²⁺]C and histamine secretion.
  
  
  CONCLUSIONS
  Our data suggests that systemic circulation of NPs may prompt histamine release at different locales causing abnormal inflammatory diseases. This study provides a novel mechanistic link between environmental TiO₂ NP exposure and allergen-independent histamine release that can exacerbate manifestations of multiple allergic responses.
authors.affiliation: Bioengineering, University of California at Merced, Merced, CA, USA, 5200 North Lake RD, Merced, CA 95343, USA.
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Chen
authors.forename: Maria
authors.initials: M
authors.lastname: Garnica
authors.forename: Yung-Chen
authors.initials: YC
authors.lastname: Wang
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Mintz
authors.forename: Chi-Shuo
authors.initials: CS
authors.lastname: Chen
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: Chin
mesh_terms: D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002460:Cell Line; D006632:Histamine / Q000378:metabolism*; D006636:Histamine Release / Q000187:drug effects*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D053758:Nanoparticles / Q000737:chemistry*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D014025:Titanium / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D017382:Reactive Oxygen Species; C009495:titanium dioxide; D006632:Histamine; D015544:Inositol 1,4,5-Trisphosphate; D014025:Titanium; D002118:Calcium