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Part Fibre Toxicol. 2012 Jan 19;9:2. doi: 10.1186/1743-8977-9-2.

A mixture of anatase and rutile TiO₂ nanoparticles induces histamine secretion in mast cells.

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  • 1Bioengineering, University of California at Merced, Merced, CA, USA, 5200 North Lake RD, Merced, CA 95343, USA.



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.


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.


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.

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