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

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.Allergic inflammation is a primary pathological feature of many debilitating diseases [1]. Among the numerous active mediators and cytokines that modulate initiation and progression of allergic inflammation, histamine is distinctly potent [1,2]. Typically, the storage of histamine is restricted to mast cells and circulating basophils [2,3]. The cardinal pathway of histamine release involves the attachment of IgE-bound allergens to high-affinity FcεRI receptors on mast cells and the crosslinking of adjacent IgE molecules by allergens [1,2]. Subsequent receptor clustering leads to a complex cascade of intracellular Ca2+ signaling resulting from increased activity of phospholipase C (PLC), generation of diacylglycerol (DAG) (activating PKC) and inositol 1,4,5-trisphosphate (IP3) which mobilizes the ER Ca2+ store and participates in final histamine secretion from mast cells. Activation of histamine receptors (H1, H2, H3 and H4) greatly influences inflammatory responses [2].Aside from inducing acute allerg