TiO 2 nanoparticles cause mitochondrial dysfunction, activate inflammatory responses, and attenuate phagocytosis in macrophages: A proteomic and metabolomic insight.

Titanium dioxide nanoparticles (TiO ₂ NPs) are widely used in food and cosmetics but the health impact of human exposure remains poorly defined. Emerging evidence suggests that TiO ₂ NPs may elicit immune responses by acting on macrophages. Our proteomic study showed that treatment of macrophages with TiO ₂ NPs led to significant re-organization of cell membrane and activation of inflammation. These observations were further corroborated with transmission electron microscopy (TEM) experiments, which demonstrated that TiO ₂ NPs were trapped inside of multi-vesicular bodies (MVB) through endocytotic pathways. TiO ₂ NP caused significant mitochondrial dysfunction by increasing levels of mitochondrial reactive oxygen species (ROS), decreasing ATP generation, and decreasing metabolic flux in tricarboxylic acid (TCA) cycle from ¹³ C-labelled glutamine using GC-MS-based metabolic flux analysis. Further lipidomic analysis showed that TiO ₂ NPs significantly decreased levels of cardiolipins, an important class of mitochondrial phospholipids for maintaining proper function of electron transport chains. Furthermore, TiO ₂ NP exposure activates inflammatory responses by increasing mRNA levels of TNF-α, iNOS, and COX-2. Consistently, our targeted metabolomic analysis showed significantly increased production of COX-2 metabolites including PGD ₂ , PGE ₂ , and 15d-PGJ ₂ . In addition, TiO ₂ NP also caused significant attenuation of phagocytotic function of macrophages. In summary, our studies utilizing multiple powerful omic techniques suggest that human exposure of TiO ₂ NPs may have profound impact on macrophage function through activating inflammatory responses and causing mitochondrial dysfunction without physical presence in mitochondria.
(Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)