Journal
ACS NANO
Volume 2, Issue 10, Pages 2121-2134Publisher
AMER CHEMICAL SOC
DOI: 10.1021/nn800511k
Keywords
nanotoxicology; nanoparticle; reactive oxygen species; oxidative stress; dissolution; nanobiointerface
Categories
Funding
- NSF
- U.S. Public Health Service [U19 A1070453, RO1 ES10553, RO1 ES015498]
- U.S. EPA STAR award [RD-83241301]
- Southern California Particle Center
- UC TSRTP
- Deutsche Forschungsgemeinschaft DFG [MA3333/1-1]
- AFSOR [F49620-03-1-0365]
- NIH [GM066466]
- NSF [CHE0507929]
- DOE BES [DE-AC0205CH 11231]
- Direct For Biological Sciences [0830117] Funding Source: National Science Foundation
- Div Of Biological Infrastructure [0830117] Funding Source: National Science Foundation
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Nanomaterials (NM) exhibit novel physicochemical properties that determine their interaction with biological substrates and processes. Three metal oxide nanoparticles that are currently being produced in high tonnage, TiO2 ZnO, and CeO2 were synthesized by flame spray pyrolysis process and compared in a mechanistic study to elucidate the physicochemical characteristics that determine cellular uptake, subcellular localization, and toxic effects based on a test paradigm that was originally developed for oxidative stress and cytotoxicity in RAW 264.7 and BEAS-2B cell lines. ZnO induced toxicity in both cells, leading to the generation of reactive oxygen species (ROS), oxidant injury, excitation of inflammation, and cell death. Using ICP-MS and fluorescent-labeled ZnO, it is found that ZnO dissolution could happen in culture medium and endosomes. Nondissolved ZnO nanoparticles enter caveolae in BEAS-2B but enter lysosomes in RAW 264.7 cells in which smaller particle remnants dissolve. In contrast, fluorescent-labeled CeO2 nanoparticles were taken up intact into caveolin-1 and LAMP-1 positive endosomal compartments, respectively, in BEAS-2B and RAW 264.7 cells, without inflammation or cytotoxicity. Instead, CeO2 suppressed ROS production and induced cellular resistance to an exogenous source of oxidative stress. Fluorescent-labeled TiO2 was processed by the same uptake pathways as CeO2 but did not elicit any adverse or protective effects. These results demonstrate that metal oxide nanoparticles induce a range of biological responses that vary from cytotoxic to cytoprotective and can only be properly understood by using a tiered test strategy such as we developed for oxidative stress and adapted to study other aspects of nanoparticle toxicity.
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