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Dissertation
ZnO nanoparticle immunotoxicity
Doctor of Philosophy (Ph.D.), Drexel University
Dec 2013
DOI:
https://doi.org/10.17918/etd-4373
Abstract
The advent of nanotechnology has revolutionized many commercial and industrial fields. Mass production of these materials warrants concerns of incidental exposure to environmental and human health alike. Zinc oxide nanoparticles (ZnO NPs) are one of the most highly produced nanoparticles and have been determined to be toxic to many cell types in vitro. The mechanism responsible for the cell death they induce and their effect on functional immunity however is largely unknown. Our preliminary findings show that ZnO NPs have a cytotoxic effect on immune cells in in vitro cultures, implicating immunotoxic potential. In this thesis, we determine the effect, and extent of the immunocompromising effect through a systematic approach. We formulate consistent ZnO NPs and characterize their capacity for inducing toxicity and elucidating the mechanism. Using a modified FluoZin-3 assay, we determine that high concentrations of zinc ions release from the surface of ZnO NPs and Zn²⁺ can directly induce cell death and this is Reactive Oxygen Species (ROS) dependent. We find that EDTA and Ca ions effectively prevent ZnO NPs from inducing death of the immune cells while glutathione (GSH) protects the cell downstream. Finally, the autophagy inhibitor 3-MA eliminates ZnO NP death at the level of cell signaling. The mode of cell death induced by ZnO NPs was found to be autophagy-related and not apoptosis, necrosis, pyroptosis, or necroptosis. Importantly, ROS were required for ZnO NP induction of autophagy. Our in vivo studies indicate ZnO NPs cause morbidity and deplete immune cell populations in the spleens of mice. Chronic exposure on the other hand, allows the mice to develop ZnO NP tolerance. Mice exhibited normal viral clearance, however distinct changes in the immune response were observed. We conclude that zinc ion release is the primary mediators of ZnO NP induced death of immune cells, initiating excessive ROS production which in turn induce autophagic death. The effect of this in vivo exposure is a much more complex, and appears to be finely balanced between detrimental and possibly beneficial to immunity due to increased inflammation.
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Details
- Title
- ZnO nanoparticle immunotoxicity
- Creators
- Brandon Mark Johnson - DU
- Contributors
- Peter D. Katsikis (Advisor) - Drexel University (1970-)Margaret A. Wheatley (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems (1997-2026); Drexel University
- Other Identifier
- 4373; 991014632300104721