Date of Award

8-19-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Applied Science

First Advisor

John Bush

Abstract

Zinc oxide nanoparticles (ZnO NPs) are very versatile due to their multifunctional properties including unique physicochemical and antimicrobial characteristics. They are widely utilized across various fields such as biomedical, industrial fields, environmental remediation, and agriculture. Therefore, their cytotoxic effects on biological systems necessitate a deeper understanding of the cellular responses to nanoparticle exposure. This project primarily investigates the impact of ZnO NPs on the model organism Dictyostelium discoideum AX4 (social amoeba) which has not been examined before unlike a vast variety of organisms in the literature. The cytotoxic effects of ZnO NPs on Dictyostelium discoideum AX4 cells are compared with several mammalian cell lines including MC3T3, MCF-7, Hek293, and HeLa, with a particular focus on HeLa cell line as it is very well studied. Remarkably, D. discoideum AX4 cells exhibited high resistance to ZnO NP-induced cytotoxicity. They could maintain cell viability even at concentrations of up to 500 µg/ml of ZnO NPs. This is in stark contrast to the significant cytotoxicity observed in mammalian cell lines. Furthermore, proteomic profiling by LCMS/MS revealed distinct differential protein expression and pathway activation between D. discoideum AX4 and HeLa cells upon exposure to ZnO NPs. In D. discoideum AX4 cells, it was observed that some of the statistically significantly upregulated proteins were involved in vesicle transport, morphogenesis, and translation. This suggests enhanced cellular functionality and resilience. Conversely, HeLa cells primarily upregulated stress response and injury repair proteins statistically significantly, highlighting a less effective cytoprotective response. Additionally, this study found that the intrinsic cellular oxidative stress levels were lower in ZnO NP-treated D. discoideum AX4 cells than their untreated counterparts. This indicated increased detoxification of reactive oxygen species (ROS) pathways playing a crucial role which was verified through proteomic analysis as well. These findings underscore the potential of D. discoideum as a model organism for studying nanoparticle-cell interactions, cellular defense strategies, and death-resistant cancer cells. This research provides significant insights into the molecular basis of nanoparticle resistance, with implications for developing nanoparticle-based therapies and enhancing our understanding on the cell death modalities.

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