Year of Award

2020

Document Type

Dissertation - Campus Access Only

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Toxicology

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Andrij Holian

Commitee Members

Elizabeth Putnam, Christopher T. Migliaccio, Yoon Hee Cho, J.B. Alexander (Sandy) Ross

Publisher

University of Montana

Abstract

Nanomaterials (NP) are increasingly used in a variety of industrial processes and consumer products. Among them, titanium dioxide (TiO2), zinc oxide (ZnO), and cerium oxide (CeO2) have the second, third, and sixth highest global production rates with extensive applications in consumer products. While it is assumed that current use of various NP is safe, an uncertainty about off-target effects in modern applications and emerging properties of these materials create concern about their safety. Several studies have shown that some NP can cause respiratory toxicity leading to lung inflammation. Furthermore, a crucial role of lysosomal membrane permeabilization (LMP) in initiation of NP-induced inflammatory responses has been recognized; however, the mechanism of LMP is still unclear. This study was designed to evaluate the contribution of membrane potential alterations to LMP. The studies were aimed to determine whether NP-induced membrane permeability was a possible mechanism of NP-induced toxicity. The studies also aimed to identify whether ZnO toxicity was correlated with the release of Zn2+ or whether it was attributable to intact ZnO. Furthermore, the contribution of lysosomal membrane potential alterations to membrane damage was investigated. For this purpose, a rapid noninvasive method for measuring lysosomal membrane potential was developed. Using this technique, for the first time, it was demonstrated that ZnO increased lysosomal cation (most likely potassium) uptake, leading to lysosomal membrane hyperpolarization. Further, the results suggested that threshold changes in lysosomal membrane hyperpolarization without repolarization may account for LMP. Finally, additional studies were conducted to determine the contribution of plasma membrane potential alterations to membrane permeabilization, which might simulate events leading to LMP. The toxic effects of NP and induction of plasma membrane permeabilization were shown to be correlated to plasma membrane depolarization. NP appeared to interfere with potassium flux in the plasma membrane. However, the causal relation between potassium flux and plasma membrane depolarization or membrane damage remains to be determined. Together, the findings presented here described a novel mechanism for lysosomal membrane-NP interactions.

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© Copyright 2020 Tahereh Ziglari