Semester

Fall

Date of Graduation

2019

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

Yon Rojanasakul

Committee Co-Chair

Liying Rojanasakul

Committee Member

James M. Antonini

Committee Member

Vincent Castranova

Committee Member

Todd Stueckle

Abstract

Nanoparticles, which measure 100 nm in at least one dimension, have surged in development, production, and use for a wide range of applications. However, the rapid pace of development for these emerging materials with unclear/unknown toxicity profiles makes it difficult to adequately assess health risk associated with exposure. One critical obstacle which limits scientific research to fill these critical knowledge gaps is the lack of accurate and predictive models for nanotoxicology studies, particularly those which involve occupationally relevant exposure scenarios (pulmonary exposure to low dose of particles in the circulating air). Typically, animal models are used to assess potential systemic toxicity. However, the time, cost, and resource heavy methods are insufficient due to the sheer number of new nanoparticles being produced and used each day. Cell culture-based systems have been suggested as a more rapid alternative which could be used to predict and rank potential toxicity of such emerging materials. However, the translation of an existing in vivo study to an in vitro model requires additional parameters to be considered for experimental design, and a lack to do so may contribute to the discrepancies and lack of clarity in the existing nanoparticle toxicity literature.

The key objective for my dissertation work was to illustrate how the better integration of in vitro and in vivo may be used to evaluate potential toxicity of two nano-metal oxides with unclear toxicity profiles: iron oxide nanoparticles (IONP) and cerium oxide nanoparticles (CONP), as well as how alterations in specific physicochemical properties may contribute to severity of the pulmonary adverse outcomes they may induce.

Some studies report IONP to be biologically benign, whereas others have linked IONP exposure to cancer-related adverse outcomes, including genotoxicity, neoplastic-like cell transformation, and tumor promotion in vivo. To assess this potential toxicity, a specific IONP (nFe2O3) was evaluated in a physiologically relevant low dose/long term in vitro exposure model to identify its general toxicity and potential carcinogenic capacity, as well as how alterations in particle surface chemistry (with the addition of an amorphous silica coating) may impact overall toxicity. Results were compared to previously published in vivo data which showed nFe2O3 would promote tumor formation in mice.

CONP has a similarly unclear toxicity profile, with some studies suggesting CONP may reduce oxidative stress, whereas others show this particle to induce robust oxidative stress and inflammatory response. The chemical composition and valence state of CONP is known to be a critical component to its toxicity, and the inability to control for this in previous studies likely obscured any other physicochemical properties which may also play a role. Therefore, we evaluated size dependent toxicity of CONP using chemically identical particles, including their ability to induce inflammation, pro-fibrotic, and potential systemic toxicity within an occupationally relevant in vivo exposure model. Corresponding dose was used in an in vitro model system for a better understanding of potential mechanism underlying these outcomes, as well as to illustrate the potential use of an in vitro/in vivo integrated model system.

Overall, my dissertation study results showed that an occupationally relevant low dose/long term exposure to IONP would induce neoplastic-like cell transformation in human bronchial epithelial cells, which was dramatically reduced with the alteration of its surface chemistry with an amorphous silica coating; Alteration of CONP size affected its inflammatory and pro-fibrotic response in male C57BL/6J mice, with smaller sizes inducing a robust and sustained inflammatory response, while larger sizes induced a milder response but with increased fibrotic potential.

These results clearly show the impact of specific physicochemical properties on overall toxicity profile, as well as the importance of careful physiologically relevant model design for better in vitro to in vivo translation, with the ultimate goal of protecting those at risk of exposure to these new materials with unclear/unknown toxicity profiles.

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