Date of Award

1-1-2017

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Biomedical Sciences

Content Description

1 online resource (ii, xiv, 123 pages) : illustrations (some color)

Dissertation/Thesis Chair

Ramune Reliene

Committee Members

Martin Tenniswood, JoEllen Welsh, Jason Herschkowitz, Andre Melendez, Ramune Reliene

Keywords

breast cancer, chemoprevention, genotoxicity, pomegranate extract, Silver nanoparticles, Silver, Pomegranate, Cancer, Breast

Subject Categories

Cell Biology | Nutrition | Toxicology

Abstract

The use of silver nanoparticles (AgNPs) in a wide variety of consumer products (i.e. toothpastes, food containers, dietary supplements and garments) for their antimicrobial properties can lead to potential oral exposure in humans. To enhance their stability, AgNPs are coated with capping agents such as citrate and polyvinylpyrrolidone (PVP). Despite the lack of significant general toxicity based on hematology, blood chemistry and histology evaluations, the potential genotoxic effects of AgNPs cannot be ruled out and have to be addressed. Studies examining the genotoxic risks of AgNPs are needed because genotoxicity is a strong indicator of cancer risk. Here we examined whether ingestion of AgNPs or silver ions (Ag+) can result in genotoxic damage and whether AgNP coatings modulate the effect. The effect of Ag+ was examined in this study because AgNPs are known to shed Ag+, which are thought to be responsible for the toxicity of AgNPs. Mice were orally exposed to 20 nm citrate-coated AgNPs, PVP-coated AgNPs, silver acetate (a source of Ag+) or respective vehicles at a 4 mg/kg dose for 7 days. Genotoxicity was examined in the systemic circulation and bone marrow at 1, 7, and 14 days post-exposure. We found that citrate-coated AgNPs induced chromosomal damage in bone marrow and oxidative DNA damage and double strand breaks (DSBs) in peripheral blood. These damages persisted for at least 14 days after exposure termination. Because oxidative DNA damage and strand breaks are repaired rapidly, their presence after exposure cessation indicates that citrate-coated AgNPs persist in the body. In contrast, PVP-coated AgNPs and silver acetate did not induce DNA or chromosomal damage at any time point measured. To determine whether coating-dependent genotoxicity is related to different AgNP changes in the gastrointestinal tract, we examined AgNP behavior and fate in an in vitro gastrointestinal digestion model using UV-visible (UV- vis) spectroscopy and dynamic light scattering (DLS). Citrate-coated AgNPs were more susceptible to agglomeration than PVP-coated AgNPs in digestive juices with or without proteins. In summary, AgNPs but not Ag+ are genotoxic following oral ingestion. Nanoparticle coatings modulate gastrointestinal transformation and genotoxicity of AgNPs, where higher agglomeration of AgNPs in gastrointestinal juices is associated with higher genotoxicity in the tissues.

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