A nanotoxicology investigation: exploring the impacts of silver and gold nanoparticles size on cell signalling pathways in lung cell lines

Bafhaid, Hanouf (2021). A nanotoxicology investigation: exploring the impacts of silver and gold nanoparticles size on cell signalling pathways in lung cell lines. University of Birmingham. Ph.D.

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Metal-containing nanoparticles (NPs), including silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs) have shown great promise in several biomedical applications. It is of importance to predict their potential adverse effects upon their cellular exposure. In this study, we hypothesise that cellular exposure to different NPs chemical compositions (AgNPs and AuNPs) with various NPs sizes (10, 40 and 80 nm) can mediate distinct biological responses in 2D and 3D cell culture models of human lung cells. The overarching aims of this study were to assess the toxicity of AgNPs and AuNPs of different sizes in normal human lung fibroblast cells (MRC-5) and human lung adenocarcinoma epithelial cells (A549) and investigate the influence of both NPs on the PI3K/AKT and Wnt/β-catenin signalling pathways. Cell viability data demonstrated the high biocompatibility of AuNPs compared to AgNPs on both cell lines. In addition, AgNPs elicited size-, concentration- and time-dependent toxicity in both lung cells. Similar responses were observed in A549 exposed to AuNPs but not MRC-5 treated with AuNPs, which illustrates high sensitivity to large sized AuNPs (80 nm). AgNPs, compared to AuNPs, induced significant oxidative stress via the overproduction of reactive oxygen species and depletion of intracellular glutathione levels. Both AgNPs and AuNPs provoked G2/M phase cell cycle arrest and mitochondrial-dysfunction mediated apoptosis in both cell lines. The A549 3D spheroidal model demonstrated lower sensitivity upon exposure to both types of NPs compared to the 2D monolayer model, but presented size-dependent toxicity when exposed to AgNPs. It was revealed that both AgNPs and AuNPs may trigger apoptosis via attenuation of the PI3K/AKT pathway activity and suppression of cell proliferation and cell cycle progression via dysregulation of Wnt/β-catenin signalling activity. Overall, this work shows the influential effects of NPs composition and size on cellular toxicity and could propose a potential use of AgNPs and AuNPs as therapeutic targets in the PI3K/AKT and Wnt/β-catenin cell signalling pathways.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
Licence: All rights reserved
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: School of Pharmacy
Funders: Other
Other Funders: Saudi ministry of higher education
Subjects: Q Science > QH Natural history > QH301 Biology
R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
URI: http://etheses.bham.ac.uk/id/eprint/11567


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