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The effects of ultra-small TiO2 nanoparticle and single walled carbon nanotubes on endothelial cells: next generation sequencing and transcriptome sequencing (RNA-seq) analysis
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0002-1986-2845
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The cardiovascular system is a key route of exposure to nanoparticles (NPs). The exposure could costendothelial cell dysfunction and impairment in blood circulation that could lead to cardiovascular diseasessuch as atherosclerosis. Currently, ultra-small nanoparticles (USNPs) at 1-3 nm, are receiving growingattention due to their unique properties. Emerging application for rutile TiO2-USNPs in medicine areexploring due to their insoluble nature, lack of oxidative activity and strong luminescence not observed inlarger NPs. On organic nanoparticle side, single walled carbon nanotubes (SWCNTs) are candidatemolecules for drug delivery from the chemical perspective. However their potential applications arehindered by their high oxidative activity and potential toxicity. Here we used transcriptome sequencing(RNA-seq) to evaluate the effects of exposure to sub-lethal concentration of TiO2-USNPs, TiO2-NPs andSWCNTs on human dermal microvascular endothelial cells. Specific toxicological effects were inferredfrom the functions of genes whose transcripts either increased or decreased. Our results show that TiO2-USNPs mostly induced the up-regulation of transcripts involved in lipid and cholesterol metabolism.TiO2-NPs induced the highest number of differentially expressed transcripts involved in cellularsenescence, endoplasmic reticulum (ER) stress, and heat shock responses as well lipid metabolism.Finally, SWCNTs affected to those genes involved in early stress and inflammatory responses.

Keyword [en]
Nanoparticles, ultra-small nanoparticles, RNA, endothelial cells, toxicity, lipid metabolism
National Category
Biochemistry and Molecular Biology Cell Biology
Research subject
URN: urn:nbn:se:su:diva-117025OAI: diva2:809747
Available from: 2015-05-05 Created: 2015-05-05 Last updated: 2016-01-29Bibliographically approved
In thesis
1. Toxicity and biological impact of metal and metal oxide nanoparticles: Focus on the vascular toxicity of ultra-small titanium dioxide nanoparticles
Open this publication in new window or tab >>Toxicity and biological impact of metal and metal oxide nanoparticles: Focus on the vascular toxicity of ultra-small titanium dioxide nanoparticles
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The application of nanoparticles (NPs) in different technologies has led to tremendous advancement in those fields.  Moreover, there is growing interest in application of ultra-small NPs (USNPs) at 1-3 nm due to their distinct molecule like features. Parallel to these promises, there is a growing concern regarding their safety. The main goal of this thesis was to investigate the toxicity and underlying mechanisms following exposure to different metal and metal oxide NPs as well as USNPs. Their effects were studied on Saccharomyces cerevisiae, on hepatocytes and endothelial cells and finally in vivo on zebrafish embryos (Danio rerio). By selecting the rutile form of titanium dioxide (TiO2-USNPs) without intrinsic or intracellular reactive oxygen species (ROS) production, we could study biological impacts solely due to size and direct interaction with the cells. We showed that TiO2-USNPs were not cytotoxic but induced DNA damage. They had anti-angiogenic effects both in vitro and in vivo. Also, at high concentrations they caused complete mortality in zebrafish embryos exposed in water, while at lower concentrations induced delay in hatching. When injected they caused malformations. They specifically induced the differential overexpression of transcripts involved in lipid and cholesterol metabolism in endothelial cells. In hepatocytes they induced the overexpression of proteins in the electron transport chain and decreased lipids in lipid rafts. At 30 nm, TiO2-NPs, were also not cytotoxic but were genotoxic. They had no effects in vivo or on angiogenesis. However, they induced differential expression of transcripts involved in endoplasmic reticulum (ER) stress and heat shock response as well as cholesterol metabolism. This suggests a more toxic response in the cells compared to TiO2-USNPs.  Single walled carbon nanotubes (SWCNTs) despite having the highest oxidative activity among the NPs studied, were not severely cyto- or genotoxic but induced expression of transcripts involved in early ER stress response. Copper oxide (CuO-NPs) was the most toxic NPs studied due to both ion release and ROS production, affecting lipid metabolism of the cells. Silver (Ag-NPs) were also cytotoxic and caused the disruption of cellular components and lipids. ZnO-NPs were not cytotoxic, did not affect cellular lipids but they increased the size of vacuoles in yeast cells. Finally by using superparamagnetic iron oxide NPs (SPIONs) with different coatings, and using a mathematical model, a nano impact index (INI) was developed as a tool to enable the comparison of nanotoxicology data.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2015. 78 p.
Nanoparticles, Nanotoxicology, Ultra-small nanoparticles
National Category
Biochemistry and Molecular Biology
Research subject
urn:nbn:se:su:diva-116708 (URN)978-91-7649-193-5 (ISBN)
Public defence
2015-06-02, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (Swedish)

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Accepted. Paper 3: Manuscript. Paper 4: Manuscript. Paper 5: Manuscript.

Available from: 2015-05-11 Created: 2015-04-23 Last updated: 2015-05-12Bibliographically approved

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Bayat, Narges
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