@phdthesis{May2018effec-44763,
  year={2018},
  title={The effect of different engineered nanomaterials (ENMs) on DNA damage and repair pathways},
  author={May, Sarah},
  address={Konstanz},
  school={Universität Konstanz}
}

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    <dc:contributor>May, Sarah</dc:contributor>
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    <dcterms:abstract xml:lang="eng">Engineered nanomaterials (ENMs) possess unique biological, physical and chemical properties due to their small size and high surface-area-to-volume-ratio. This makes these novel nano-sized materials particularly interesting for a very broad range of applications. Thus, the field of nanotechnology has undergone an enormous development in the last decades. However, the tremendous increase in production and utilization of various ENMs in consumer products and biomedical applications has led to growing concerns on potential unfavorable effects of ENM exposure to humans and the environment. While some studies demonstrated the absence of any ENM-dependent effects, adverse effects ascribed to the presence of ENMs have been reported for microorganisms, animals and human cells. Due to the enormous spectra of materials with diverse physico-chemical characteristics, the complexity of environmental and biological systems and the poor comparability of performed in vitro and in vivo studies, interpretation and generalization of these data remain a challenge. Nevertheless, for regulatory purposes, to prevent potential harm arising from future ENM application, but also to profit from the beneficial properties of ENM e.g. in prospective applications in clinical settings, detailed information on potential nanotoxicity is required. Since damage to the genetic material can lead to induction or promotion of carcinogenesis the DNA damaging potential of ENMs is of particular importance. Even though literature on nanomaterial genotoxicity grew over the past years, published data is still quite often inconclusive or controversial. Consequently, further clarification on potential ENM genotoxicity through reliable and robust toxicological in vitro and in vivo studies is still required. Providing this knowledge is a necessity for the future development of safe and effective nano-based biomedical applications. This thesis aims to explore and characterize the genotoxic mechanism of industrially and medically relevant ENMs and to correlate their physico-chemical properties to a biological response. For this reason, a panel of different ENMs with highly varying chemical composition, size and functionalization was chosen for an initial genotoxicity screening, which was followed by an in-depth analysis of selected ENMs. Analyzed materials include graphene oxide (GO) as novel 2D-material, two types of multi-walled carbon nanotubes (MWNTs) as fiber-like structures, spherical particles such as amine-modified positively charged polystyrene nanoparticle (PS-NP) and three gold nanoparticles (Au-NPs) with a primary core size of 2-4 nm and different surface functionalization and charge. Besides Au-NPs, also other metal-based ENMs were integrated in this study. These include one type of titanium dioxide nanoparticle (TiO2-NP), zinc oxide nanoparticle (Zn-NP), as well as six silica nanoparticles (SiO2-NPs) with varying size and porosity. Experiments were performed on the T-lymphocyte cell line Jurkat E6-I grown in suspension culture, which represents the immune barrier and the adherently growing lung epithelial cell line A549, which in the past has been frequently used for assessment of occupational ENM exposure and toxicity studies. Potential genotoxicity of these ENMs was investigated with means of the alkaline single cell gel electrophoresis (comet assay), which is considered as gold standard in genotoxicity assessment and the most frequently used method for detection of ENM genotoxicity. It enables detection of DNA strand breaks, abasic and alkali-labile sites, however assay performance and analysis are quite time consuming. In contrast, the FADU (fluorimetric detection of alkaline DNA unwinding) assay as new emerging semi-automated technology for genotoxicity detection measures DNA strand breaks rapidly in a 96-well format. Both methods were employed, obtained results compared and advantages of each, also regarding potential ENM-induced interferences are discussed. In conclusion, the genotoxicity screening revealed that most analyzed ENMs were non-genotoxic. Interestingly, out of the broad variety of analyzed materials genotoxicity was only detected for soluble ZnO-NP and extremely small Au-NPs. The results on Au-NP induced genotoxicity were rather surprising, since gold has been considered an inert material and is currently being examined for diverse applications in the biomedical field. Therefore, the following detailed study focused on unravelling of Au-NP-cell interactions taking place in A549 cells and how these might contribute to the observed DNA damage induction. Investigations were performed according to the so-called ROS paradigm, which includes ENM uptake, ROS production and oxidative stress, inflammation and cell viability, as well as genotoxicity. We could demonstrate that Au-NPs are taken up by A549 cells without directly affecting cellular viability. Oxidative stress is observed; however, no inflammatory reactions are induced. Positively charged Au-NPs had the strongest capacity for DNA damage through induction of mainly alkali-labile sites. Importantly, we could show that despite massive induction of DNA damage, cells could recover and repair damaged DNA over time. Our data highlight the importance of investigating ENM-cell interactions, not only based on acute in vitro toxicity studies, but with additional focus on potential long-term effects and DNA repair processes as ENM-induced DNA damage can be of transient nature.</dcterms:abstract>
    <dcterms:issued>2018</dcterms:issued>
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    <dcterms:title>The effect of different engineered nanomaterials (ENMs) on DNA damage and repair pathways</dcterms:title>
    <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2019-01-30T06:36:47Z</dc:date>
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