Direct Dna Damage - Knowledge and References | Taylor & Francis (2024)

Introduction to Toxicology

David Woolley, Adam Woolley in Practical Toxicology, 2017

One of the most important questions to consider is, at what point should findings in toxicological experiments alert us to hazards arising from routine exposure to individual chemicals? To answer this requires that the toxicological hazard is actually due to the chemical under study coupled with confirmation that the mechanism of toxicity is relevant to humans. For some rodent carcinogens, this question is easy to answer. Where there is a direct effect on DNA that can lead to cancer, often at low doses, as for aflatoxin, there is a clear human-relevant hazard. Where the mechanism of carcinogenicity is not related to direct DNA damage but to a nongenotoxic effect, the answer is less clear. However, this cozy distinction between genotoxic and nongenotoxic has been thrown into doubt by the realization that epigenetic change (such as changes in DNA methylation or histone changes) can lead to heritable genomic change.

Use of Spheroids in Hyperthermia Research

Rolf Bjerkvig in Spheroid Culture in Cancer Research, 2017

The cytotoxic effect of hyperthermia is probably caused by several mechanisms.3 The activation energy of hyperthermic cytotoxicity, analyzed by Arrhenius plots, is in the same range as that described for denaturation of proteins.4 Changes in protein structure will affect a large number of cellular functions, causing altered transport of ions and signal substances as well as modification of receptor functions.5 There are also reports indicating direct DNA damage probably caused by increased amounts of nuclear proteins and impaired DNA repair.3,6 The cell membrane structure may also be a target for hyperthermia, leading to alterations of endoplasmatic reticulum and destabilization of lysosomal membranes.7 Hyperthermia may also increase the speed of chemical reactions and thereby deplete the cellular energy reservoirs, resulting in activation of anaerobic glycolysis and reduced intracellular pH. The speed of chemical reactions with increased activation and decomposition of drugs, as well as reduced pH, are of interest when combining hyperthermia and cytotoxic drugs.6

Toxicogenomics in Toxicologic Pathology

Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard in Toxicologic Pathology, 2018

Genotoxic mechanisms of direct DNA damage are a hallmark of carcinogenesis. Prediction of carcinogenicity of compounds in vitro, using standard genotoxicity assays, is the current standard by which prediction of genotoxic mechanisms is measured. However, current assays that are used to detect genotoxicity are somewhat imprecise, have low specificity, and are generally insufficient to model the complex disease of cancer, and can often over-predict carcinogenesis, leading to false-positive results (Ellinger-Ziegelbauer et al. 2008, 2009; Kirkland et al. 2005; Kirkland et al. 2006; Ward 2007). In addition, over ½ of chemically induced tumors are caused by non-genotoxic compounds, which are difficult to predict in short-term assays (Nie et al. 2006). Furthermore, non-genotoxic compounds may induce a genotoxic response in vitro using current genotoxicity assays, due to secondary mechanisms of DNA damage, as discussed previously. This makes interpretation of genotoxicity data for non-genotoxic compounds confusing and difficult in terms of human risk assessment. In fact, the ability to predict carcinogenicity in humans as a result of these assays has been questioned (Ellinger-Ziegelbauer et al. 2009; Kirkland et al. 2006; Waters et al. 2010). Additionally, since non-genotoxic mechanisms may be dictated or influenced by a dose response and be subject to a no adverse effect level (NOAEL), both the assessment of mechanism as well as prediction of carcinogenesis based on dose response, are important for non-genotoxic compounds relative to risk assessment.

Assessment of DNA damages in lymphocytes of agricultural workers exposed to pesticides by comet assay in a cross-sectional study

Published in Biomarkers, 2018

Graziana Intranuovo, Nunzia Schiavulli, Domenica Cavone, Francesco Birtolo, Pierluigi Cocco, Luigi Vimercati, Linda Macinagrossa, Annamaria Giordano, Tommasina Perrone, Giuseppe Ingravallo, Patrizio Mazza, Michela Strusi, Caterina Spinosa, Giorgina Specchia, Giovanni M. Ferri

Direct DNA damage of single-stranded DNA or DNA strand breaks can be caused by chemical agents or their metabolites (Sies 1985, Barnett and Barnett 1998, Van Gent etal.2001, Jackson 2002, Krejci etal.2003), the processes of DNA excision, replication and recombination or by apoptosis processes (Eastman and Barry 1992) or the interaction of reactive oxygen species (ROS) with DNA (Møller and Wallin 1998). The comet assay, or single cell gel electrophoresis (SCGE), is a genotoxicity test that exploits the ability of DNA to migrate when immersed in an electric field (Lindahl and Andersson 1972), allowing it to cumulatively evaluate both DNA damage and alkaline-labile sites in any type of eukaryotic cell; alkaline labile sites exhibit alkylation of phosphate and are susceptible to filament rupture related to pH and alkaline exposure (Azqueta etal.2014). This simple economical technique has been used for several years in various applications, such as for in vitro and in vivo tests of the potential genotoxicity of substances and preparations, biomonitoring of human exposure to mutagenic agents (Anderson etal.2013), or evaluations of the efficacy of DNA repair systems (Rojas etal.1999, Collins 2004). The combination of the standard comet assay with enzymes that recognize oxidized nucleotides and cut the DNA backbone have made this technique a valuable means to study oxidative damage of DNA (Collins 2014a).

Genotoxicity induced by metal oxide nanoparticles: a weight of evidence study and effect of particle surface and electronic properties

Published in Nanotoxicology, 2018

Azadi Golbamaki, Nazanin Golbamaki, Natalia Sizochenko, Bakhtiyor Rasulev, Jerzy Leszczynski, Emilio Benfenati

Although the mechanisms of nanoparticles genotoxicity are still not fully discovered, but direct DNA damage and oxidative stress are considered important (Magdolenova etal. 2014; Singh etal. 2009). Direct DNA damage mechanism is assumed to be more nano-specific, because small nanoparticles may reach the nucleus through the nuclear pore complexes (Nabiev etal. 2007). However, the observation of larger nanoparticles in the nucleus hints that larger nanoparticles may get access to the DNA in dividing cells during the nuclear membrane dissemblance (Karlsson etal. 2014). Oxidative stress is induced by overproduction of ROS, resulting in the loss of normal physiological redox-regulated functions in the cells. This triggers DNA damage, unregulated cell signaling, change in cell motility, cytotoxicity, apoptosis, and cancer initiation (Fu etal. 2014). The relationship between DNA adducts and oxidation-induced DNA fragmentation and exposure to metal oxide nanoparticles is confirmed in numerous studies (Lin etal. 2009; Karlsson etal. 2008; Bhattacharya etal. 2009; Falck etal. 2009; Rahman etal. 2002). Huang, Wu, and Aronstam (2010) reported a detailed description of the genotoxic mechanisms of action of metal oxide nanoparticles. Our model indirectly represents DNA damage via metal-mediated (COSMO-SA and HF descriptors) and indirect ROS-induced (HF descriptor) mechanisms (Angelé-Martínez, Goodman, and Brumaghim 2014; Puzyn etal. 2011).

Biological outcomes of γ-radiation induced DNA damages in breast and lung cancer cells pretreated with free radical scavengers

Published in International Journal of Radiation Biology, 2019

Vladana D. Petković, Otilija D. Keta, Marija Z. Vidosavljević, Sebastien Incerti, Aleksandra M. Ristić Fira, Ivan M. Petrović

In this work we aim to establish a system which would as close as possible reflect early irradiation events to be simulated with Geant4-DNA tool. If we consider that early irradiation events correspond to direct DNA damage caused by physical interactions between irradiation and DNA molecule (Meylan etal. 2017), indirect effects arising from free radical DNA damage should be minimized. For this purpose, we employed glycerol and DMSO as free radical scavengers. As a model system, we used two cancer cell lines originating from breast and lung tumors. These cell lines were chosen due to the current therapeutic interest for these types of malignancies. Lung and breast tumors are among the leading causes of death globally (Park etal. 2010; Howell etal. 2014), and improving treatment planning for these types of tumors is important both in conventional radiotherapy, as well as in hadron therapy. The cells were irradiated with low LET γ-irradiations, and the impact of direct radiation effects is estimated by assessing various biological endpoints, such as cell viability-survival, cell cycle distribution and cellular mechanisms related to DNA DSB generation and repair. These findings, being the starting point of our study, would serve as the reference for comparing with the direct effects produced by high LET radiations, i.e. protons and carbon ions, and corresponding numerical simulations.

Direct Dna Damage - Knowledge and References | Taylor & Francis (2024)
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