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Carcinogenic and Mutagenic Substances
Published in Małgorzata Pośniak, Emerging Chemical Risks in the Work Environment, 2020
The first stage, initiation, takes place quickly and seems to be irreversible. The available data indicates that initiation usually results from one or more mutations of cellular DNA. The main reason for these mutations is covalent reactions of electrophilic derivatives of carcinogenic factors with the DNA. Factors causing DNA damage have the capacity for causing permanent genetic disruption and contribute to an increase in the frequency of changes in the genome. DNA damage can cause genotoxic and cytotoxic effects in the cells. Genotoxic activity is the ability to cause changes in the DNA – directly or through a particular compound or its active metabolite. Genotoxic activity can encompass changes at the level of a single gene, a chromosome, or the entire genome. The disruption or inhibition of the replication process and DNA transcription results from the cytotoxicity of a given compound and can lead to apoptosis (death) of a cell. The most common kinds of DNA damage, caused by mutagenic factors, are the loss of a nitrogen base, intercalation of the agent between base pairs, modification of nitrogen bases through hydrolysis, alkylation, and oxidation. Mutagens can cause the formation of crosslinks inside and between DNA strands, as well as causing photodamage and single- or double-strand DNA breakage [Mol and Stolarek 2011].
In Vitro Testing
Published in Julián Blasco, Ilaria Corsi, Ecotoxicology of Nanoparticles in Aquatic Systems, 2019
Alberto Katsumiti, Miren P. Cajaraville
Many in vitro studies have shown that exposure to NPs elevates cellular oxidative stress (Limbach et al. 2007, Fahmy and Cormier 2009, Canesi et al. 2010, Ciacci et al. 2012, Christen and Fent 2012, Christen et al. 2013, Fernández-Cruz et al. 2013, Song et al. 2014, Lammel and Navas 2014, Taju et al. 2014, Drasler et al. 2017, Akter et al. 2018). To cope with elevated ROS levels, cells display various protective responses, including activation of enzymatic and non-enzymatic antioxidant defence mechanisms. Catalase, besides other antioxidant enzymes such as glutathione peroxidase and superoxide dismutase, and phase II biotransformation enzymes, plays essential roles in returning cells to a normal redox state (Sheehan 2000). When oxidative stress overwhelms defence mechanisms, cellular macromolecules such as proteins, lipids and DNA are subject to damage. DNA damage includes chromosome deletions, mutations and single- and double-strand breakages. In mussels, several studies have confirmed the formation of DNA adducts and oxidation-induced DNA fragmentation following exposure to metal-bearing NPs such as CuO and Ag NPs (Gomes et al. 2013a, Ruiz et al. 2015, Munari et al. 2014, Chelomin et al. 2017, Mahaye et al. 2017). In response to DNA damage, cells trigger mechanisms to repair the damaged DNA. In the case of severe damage to DNA, cells may die by either necrosis or apoptosis.
Mammography, Breast Tomosynthesis, and Risk of Radiation-Induced Breast Cancer
Published in Paolo Russo, Handbook of X-ray Imaging, 2017
Generally, normal cellular repair mechanisms can repair DNA damage. These mechanisms deal with the inherent instability of the DNA molecule. In a typical cell, DNA may undergo several thousand damage events per day, which generally corrected by DNA repair mechanisms (BEIR, National Research Council 2006, pp. 30, 33–39) (Saul and Ames 1986). However, an ionizing radiation event may cause many localized simultaneous breaks and, if there are enough events, the repair mechanisms may fail to correct the damage. If the radiation dose is high enough in the cell, the DNA damage may be so severe that it causes the cell to die. However, at sub-lethal doses, the DNA may be incorrectly repaired, resulting in a cell transformation. A transformed cell with a mutation in a tumor suppressor gene or a proto-oncogene will pass this on to progeny cells, and may ultimately lead to malignancy.
Licochalcone A, a licorice flavonoid: antioxidant, cytotoxic, genotoxic, and chemopreventive potential
Published in Journal of Toxicology and Environmental Health, Part A, 2020
Karoline Soares de Freitas, Iara Silva Squarisi, Nathália Oliveira Acésio, Heloiza Diniz Nicolella, Saulo Duarte Ozelin, Matheus Reis Santos de Melo, Ana Paula Prado Guissone, Gabriela Fernandes, Lívia Mara Silva, Ademar Alves da Silva Filho, Denise Crispim Tavares
The results obtained by the in vitro MN test also showed that LicoA diminished the damage initiated by MMS. This SN2 alkylating agent exhibits high affinity for nitrogen in purines, resulting in N-alkylation. The methylation process mediated by MMS leads to formation of adducts such as N7- and N3-methyladenine, which induce double-strand breaks or inhibit DNA replication. If not repaired, these events are responsible for mutagenic consequences (Kaina 2004; Wyatt and Pittman 2006). DNA damage mediated by these agents is mainly repaired by base excision repair, with the participation of glycosylases. The N7- and N3-methyladenine adducts are repaired by DNA glycosylase (Baute and Depicker 2008; Sedgwick 2004). LicoA exhibited antimutagenic activity against the direct-acting alkylating agent N-methyl-N-nitrosourea as demonstrated by the Ames test (Inami et al. 2017).
An in vivo study of nanorod, nanosphere, and nanowire forms of titanium dioxide using Drosophila melanogaster: toxicity, cellular uptake, oxidative stress, and DNA damage
Published in Journal of Toxicology and Environmental Health, Part A, 2020
To address the potential genotoxic effects of TiO2 (NRs, NSs, or NWs) and TiO2 in D. melanogaster a well-known genotoxicity assay was used. The Comet assay detects primary DNA damage, mainly single and double DNA-strand breaks. The Comet assay for hemocytes treated with TiO2 (NRs, NSs, or NWs) and TiO2 showed significant concentration-dependent increases in % DNA-strand breaks in comparison with negative control (distilled water). In addition, Comet assay findings noted that titanium, regardless of its form, either particles or ions, failed to markedly affect levels of DNA damage in hemocytes of Drosophila larvae (Figure 7). The highest levels of DNA damage appeared at exposure to 10 mM TiO2 (NRs, NSs, or NWs), which suggests that the nanosized form appears to be more genotoxic than the ionic one. The relative genotoxic potencies according to the observed DNA damage at the highest concentrations are as follows: NWs (32% of DNA tail), NSs (30% of DNA tail), and NRs (27% of DNA tail) (Figure 7). Evidence indicates that shape may be associated with adverse effects.
Antimicrobial and antileukemic effects: in vitro activity of Calyptranthes grandifolia aqueous leaf extract
Published in Journal of Toxicology and Environmental Health, Part A, 2020
Fernanda Majolo, Shanna Bitencourt, Bruna Wissmann Monteiro, Gabriela Viegas Haute, Celso Alves, Joana Silva, Susete Pinteus, Roberto Christ Vianna Santos, Heron Fernandes Vieira Torquato, Edgar Julian Paredes-Gamero, Jarbas Rodrigues Oliveira, Claucia Fernanda Volken De Souza, Rui Felipe Pinto Pedrosa, Stefan Laufer, Márcia Inês Goettert
Normally, the results obtained from the comet assay indicate early or immediate DNA responses and are essential for safety and efficacy evaluation of the compounds present in medicinal plants (Araldi et al. 2015). DNA damage may be transient and prone to repair (Avishai, Rabinowitz, and Rinkevich 2003; Kich et al. 2017). The comet assay was performed under alkaline conditions as previously described (Singh et al. 1988). Briefly, RAW 264.7 cells were plated (2 x 104 cells/ml) in a 12-well microplate and challenged with increasing concentrations (25, 50, 100, and 200 μg/ml) of C. grandifolia extract for 3 hr. Ethyl methanesulfonate (EMS) was used as a positive control. Samples were analyzed at 400x magnification under a light microscope. DNA damage in the cells was assessed by quantification of the amount of DNA released from the core of the nucleus. Extension and distribution of DNA damage were evaluated by analysis of 100 cells/sample randomly selected and non-overlapping. Comets were visually scored into five classes according to tail length: (Class 0) undamaged, without a tail; (Class 1) short tail, smaller than the diameter of the head (nucleus); (Class 2) medium tail, up to twice the diameter of the head; (Class 3) long tail, more than twice the diameter of the head; (Class 4) very wide tail, comet without head, maximum DNA damage. The damage to DNA was presented as DNA damage index (DI) and calculated as follows: DI = n1 + 2n2 + 3n3 + 4n4; where n1-n4 represents the number of cells with level 1–4 of damage.