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Arsenic Poisoning through Ages
Published in M. Manzurul Hassan, Arsenic in Groundwater, 2018
Epigenetic mechanisms such as altered DNA methylation have a role in arsenic toxicity and carcinogenicity. Arsenic induces cytotoxicity by generating ROS (Selvaraj et al., 2013) and arsenic results in cytotoxicity by affecting the status of tumor-suppressor protein 53 (Huang et al., 1999; Yih and Lee, 2000). The protein 53 has a role in cell cycle regulation. Inhibition of its expression by hypermethylation of its promoter region could potentially lead to the development of cancer (Hughes et al., 2011). Genotoxicity occurs since ROS reacts with both deoxyribose and bases in DNA, causing base lesions and strand breaks. ROS are involved in oxidation of DNA, alteration of DNA repair, gene regulation mechanism, and threatening of gene stability (Shankar et al., 2014). Chronic exposure of cells to an elevated level of arsenic can result in induction of SAM depletion in cells, leading to loss of DNA methylation, and subsequently DNA hypomethylation in turn affects the genomic instability (Sciandrello et al., 2004). Enzymes involved in nucleotide excision repair (NER) and base excision repair (BER) are affected by arsenic (Hartwig et al., 2003; Schoen et al., 2004; Sykora and Snow, 2008). In their research, Andrew et al. (2003) found toenail arsenic levels to be inversely correlated with the expression of three NER genes in a small group of individuals exposed to arsenic in drinking water. This result suggests that carcinogenicity of arsenic includes inhibition of DNA repair under conditions of oxidative stress, inflammation, and proliferative signaling (Druwe and Vaillancourt, 2010; Hughes et al., 2011).
Optical Methods of Single Molecule Detection and Applications in Biosensors
Published in George K. Knopf, Amarjeet S. Bassi, Smart Biosensor Technology, 2018
Anna Shahmuradyan, Ulrich J. Krull
DNA repair mechanisms are a subject of interest due to their importance in understanding mutations and cancer-causing alterations in DNA sequences. It is known that DNA repair proteins undergo conformational changes in the presence of damaged DNA. Ghoneim and Spies provided a new optical setup using dual labeling and single-molecule imaging TIRF microscopy to establish a direct and real-time correlation between protein domain motions and DNA binding (121). Their study was focused on the Xeroderma pigmentosum complementation group D (XPD), which is a DNA helicase that has an important role in nucleotide excision repair. XPD is composed of four domains, two of which are motor core domains, HD1 and HD2, and the other two are accessory domains; iron-sulfur (FeS) and ARCH domains (121). Single protein molecules were tethered to the surface of an imaging platform and the motion of the fluorescently labeled ARCH domain was monitored by following the FeS cluster-mediated quenching. The binding of the DNA substrates was also studied by observing the quenching of a fluorophore by the FeS domain. The ARCH was labeled with a Cy3 dye, whereas the DNA was labeled with a Cy5 dye. The dyes were located to prevent FRET, and a dichroic mirror as well as filters were used to avoid optical leakage between the wavelength channels. Fluctuations in the fluorescence intensity were used to characterize the association and dissociation of the DNA substrate, as well as the changes in the conformation of the ARCH associated with the open and closed states. The results revealed a kinetic enhancement in damage detection and downstream signaling caused by the DNA binding events and the conformational changes of the ARCH domain.
Approaching Cancer Therapy with Ruthenium Complexes by Their Interaction with DNA
Published in Ajay Kumar Mishra, Lallan Mishra, Ruthenium Chemistry, 2018
The activity of two Ru(II) arene complexes containing tetrahydroanthracene or p-cymene ligand has also been examined in two tumor cell lines A2780 (human ovarian cancer cell line) and HT29 (Human Colorectal Adenocarcinoma Cell Line). These complexes were chosen as representatives of two different classes of Ru(II) arene compounds for which initial studies of global modification of natural DNA was revealed (Novakova et al., 2003). They have different binding modes: one may involve DNA intercalation (tricyclic-ring Ru(II) complex containing tetra hydroanthracene ligand) and other (mono-ring Ru(II) complex containing the p-cymene ligand) cannot interact with double-helical DNA by intercalation. These ruthenium complexes are capable of non-covalent, hydrophobic interaction with DNA considerably with enhanced cytotoxicity against tumor cell lines owing to presence of arene ligand (Novakova et al., 2005). An analysis of DNA duplexes modified by mono-ring and tricyclic ring Ru(II) compounds revealed substantial differences in the impact of their monofunctional adducts on the conformation and thermodynamic stability of DNA and DNA polymerization in vitro (Novakova et al., 2005). The adducts of Ru(II) arene compounds are preferentially removed from DNA by mechanisms other than by nucleotide excision repair. This repair mechanism is believed to be the main process by which major cisplatin adducts are removed from DNA (Kartalou and Essigmann, 2001). The latter observation provides additional support for a mechanism underlying antitumor activity of Ru(II) arene compounds, different to that of cisplatin (Novakova et al., 2005). Thus, these results support the view that the different character of conformational alterations induced in DNA as a consequence of its global modification by Ru(II) arene compounds may damage DNA. Consequently, different biological effects may result in this new class of metal-based antitumor compounds (Novakova et al., 2005).
Benzo[a]pyrene osteotoxicity and the regulatory roles of genetic and epigenetic factors: A review
Published in Critical Reviews in Environmental Science and Technology, 2022
Jiezhang Mo, Doris Wai-Ting Au, Jiahua Guo, Christoph Winkler, Richard Yuen-Chong Kong, Frauke Seemann
In phase I activation, BaP is converted to epoxides by CYPs (e.g., CYP1A1, CYP1A2, CYP1B1), followed by hydration to form diols catalyzed by epoxide hydrolase (EH), as indicated in Figure 1 (IARC, 2010). BaP diols are then converted to catechols by Aldo-keto reductases (AKRs) (Gelboin, 1980; Moffat et al., 2015; Xue & Warshawsky, 2005). Notably, BaP 7,8-catechol generated through the BaP-7,8-dihydrodiol-AKR pathway can autoxidize and form a DNA-reactive BaP metabolite, BaP-7,8-quinone. The BaP metabolites can be further epoxidated by CYPs to produce diol epoxides. BaP-7,8-diol-9,10-epoxide (BPDE), the most mutagenic BaP diol epoxide, can bind covalently with DNA to form 10-(deoxyguanosin-N2-yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (dG-N2-BPDE) (Boysen & Hecht, 2003; Shiizaki et al., 2017; Willett et al., 2000). The presence of DNA adducts attracts the nucleotide excision repair to restore the damaged DNA; otherwise, adduct binding distorts the DNA strand and causes a G to T transversion mutation after uncorrected DNA repair, inducing genotoxicity and carcinogenicity (Nebert et al., 2013; Santos et al., 2018; Xue & Warshawsky, 2005).
The expression of microRNAs and exposure to environmental contaminants related to human health: a review
Published in International Journal of Environmental Health Research, 2022
Maria Rosaria Tumolo, Alessandra Panico, Antonella De Donno, Pierpaolo Mincarone, Carlo Giacomo Leo, Roberto Guarino, Francesco Bagordo, Francesca Serio, Adele Idolo, Tiziana Grassi, Saverio Sabina
The association between several metals and PAHs with miRNAs expression was analyzed in a case–control study involving 360 healthy male coke oven workers. The expression of many plasma miRNAs was found to be negatively associated with aluminum, antimony, Pb, and titanium, and positively associated with molybdenum and tin. This study demonstrated a relationship between some miRNAs and biomarkers for genetic damage and oxidative stress, such as micronuclei and 8-OH-dG (Deng et al. 2019). Among the analyzed miRNAs, some have important functions. Let-7b-5p can regulate the expression of genes deputated to DNA-repair (Spolverini et al. 2017) and it is involved in p53-regulated pro-apoptotic pathway and nucleotide excision repair pathway (Saleh et al. 2011; Encarnación et al. 2016). miR-126-3p plays a role in cancer-related processes, such as inflammatory responses (Zampetaki and Mayr 2012). Improper expression of miR-16-5p can negatively affect DNA repair mechanism influencing the expression of DNA damage-related proteins (Patel et al. 2017). Finally, miR-320b is known to be down-regulated in human cancers; its target is TP53 regulated inhibitor of apoptosis 1 (TRIAP1) through which may control apoptosis process (Li et al. 2016). These findings may suggest a potential linkage between the metal-PAH complex interactions and the early harmful effects on human health (Deng et al. 2019).
Performance of HepaRG and HepG2 cells in the high-throughput micronucleus assay for in vitro genotoxicity assessment
Published in Journal of Toxicology and Environmental Health, Part A, 2020
Xiaoqing Guo, Ji-Eun Seo, Dayton Petibone, Volodymyr Tryndyak, Un Jung Lee, Tong Zhou, Timothy W. Robison, Nan Mei
Both hepatoma cell lines displayed a high sensitivity in detecting the 7 direct-acting genotoxic compounds, with a negative response observed only for the inorganic carcinogen, CdCl2, in HepaRG cells (Tables 1 and 2). Previously, our investigations and others noted that CdCl2 induced DNA damage in HepG2 cells, but not in HepaRG cells (Le Hegarat et al. 2014; Seo et al. 2019; Skipper et al. 2016). Induction of reactive oxygen species (ROS) and inhibition of DNA nucleotide excision repair, base excision repair, and mismatch repair are important mechanisms for Cd-induced genotoxicity and carcinogenicity (Filipic, Fatur, and Vudrag 2006; Hartwig 2010). HepaRG cells produce high levels of glutathione (GSH) which may mitigate CdCl2-induced oxidative DNA damage (Badisa et al. 2007; Xu, Oda, and Yokoi 2018). Although positive in both cell lines, the MN frequencies induced by DNA alkylating agents MMS and cross-linking agent cisplatin, at concentrations producing 55% cytotoxicity relative to control, were 5-fold higher in HepaRG than HepG2 cells (Table 1). Previously Seo et al. (2020) also observed a 2–2.5-fold higher % tail DNA in MMS- or cisplatin-treated HepaRG compared to HepG2 cells, and the induced DNA damage responses in HepaRG cells were similar to those found in PHHs. In this study, the MN assay was not conducted using PHHs due to lack of proliferation in these cells. However, the similarity of responses induced by MMS and cisplatin in the two genotoxicity endpoints provides further evidence that HepaRG cells may serve as a potential surrogate for PHHs in genotoxicity testing.