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Environmental and Molecular Mutagenesis

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https://www.readbyqxmd.com/read/28485542/use-of-genetic-toxicity-data-in-ghs-mutagenicity-classification-and-labeling-of-substances
#1
Nicholas S Ball, Heli M Hollnagel
One of the key outcomes of testing the potential genotoxicity or mutagenicity of a substance is the conclusion on whether the substance should be classified as a germ cell mutagen and the significance of this for other endpoints such as carcinogenicity. The basis for this conclusion are the criteria presented in classification and labelling systems such as the Globally Harmonized System for classification and labeling (GHS). This article reviews the classification criteria for germ cell mutagenicity and carcinogenicity and how they are applied to substances with evidence of mutagenicity...
May 9, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28485537/mechanisms-of-dna-damage-repair-and-mutagenesis
#2
REVIEW
Nimrat Chatterjee, Graham C Walker
Living organisms are continuously exposed to a myriad of DNA damaging agents that can impact health and modulate disease-states. However, robust DNA repair and damage-bypass mechanisms faithfully protect the DNA by either removing or tolerating the damage to ensure an overall survival. Deviations in this fine-tuning are known to destabilize cellular metabolic homeostasis, as exemplified in diverse cancers where disruption or deregulation of DNA repair pathways results in genome instability. Because routinely used biological, physical and chemical agents impact human health, testing their genotoxicity and regulating their use have become important...
May 9, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28436560/development-of-a-high-throughput-genotoxicity-assay-using-umu-test-strains-expressing-human-cytochrome-p450s-and-nadph-p450-reductase-and-bacterial-o-acetyltransferase
#3
Hisako Hori, Daisuke Hirata, Wataru Fujii, Yoshimitsu Oda
Umu test is one of the in vitro genotoxicity test that has been used widely. It was developed as a high-throughput test system using the 96-well microplate. We have previously constructed new umu test strains for the evaluation of genotoxicity of procarcinogenic metabolic products formed by cytochrome P450 (CYP) enzymes. In this study, a highly sensitive high-throughput genotoxicity test was developed using four umu test strains (OY1002/1A1, OY1002/1B1, OY1002/1A2, and OY1002/3A4) that express human CYPs and NADPH-P450 reductase...
April 24, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28436537/error-prone-replication-bypass-of-the-imidazole-ring-opened-formamidopyrimidine-deoxyguanosine-adduct
#4
Yan Sha, Irina G Minko, Chanchal K Malik, Carmelo J Rizzo, R Stephen Lloyd
Addition of hydroxyl radicals to the C8 position of 2'-deoxyguanosine generates an 8-hydroxyguanyl radical that can be converted into either 8-oxo-7,8-dihydro-2'-deoxyguanosine or N-(2-deoxy-d-pentofuranosyl)-N-(2,6-diamino-4-hydroxy-5-formamidopyrimidine) (Fapy-dG). The Fapy-dG adduct can adopt different conformations and in particular, can exist in an unnatural α anomeric configuration in addition to canonical β configuration. Previous studies reported that in 5'-TGN-3' sequences, Fapy-dG predominantly induced G → T transversions in both mammalian cells and Escherichia coli, suggesting that mutations could be formed either via insertion of a dA opposite the 5' dT due to primer/template misalignment or as result of direct miscoding...
April 24, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28329407/regulatory-requirements-for-genotoxicity-assessment-of-plant-protection-product-active-ingredients-impurities-and-metabolites
#5
REVIEW
Ewan D Booth, Paul J Rawlinson, Priscila Maria Fagundes, Kevin A Leiner
Active ingredients in plant protection products are subject to rigorous safety assessment during their development, including assessment of genotoxicity. Plant protection products are used for agriculture in multiple regions and for the registration of active ingredients it is necessary to satisfy the data requirements of these different regions. There are no overarching global agreements on which genotoxicity studies need to be conducted to satisfy the majority of regulatory authorities. The implementation of new OECD guidelines for the in vitro micronucleus, transgenic rodent somatic and germ cell gene mutation and in vivo comet assays, as well as the revision of a number of other OECD test guidelines has resulted in some changes to data requirements...
March 22, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28299826/international-regulatory-requirements-for-genotoxicity-testing-for-pharmaceuticals-used-in-human-medicine-and-their-impurities-and-metabolites
#6
REVIEW
Sheila M Galloway
The process of developing international (ICH) guidelines is described, and the main guidelines reviewed are the ICH S2(R1) guideline that includes the genotoxicity test battery for human pharmaceuticals, and the ICH M7 guideline for assessing and limiting potentially mutagenic impurities and degradation products in drugs. Key aspects of the guidelines are reviewed in the context of drug development, for example the incorporation of genotoxicity assessment into non-clinical toxicity studies, and ways to develop and assess weight of evidence...
March 16, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28266084/recommendations-for-the-evaluation-of-complex-genetic-toxicity-data-sets-when-assessing-carcinogenic-risks-to-humans
#7
David A Eastmond
Genotoxicity testing plays an important role in the assessment of carcinogenic and heritable risks. In many cases, experts charged with assessing genotoxicity test results need to evaluate widely varying numbers and types of bioassays of differing quality, conducted in a variety of cells and species using a wide range of protocols. The recommendations in this article were initially prepared as general guidelines to assist experts involved in the 2016 Joint Food and Agricultural Organization and World Health Organization Meeting on Pesticide Residues (JMPR) in their evaluation of the human health risks associated with exposure to pesticide residues in the diet...
March 7, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28266061/main-issues-addressed-in-the-2014-2015-revisions-to-the-oecd-genetic-toxicology-test-guidelines
#8
Veronique Thybaud, Elisabeth Lorge, Dan D Levy, Jan van Benthem, George R Douglas, Francesco Marchetti, Martha M Moore, Rita Schoeny
The Organization for Economic Cooperation and Development (OECD) recently revised the test guidelines (TGs) for genetic toxicology. This article describes the main issues addressed during the revision process, and the new and consistent recommendations made in the revised TGs for: (1) demonstration of laboratory proficiency; (2) generation and use of robust historical control data; (3) improvement of the statistical power of the tests; (4) selection of top concentration for in vitro assays; (5) consistent data interpretation and determination of whether the result is clearly positive, clearly negative or needs closer consideration; and, (6) consideration of 3R's for in vivo assay design...
March 7, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28444994/induction-of-micronuclei-and-cell-cycle-arrest-by-some-tri-and-tetrachlorobiphenyls-in-mammalian-cells-deficient-in-xenobiotic-metabolizing-enzymes
#9
Haiyan Wang, Liwen Wei, Yifan Wu, Hansi Jia, Hao Jiang, Yungang Liu
Polychlorinated biphenyls (PCBs) are persistent organic pollutants with continued public health concerns. The lower chlorinated biphenyls are supposed to be mutagenic following metabolic activation. However, in a preliminary study, we recently observed induction of micronuclei by several PCBs in a subclone of Chinese hamster V79 cell line, V79-Mz, which is deficient in xenobiotic-metabolizing enzyme activities. In this study, metabolism-free genotoxicity of PCBs was investigated, using 10 tri- and tetrachlorobiphenyls, in V79, V79-Mz, and human hepatoma (HepG2) cell lines...
May 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28444993/comparative-tumor-promotion-assessment-of-e-cigarette-and-cigarettes-using-the-in-vitro-bhas-42-cell-transformation-assay
#10
Damien Breheny, Oluwatobiloba Oke, Kamala Pant, Marianna Gaça
In vitro cell transformation assays (CTA) are used to assess the carcinogenic potential of chemicals and complex mixtures and can detect nongenotoxic as well as genotoxic carcinogens. The Bhas 42 CTA has been developed with both initiation and promotion protocols to distinguish between these two carcinogen classes. Cigarette smoke is known to be carcinogenic and is positive in in vitro genotoxicity assays. Cigarette smoke also contains nongenotoxic carcinogens and is a tumour promoter and cocarcinogen in vivo...
May 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28436563/an-in-vitro-system-for-measuring-genotoxicity-mediated-by-human-cyp3a4-in-saccharomyces-cerevisiae
#11
Michael Fasullo, Julian Freedland, Nicholas St John, Cinzia Cera, Patricia Egner, Matthew Hartog, Xinxin Ding
P450 activity is required to metabolically activate many chemical carcinogens, rendering them highly genotoxic. CYP3A4 is the most abundantly expressed P450 enzyme in the liver, accounting for most drug metabolism and constituting 50% of all hepatic P450 activity. CYP3A4 is also expressed in extrahepatic tissues, including the intestine. However, the role of CYP3A4 in activating chemical carcinogens into potent genotoxins is unclear. To facilitate efforts to determine whether CYP3A4, per se, can activate carcinogens into potent genotoxins, we expressed human CYP3A4 in the DNA-repair mutant (rad4 rad51) strain of budding yeast Saccharomyces cerevisiae and tested the novel, recombinant yeast strain for ability to report CYP3A4-mediated genotoxicity of a well-known genotoxin, aflatoxin B1 (AFB1 )...
May 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28370325/mutagenicity-and-oxidative-damage-induced-by-an-organic-extract-of-the-particulate-emissions-from-a-simulation-of-the-deepwater-horizon-surface-oil-burns
#12
David M DeMarini, Sarah H Warren, Katelyn Lavrich, Alexis Flen, Johanna Aurell, William Mitchell, Dale Greenwell, William Preston, Judith E Schmid, William P Linak, Michael D Hays, James M Samet, Brian K Gullett
Emissions from oil fires associated with the "Deepwater Horizon" explosion and oil discharge that began on April 20, 2010 in the Gulf of Mexico were analyzed chemically to only a limited extent at the time but were shown to induce oxidative damage in vitro and in mice. To extend this work, we burned oil floating on sea water and performed extensive chemical analyses of the emissions (Gullett et al., Marine Pollut Bull, in press, ). Here, we examine the ability of a dichloromethane extract of the particulate material with an aerodynamic size ≤ 2...
April 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28370324/investigation-of-toxicity-and-mutagenicity-of-cold-atmospheric-argon-plasma
#13
T Maisch, A K Bosserhoff, P Unger, J Heider, T Shimizu, J L Zimmermann, G E Morfill, M Landthaler, S Karrer
Cold atmospheric argon plasma is recognized as a new contact free approach for the decrease of bacterial load on chronic wounds in patients. So far very limited data are available on its toxicity and mutagenicity on eukaryotic cells. Thus, the toxic/mutagenic potential of cold atmospheric argon plasma using the MicroPlaSter β(®) , which has been used efficiently in humans treating chronic and acute wounds, was investigated using the XTT assay in keratinocytes and fibroblasts and the HGPRT (hypoxanthine guanine phosphoribosyl transferase) assay with V79 Chinese hamster cells...
April 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28370323/recombinant-cells-in-the-lung-increase-with-age-via-de-novo-recombination-events-and-clonal-expansion
#14
Takafumi Kimoto, Jennifer E Kay, Na Li, Bevin P Engelward
Homologous recombination (HR) is a critical DNA repair pathway, which is usually error-free, but can sometimes lead to cancer-promoting mutations. Despite the importance of HR as a driver of mutations, the spontaneous frequency of such mutations has proven difficult to study. To gain insight to location, cell type, and subsequent proliferation of mutated cells, we used the Rosa26 Direct Repeat (RaDR) mice for in situ detection and quantification of recombinant cells in the lung. We developed a method for automated enumeration of recombinant cells in lung tissue using the Metafer 4 slide-scanning platform...
April 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28370322/interlaboratory-evaluation-of-a-multiplexed-high-information-content-in-vitro-genotoxicity-assay
#15
Steven M Bryce, Derek T Bernacki, Jeffrey C Bemis, Richard A Spellman, Maria E Engel, Maik Schuler, Elisabeth Lorge, Pekka T Heikkinen, Ulrike Hemmann, Véronique Thybaud, Sabrina Wilde, Nina Queisser, Andreas Sutter, Andreas Zeller, Melanie Guérard, David Kirkland, Stephen D Dertinger
We previously described a multiplexed in vitro genotoxicity assay based on flow cytometric analysis of detergent-liberated nuclei that are simultaneously stained with propidium iodide and labeled with fluorescent antibodies against p53, γH2AX, and phospho-histone H3. Inclusion of a known number of microspheres provides absolute nuclei counts. The work described herein was undertaken to evaluate the interlaboratory transferability of this assay, commercially known as MultiFlow(®) DNA Damage Kit-p53, γH2AX, Phospho-Histone H3...
April 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28326610/dose-and-temporal-evaluation-of-ethylene-oxide-induced-mutagenicity-in-the-lungs-of-male-big-blue-mice-following-inhalation-exposure-to-carcinogenic-concentrations
#16
Mugimane G Manjanatha, Sharon D Shelton, Ying Chen, Barbara L Parsons, Meagan B Myers, Karen L McKim, B Bhaskar Gollapudi, Nigel P Moore, Lynne T Haber, Bruce Allen, Martha M Moore
Ethylene oxide (EO) is a direct acting alkylating agent; in vitro and in vivo studies indicate that it is both a mutagen and a carcinogen. However, it remains unclear whether the mode of action (MOA) for cancer for EO is a mutagenic MOA, specifically via point mutation. To investigate the MOA for EO-induced mouse lung tumors, male Big Blue (BB) B6C3F1 mice (10/group) were exposed to EO by inhalation, 6 hr/day, 5 days/week for 4 (0, 10, 50, 100, or 200 ppm EO), 8, or 12 weeks (0, 100, or 200 ppm EO). Lung DNA samples were analyzed for cII mutant frequency (MF) at 4, 8 and 12 weeks of exposure; the mutation spectrum was analyzed for mutants from control and 200 ppm EO treatments...
April 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28295562/locked-nucleic-acid-lna-based-single-stranded-oligonucleotides-are-not-genotoxic
#17
Melanie Guérard, Zeller Andreas, Koller Erich, Marchand Christine, Müller B Martina, Weile Christian, Schuler Franz, Singer Thomas, Tessier Yann
Over the last decade, single stranded oligonucleotides (ON) have gained increased attention as a new drug modality. Because the assessment of genotoxicity risk during early development of pharmaceuticals is essential, we evaluated the potential of locked nucleic acids (LNA)-ONs to induce DNA damage in L5178Y tk(+/-) cells both with the mouse lymphoma assay (MLA) and the micronucleus test (MNT). Further, the MLA was performed to assess gene and chromosome mutation over 3 and 24h (± metabolic activation). In addition, the MNT was performed to assess, in addition, a potential aneugenic liability...
April 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28205273/in-vitro-responses-to-known-in-vivo-genotoxic-agents-in-mouse-germ-cells
#18
Khaled Habas, Martin H Brinkworth, Diana Anderson
Genotoxic compounds have induced DNA damage in male germ cells and have been associated with adverse clinical outcomes including enhanced risks for maternal, paternal and offspring health. DNA strand breaks represent a great threat to the genomic integrity of germ cells. Such integrity is essential to maintain spermatogenesis and prevent reproduction failure. The Comet assay results revealed that the incubation of isolated germ cells with n-ethyl-n-nitrosourea (ENU), 6-mercaptopurine (6-MP) and methyl methanesulphonate (MMS) led to increase in length of Olive tail moment and % tail DNA when compared with the untreated control cells and these effects were concentration-dependent...
March 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28181297/induction-of-oxidative-stress-by-bisphenol-a-and-its-pleiotropic-effects
#19
REVIEW
Natalie R Gassman
Bisphenol A (BPA) has become a target of intense public scrutiny since concerns about its association with human diseases such as obesity, diabetes, reproductive disorders, and cancer have emerged. BPA is a highly prevalent chemical in consumer products, and human exposure is thought to be ubiquitous. Numerous studies have demonstrated its endocrine disrupting properties and attributed exposure with cytotoxic, genotoxic, and carcinogenic effects; however, the results of these studies are still highly debated and a consensus about BPA's safety and its role in human disease has not been reached...
March 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28181292/tumor-associated-ape1-variant-exhibits-reduced-complementation-efficiency-but-does-not-promote-cancer-cell-phenotypes
#20
Jennifer L Illuzzi, Daniel R McNeill, Paul Bastian, Boris Brenerman, Robert Wersto, Helen R Russell, Fred Bunz, Peter J McKinnon, Kevin G Becker, David M Wilson
Base excision repair (BER) is the major pathway for coping with most forms of endogenous DNA damage, and defects in the process have been associated with carcinogenesis. Apurinic/apyrimidinic endonuclease 1 (APE1) is a central participant in BER, functioning as a critical endonuclease in the processing of noncoding abasic sites in DNA. Evidence has suggested that APE1 missense mutants, as well as altered expression or localization of the protein, can contribute to disease manifestation. We report herein that the tumor-associated APE1 variant, R237C, shows reduced complementation efficiency of the methyl methanesulfonate hypersensitivity and impaired cell growth exhibited by APE1-deficient mouse embryonic fibroblasts...
March 2017: Environmental and Molecular Mutagenesis
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