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Development of a high ‐throughput genotoxicity assay using Umu test strains expressing human cytochrome P450s and NADPH‐P450 reductase and bacterial O‐acetyltransferase
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. We found that the modified umu‐microplate method was more sensitive than the conventional microplate method using strain OY1002/1A2. In addition, the new microplate method was better able to detect genotoxicity than the test tube method when the strain OY1002/1A2 was used and had similar sensitivity for the remaining three strains. When the microplate method was used, OY1002/1A2 showed stronger umuC gene exp...
Source: Environmental and Molecular Mutagenesis - April 24, 2017 Category: Molecular Biology Authors: Hisako Hori, Daisuke Hirata, Wataru Fujii, Yoshimitsu Oda Tags: Research Article Source Type: research

Error ‐prone replication bypass of the imidazole ring‐opened formamidopyrimidine deoxyguanosine adduct
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 Escher...
Source: Environmental and Molecular Mutagenesis - April 1, 2017 Category: Molecular Biology Authors: Yan Sha, Irina G. Minko, Chanchal K. Malik, Carmelo J. Rizzo, R. Stephen Lloyd Tags: Research Article Source Type: research

Investigation of toxicity and mutagenicity of cold atmospheric argon plasma
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. The tested clinical parameter of a 2 min cold atm...
Source: Environmental and Molecular Mutagenesis - March 28, 2017 Category: Molecular Biology Authors: T. Maisch, A. K. Bosserhoff, P. Unger, J. Heider, T. Shimizu, J. L. Zimmermann, G. E. Morfill, M. Landthaler, S. Karrer Tags: Research Article Source Type: research

Mutagenicity and oxidative damage induced by an organic extract of the particulate emissions from a simulation of the deepwater horizon surface oil burns
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 ≤ 2.5 µm (PM2.5) from those emissions to induce oxidative damage in huma...
Source: Environmental and Molecular Mutagenesis - March 28, 2017 Category: Molecular Biology Authors: 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 Tags: Research Article Source Type: research

Interlaboratory evaluation of a multiplexed high information content in vitro genotoxicity assay
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. For these experiments, seven laboratories studied reference chemicals from a group of 84 r...
Source: Environmental and Molecular Mutagenesis - March 28, 2017 Category: Molecular Biology Authors: Steven M. Bryce, Derek T. Bernacki, Jeffrey C. Bemis, Richard A. Spellman, Maria E. Engel, Maik Schuler, Elisabeth Lorge, Pekka T. Heikkinen, Ulrike Hemmann, V éronique Thybaud, Sabrina Wilde, Nina Queisser, Andreas Sutter, Andreas Zeller, Melanie Guéra Tags: Research Article Source Type: research

Recombinant cells in the lung increase with age via de novo recombination events and clonal expansion
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. The mean sp...
Source: Environmental and Molecular Mutagenesis - March 28, 2017 Category: Molecular Biology Authors: Takafumi Kimoto, Jennifer E. Kay, Na Li, Bevin P. Engelward Tags: Research Article Source Type: research

Issue Information
(Source: Environmental and Molecular Mutagenesis)
Source: Environmental and Molecular Mutagenesis - March 28, 2017 Category: Molecular Biology Tags: Issue Information Source Type: research

Dose and temporal evaluation of ethylene oxide ‐induced mutagenicity in the lungs of male big blue mice following inhalation exposure to carcinogenic concentrations
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 an...
Source: Environmental and Molecular Mutagenesis - March 22, 2017 Category: Molecular Biology Authors: 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 Tags: Research Article Source Type: research

Recommendations for the evaluation of complex genetic toxicity data sets when assessing carcinogenic risks to humans
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 expos...
Source: Environmental and Molecular Mutagenesis - March 6, 2017 Category: Molecular Biology Authors: David A. Eastmond Tags: Commentary Source Type: research

Regulatory requirements for genotoxicity assessment of plant protection product active ingredients, impurities, and metabolites
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 vi...
Source: Environmental and Molecular Mutagenesis - March 1, 2017 Category: Molecular Biology Authors: Ewan D. Booth, Paul J. Rawlinson, Priscila Maria Fagundes, Kevin A. Leiner Tags: Review Source Type: research

International regulatory requirements for genotoxicity testing for pharmaceuticals used in human medicine, and their impurities and metabolites
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. In both guidelines, the existence of “thresholds” or non‐linear dose respon...
Source: Environmental and Molecular Mutagenesis - February 28, 2017 Category: Molecular Biology Authors: Sheila M. Galloway Tags: Review Source Type: research

Locked nucleic acid (LNA): Based single ‐stranded oligonucleotides are not genotoxic
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. None of the experiments de...
Source: Environmental and Molecular Mutagenesis - February 28, 2017 Category: Molecular Biology Authors: Gu érard Melanie, Zeller Andreas, Koller Erich, Marchand Christine, Müller B. Martina, Weile Christian, Schuler Franz, Singer Thomas, Tessier Yann Tags: Research Article Source Type: research

Main issues addressed in the 2014 –2015 revisions to the OECD Genetic Toxicology Test Guidelines
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. The revision process resulted in improved consistency among OECD ...
Source: Environmental and Molecular Mutagenesis - February 28, 2017 Category: Molecular Biology Authors: Veronique Thybaud, Elisabeth Lorge, Dan D. Levy, Jan Benthem, George R. Douglas, Francesco Marchetti, Martha M. Moore, Rita Schoeny Tags: Commentary Source Type: research

Issue Information
(Source: Environmental and Molecular Mutagenesis)
Source: Environmental and Molecular Mutagenesis - February 21, 2017 Category: Molecular Biology Tags: Issue Information Source Type: research

Induction of oxidative stress by bisphenol A and its pleiotropic effects
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. One of the contributing facto...
Source: Environmental and Molecular Mutagenesis - February 8, 2017 Category: Molecular Biology Authors: Natalie R. Gassman Tags: Review Source Type: research