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Environmental and Molecular Mutagenesis

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https://www.readbyqxmd.com/read/28329407/regulatory-requirements-for-genotoxicity-assessment-of-plant-protection-product-active-ingredients-impurities-and-metabolites
#1
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/28326610/dose-and-temporal-evaluation-of-ethylene-oxide-induced-mutagenicity-in-the-lungs-of-male-big-blue-mice-following-inhalation-exposure-to-carcinogenic-concentrations
#2
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...
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
#3
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/28295562/locked-nucleic-acid-lna-based-single-stranded-oligonucleotides-are-not-genotoxic
#4
Guérard Melanie, 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...
March 10, 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
#5
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
#6
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/28195382/contribution-of-atm-and-atr-kinase-pathways-to-p53-mediated-response-in-etoposide-and-methyl-methanesulfonate-induced-dna-damage
#7
Bin Sun, Susan M Ross, Sean Rowley, Yeyejide Adeleye, Rebecca A Clewell
p53 is a key integrator of cellular response to DNA damage, supporting post-translational repair and driving transcription-mediated responses including cell cycle arrest, apoptosis, and repair. DNA damage sensing kinases recognize different types of DNA damage and initiate specific responses through various post-translational modifications of p53. This study evaluated chemical specificity of the p53 pathway response by manipulating p53 or its upstream kinases and assessing the effect on DNA damage and cellular responses to prototype chemicals: etoposide (ETP, topoisomerase II inhibitor) and methyl methane sulfonate (MMS, alkylating agent)...
February 14, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28181297/induction-of-oxidative-stress-by-bisphenol-a-and-its-pleiotropic-effects
#8
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...
February 9, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28079927/developmental-programming-interaction-between-prenatal-bpa-and-postnatal-overfeeding-on-cardiac-tissue-gene-expression-in-female-sheep
#9
L A Koneva, A K Vyas, R C McEachin, M Puttabyatappa, H-S Wang, M A Sartor, V Padmanabhan
Epidemiologic studies and studies in rodents point to potential risks from developmental exposure to BPA on cardiometabolic diseases. Furthermore, it is becoming increasingly evident that the manifestation and severity of adverse outcomes is the result of interaction between developmental insults and the prevailing environment. Consistent with this premise, recent studies in sheep found prenatal BPA treatment prevented the adverse effects of postnatal obesity in inducing hypertension. The gene networks underlying these complex interactions are not known...
January 12, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28079919/copper-oxide-nanoparticles-and-copper-sulphate-act-as-antigenotoxic-agents-in-drosophila-melanogaster
#10
Mohamed Alaraby, Alba Hernández, Ricard Marcos
The biological reactivity of metal and metal oxide nanomaterials is attributed to their redox properties, which would explain their pro- or anti-cancer properties depending on exposure circumstances. In this sense, copper oxide nanoparticles (CuONP) have been proposed as a potential anti-tumoral agent. The aim of this study was to assess if CuONP can exert antigenotoxic effects using Drosophila melanogaster as an in vivo model. Genotoxicity was induced by two well-known genotoxic compounds, namely potassium dichromate (PD) and ethyl methanesulfonate (EMS)...
January 12, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28205273/in-vitro-responses-to-known-in-vivo-genotoxic-agents-in-mouse-germ-cells
#11
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/28181292/tumor-associated-ape1-variant-exhibits-reduced-complementation-efficiency-but-does-not-promote-cancer-cell-phenotypes
#12
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
https://www.readbyqxmd.com/read/28116766/a-longitudinal-study-of-atrazine-and-2-4-d-exposure-and-oxidative-stress-markers-among-iowa-corn-farmers
#13
Catherine C Lerro, Laura E Beane Freeman, Lützen Portengen, Daehee Kang, Kyoungho Lee, Aaron Blair, Charles F Lynch, Berit Bakke, Anneclaire J De Roos, Roel C H Vermeulen
Reactive oxygen species, potentially formed through environmental exposures, can overwhelm an organism's antioxidant capabilities resulting in oxidative stress. Long-term oxidative stress is linked with chronic diseases. Pesticide exposures have been shown to cause oxidative stress in vivo. We utilized a longitudinal study of corn farmers and non-farming controls in Iowa to examine the impact of exposure to the widely used herbicides atrazine and 2,4-dichlorophenoxyacetic acid (2,4-D) on markers of oxidative stress...
January 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/27996157/high-pesticide-exposure-events-and-dna-methylation-among-pesticide-applicators-in-the-agricultural-health-study
#14
Jennifer A Rusiecki, Laura E Beane Freeman, Matthew R Bonner, Melannie Alexander, Ligong Chen, Gabriella Andreotti, Kathryn H Barry, Lee E Moore, Hyang-Min Byun, Freya Kamel, Michael Alavanja, Jane A Hoppin, Andrea Baccarelli
Pesticide exposure has been associated with acute and chronic adverse health effects. DNA methylation (DNAm) may mediate these effects. We evaluated the association between experiencing unusually high pesticide exposure events (HPEEs) and DNAm among pesticide applicators in the Agricultural Health Study (AHS), a prospective study of applicators from Iowa and North Carolina. DNA was extracted from whole blood from male AHS pesticide applicators (n = 695). Questionnaire data were used to ascertain the occurrence of HPEEs over the participant's lifetime...
December 20, 2016: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/27862311/the-micro-ames-test-a-direct-comparison-of-the-performance-and-sensitivities-of-the-standard-and-24-well-plate-versions-of-the-bacterial-mutation-test
#15
Raymond Proudlock, Kristie Evans
"Ames" bacterial mutation tests are widely performed for evaluation and registration of new materials including industrial chemicals, agrochemicals, medical devices, pharmaceuticals, pharmaceutical impurities and other materials. Tests are used to predict their potential long-term adverse health effects (including carcinogenicity). Given their importance, pre-screening 'miniaturized' versions have been developed which allow higher throughput and use less test material, including the widely-employed 24-well micro-Ames (µAmes) test which uses 20 times less material...
December 2016: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/27862296/dna-methylation-changes-in-mexican-children-exposed-to-arsenic-from-two-historic-mining-areas-in-san-luis-potos%C3%A3
#16
Jorge Alejandro Alegría-Torres, Leticia Carrizales-Yánez, Fernando Díaz-Barriga, Fernando Rosso-Camacho, Valeria Motta, Letizia Tarantini, Valentina Bollati
Arsenic is a carcinogen and epimutagen that threatens the health of exposed populations worldwide. In this study, we examined the methylation status of Alu and long interspersed nucleotide elements (LINE-1) and their association with levels of urinary arsenic in 84 Mexican children between 6 and 12 years old from two historic mining areas in the State of San Luis Potosí, Mexico. Urinary arsenic levels were determined by atomic absorption spectrophotometry and DNA methylation analysis was performed in peripheral blood leukocytes by bisulfite-pyrosequencing...
December 2016: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/27859739/transcriptomic-responses-in-the-oral-cavity-of-f344-rats-and-b6c3f1-mice-following-exposure-to-cr-vi-implications-for-risk-assessment
#17
Chad M Thompson, Julia E Rager, Mina Suh, Caroline L Ring, Deborah M Proctor, Laurie C Haws, Rebecca C Fry, Mark A Harris
Exposure to hexavalent chromium [Cr(VI)] in drinking water was previously reported to increase oral tumor incidence in F344 rats. To investigate the mode of action for these tumors, transcriptomic profiles in oral mucosa samples of F344 rats and B6C3F1 mice were analyzed following exposure to 0.1-180 ppm Cr(VI) for 7 or 90 days. In rats, genome-wide microarray analyses identified no significantly differentially expressed genes (DEGs) at either time point. In mice, 14 and 1 DEGs were respectively identified after 7 and 90 days of exposure...
December 2016: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/27859631/evaluation-of-the-lacz-reporter-assay-in-cryopreserved-primary-hepatocytes-for-in-vitro-genotoxicity-testing
#18
Mirjam Luijten, Edwin P Zwart, Martijn E T Dollé, Maaike de Pooter, Julie A Cox, Paul A White, Jan van Benthem
Assessment of genotoxic potential is an important step in the safety evaluation of chemical substances. Under most regulatory jurisdictions, the first tier of testing comprises a standard battery of in vitro genotoxicity tests in bacterial and mammalian cells. However, the mammalian cell tests commonly used exhibit a relatively high rate of misleading positive results, which may lead to unnecessary in vivo testing. We previously established a proof-of-concept for the LacZ reporter assay in proliferating primary hepatocytes as a promising alternative genotoxicity test...
December 2016: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/27801952/human-t-lymphocytes-bioactivate-heterocyclic-aromatic-amines-by-forming-dna-adducts
#19
Medjda Bellamri, Ludovic Le Hegarat, Laurent Vernhet, Georges Baffet, Robert J Turesky, Sophie Langouët
Heterocyclic aromatic amines (HAA) are formed in cooked meat, poultry and fish but also arise in tobacco smoke and exhaust gases. HAA are potential human carcinogens, which require metabolic activation to exert their genotoxicity. Human tissues can bioactivate HAA to produce reactive intermediates that bind to DNA. HAA DNA adduct formation occurs in human hepatocytes; however, the potential of HAA to form DNA adducts has not been investigated in human T lymphocytes. In this study, we investigated the ability of human T lymphocytes activated with PMA/Ionomycin or CD3/CD28 to express functional CYP1 activity and bioactivate three major HAA: 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-9H-pyrido[2,3-b]indole (AαC) to form DNA adducts...
December 2016: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/27770464/in-vivo-pig-a-gene-mutation-assay-guidance-for-3rs-friendly-implementation
#20
Marian Raschke, Bernd-W Igl, Julia Kenny, Joanne Collins, Stephen D Dertinger, Carson Labash, Javed A Bhalli, Cameron C M Tebbe, Kylie M McNeil, Andreas Sutter
The rodent Pig-a assay is an in vivo method for the detection of gene mutation, where lack of glycosylphosphatidylinositol-anchored proteins on the surface of circulating red blood cells (RBCs) serves as a reporter for Pig-a gene mutation. In the case of rats, the frequency of mutant phenotype RBCs is measured via fluorescent anti-CD59 antibodies and flow cytometry. The Pig-a assay meets the growing expectations for novel approaches in animal experimentation not only focusing on the scientific value of the assay but also on animal welfare aspects (3Rs principles), for example, amenable to integration into pivotal rodent 28-day general toxicology studies...
December 2016: Environmental and Molecular Mutagenesis
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