The Experts below are selected from a list of 144936 Experts worldwide ranked by ideXlab platform
Andrew R Kraynak - One of the best experts on this subject based on the ideXlab platform.
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jacvam organized international validation study of the in vivo rodent alkaline comet assay for the detection of Genotoxic carcinogens i summary of pre validation study results
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2015Co-Authors: Hajime Kojima, Takashi Omori, Raffaella Corvi, Masamistu Honma, Leonard M Schechtman, Raymond R Tice, Brian Burlinson, Patricia A Escobar, Andrew R Kraynak, Yuzuki NakagawaAbstract:Abstract The in vivo rodent alkaline comet assay (comet assay) is used internationally to investigate the in vivo Genotoxic potential of test chemicals. This assay, however, has not previously been formally validated. The Japanese Center for the Validation of Alternative Methods (JaCVAM), with the cooperation of the U.S. NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)/the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), the European Centre for the Validation of Alternative Methods (ECVAM), and the Japanese Environmental Mutagen Society/Mammalian Mutagenesis Study Group (JEMS/MMS), organized an international validation study to evaluate the reliability and relevance of the assay for identifying Genotoxic carcinogens, using liver and stomach as target organs. The ultimate goal of this exercise was to establish an Organisation for Economic Co-operation and Development (OECD) test guideline. The study protocol was optimized in the pre-validation studies, and then the definitive (4th phase) validation study was conducted in two steps. In the 1st step, assay reproducibility was confirmed among laboratories using four coded reference chemicals and the positive control ethyl methanesulfonate. In the 2nd step, the predictive capability was investigated using 40 coded chemicals with known Genotoxic and carcinogenic activity (i.e., Genotoxic carcinogens, Genotoxic non-carcinogens, non-Genotoxic carcinogens, and non-Genotoxic non-carcinogens). Based on the results obtained, the in vivo comet assay is concluded to be highly capable of identifying Genotoxic chemicals and therefore can serve as a reliable predictor of rodent carcinogenicity.
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alkaline comet assay in liver and stomach and micronucleus assay in bone marrow from rats treated with 2 acetylaminofluorene azidothymidine cisplatin or isobutyraldehyde
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2015Co-Authors: Andrew R Kraynak, John E Barnum, Caron L Cunningham, B A Ykoruk, B Bennet, D Stoffregen, M Merschman, E Freeland, Sheila M GallowayAbstract:As part of the Japanese Center for the Validation of Alternative Methods (JaCVAM) initiative international validation study of the in vivo rat alkaline comet assay (comet assay), we examined the ability of the assay to determine the Genotoxicity of 2-acetylaminofluorene (AAF), azidothymidine (AZT), cisplatin (CPN), and isobutyraldehyde (IBA) in liver and glandular stomach of male Sprague-Dawley rats. Rats were given oral doses of test compound or control once daily for three days. High dose levels were approximately maximum tolerated doses and were based on preliminary range-finding studies. Tissues were harvested 3h after the final dose (48h after the initial dose). A bone marrow micronucleus assay (MN) was also conducted on the rats treated with AZT, CPN, and IBA. Acute toxic effects of treatment were determined primarily through histomorphologic analysis of liver and stomach but also by body weight and serum liver enzyme changes. The comet assay was conducted on fresh tissue preparations but frozen samples from two studies were also assayed. Statistically significant dose-related differences in comet % DNA in tail were found in liver and stomach for the genotoxin AZT and in liver for the genotoxin CPN, but not in liver or stomach for the non-genotoxin IBA. Statistically significant differences in % DNA in tail were measured in liver for the low and mid dose of the genotoxin AAF, but not the high dose. The comet assays of frozen liver suspensions from CPN- and AAF-treated rats yielded comparable results to the assays of fresh preparations. There were no indications of significant toxicity induced by any treatment. The micronucleus assay was positive for CPN and AZT and negative for IBA. In conclusion, the in vivo comet assay is capable of detecting Genotoxic effects of a variety of chemicals and may fill an important role in the Genotoxicity test battery.
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jacvam organized international validation study of the in vivo rodent alkaline comet assay for detection of Genotoxic carcinogens ii summary of definitive validation study results
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2015Co-Authors: Yoshifumi Uno, Hajime Kojima, Takashi Omori, Raffaella Corvi, Masamistu Honma, Leonard M Schechtman, Raymond R Tice, Brian Burlinson, Patricia A Escobar, Andrew R KraynakAbstract:The in vivo rodent alkaline comet assay (comet assay) is used internationally to investigate the in vivo Genotoxic potential of test chemicals. This assay, however, has not previously been formally validated. The Japanese Center for the Validation of Alternative Methods (JaCVAM), with the cooperation of the U.S. NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)/the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), the European Centre for the Validation of Alternative Methods (ECVAM), and the Japanese Environmental Mutagen Society/Mammalian Mutagenesis Study Group (JEMS/MMS), organized an international validation study to evaluate the reliability and relevance of the assay for identifying Genotoxic carcinogens, using liver and stomach as target organs. The ultimate goal of this exercise was to establish an Organisation for Economic Co-operation and Development (OECD) test guideline. The study protocol was optimized in the pre-validation studies, and then the definitive (4th phase) validation study was conducted in two steps. In the 1st step, assay reproducibility was confirmed among laboratories using four coded reference chemicals and the positive control ethyl methanesulfonate. In the 2nd step, the predictive capability was investigated using 40 coded chemicals with known Genotoxic and carcinogenic activity (i.e., Genotoxic carcinogens, Genotoxic non-carcinogens, non-Genotoxic carcinogens, and non-Genotoxic non-carcinogens). Based on the results obtained, the in vivo comet assay is concluded to be highly capable of identifying Genotoxic chemicals and therefore can serve as a reliable predictor of rodent carcinogenicity.
Leonard M Schechtman - One of the best experts on this subject based on the ideXlab platform.
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jacvam organized international validation study of the in vivo rodent alkaline comet assay for the detection of Genotoxic carcinogens i summary of pre validation study results
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2015Co-Authors: Hajime Kojima, Takashi Omori, Raffaella Corvi, Masamistu Honma, Leonard M Schechtman, Raymond R Tice, Brian Burlinson, Patricia A Escobar, Andrew R Kraynak, Yuzuki NakagawaAbstract:Abstract The in vivo rodent alkaline comet assay (comet assay) is used internationally to investigate the in vivo Genotoxic potential of test chemicals. This assay, however, has not previously been formally validated. The Japanese Center for the Validation of Alternative Methods (JaCVAM), with the cooperation of the U.S. NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)/the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), the European Centre for the Validation of Alternative Methods (ECVAM), and the Japanese Environmental Mutagen Society/Mammalian Mutagenesis Study Group (JEMS/MMS), organized an international validation study to evaluate the reliability and relevance of the assay for identifying Genotoxic carcinogens, using liver and stomach as target organs. The ultimate goal of this exercise was to establish an Organisation for Economic Co-operation and Development (OECD) test guideline. The study protocol was optimized in the pre-validation studies, and then the definitive (4th phase) validation study was conducted in two steps. In the 1st step, assay reproducibility was confirmed among laboratories using four coded reference chemicals and the positive control ethyl methanesulfonate. In the 2nd step, the predictive capability was investigated using 40 coded chemicals with known Genotoxic and carcinogenic activity (i.e., Genotoxic carcinogens, Genotoxic non-carcinogens, non-Genotoxic carcinogens, and non-Genotoxic non-carcinogens). Based on the results obtained, the in vivo comet assay is concluded to be highly capable of identifying Genotoxic chemicals and therefore can serve as a reliable predictor of rodent carcinogenicity.
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jacvam organized international validation study of the in vivo rodent alkaline comet assay for detection of Genotoxic carcinogens ii summary of definitive validation study results
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2015Co-Authors: Yoshifumi Uno, Hajime Kojima, Takashi Omori, Raffaella Corvi, Masamistu Honma, Leonard M Schechtman, Raymond R Tice, Brian Burlinson, Patricia A Escobar, Andrew R KraynakAbstract:The in vivo rodent alkaline comet assay (comet assay) is used internationally to investigate the in vivo Genotoxic potential of test chemicals. This assay, however, has not previously been formally validated. The Japanese Center for the Validation of Alternative Methods (JaCVAM), with the cooperation of the U.S. NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)/the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), the European Centre for the Validation of Alternative Methods (ECVAM), and the Japanese Environmental Mutagen Society/Mammalian Mutagenesis Study Group (JEMS/MMS), organized an international validation study to evaluate the reliability and relevance of the assay for identifying Genotoxic carcinogens, using liver and stomach as target organs. The ultimate goal of this exercise was to establish an Organisation for Economic Co-operation and Development (OECD) test guideline. The study protocol was optimized in the pre-validation studies, and then the definitive (4th phase) validation study was conducted in two steps. In the 1st step, assay reproducibility was confirmed among laboratories using four coded reference chemicals and the positive control ethyl methanesulfonate. In the 2nd step, the predictive capability was investigated using 40 coded chemicals with known Genotoxic and carcinogenic activity (i.e., Genotoxic carcinogens, Genotoxic non-carcinogens, non-Genotoxic carcinogens, and non-Genotoxic non-carcinogens). Based on the results obtained, the in vivo comet assay is concluded to be highly capable of identifying Genotoxic chemicals and therefore can serve as a reliable predictor of rodent carcinogenicity.
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the jacvam international validation study on the in vivo comet assay selection of test chemicals
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2015Co-Authors: Takeshi Morita, Hajime Kojima, Raffaella Corvi, Raymond R Tice, Masamitsu Honma, Makoto Hayashi, Leonard M SchechtmanAbstract:Abstract The Japanese Center for the Validation of Alternative Methods (JaCVAM) sponsored an international prevalidation and validation study of the in vivo rat alkaline pH comet assay. The main objective of the study was to assess the sensitivity and specificity of the assay for correctly identifying Genotoxic carcinogens, as compared with the traditional rat liver unscheduled DNA synthesis assay. Based on existing carcinogenicity and Genotoxicity data and chemical class information, 90 chemicals were identified as primary candidates for use in the validation study. From these 90 chemicals, 46 secondary candidates and then 40 final chemicals were selected based on a sufficiency of carcinogenic and Genotoxic data, differences in chemical class or Genotoxic or carcinogenic mode of action (MOA), availability, price, and ease of handling. These 40 chemicals included 19 Genotoxic carcinogens, 6 Genotoxic non-carcinogens, 7 non-Genotoxic carcinogens and 8 non-Genotoxic non-carcinogens. “Genotoxicity” was defined as positive in the Ames mutagenicity test or in one of the standard in vivo Genotoxicity tests (primarily the erythrocyte micronucleus assay). These chemicals covered various chemicals classes, MOAs, and Genotoxicity profiles and were considered to be suitable for the purpose of the validation study. General principles of chemical selection for validation studies are discussed.
Jean-philippe Nougayrède - One of the best experts on this subject based on the ideXlab platform.
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Deciphering the interplay between the Genotoxic and probiotic activities of Escherichia coli Nissle 1917
PLoS Pathogens, 2019Co-Authors: Clémence Massip, Michèle Boury, Thomas Secher, Nadège Bossuet-greif, Patricia Martin, Priscilla Branchu, Camille Chagneau, Déborah Gaillard, Damien Dubois, Jean-philippe NougayrèdeAbstract:Although Escherichia coli Nissle 1917 (EcN) has been used therapeutically for over a century, the determinants of its probiotic properties remain elusive. EcN produces two siderophore-microcins (Mcc) responsible for an antagonistic activity against other Enterobacteriaceae. EcN also synthesizes the genotoxin colibactin encoded by the pks island. Colibactin is a virulence factor and a putative pro-carcinogenic compound. Therefore, we aimed to decouple the antagonistic activity of EcN from its Genotoxic activity. We demonstrated that the pks-encoded ClbP, the peptidase that activates colibactin, is required for the antagonistic activity of EcN. The analysis of a series of ClbP mutants revealed that this activity is linked to the transmembrane helices of ClbP and not the periplasmic peptidase domain, indicating the transmembrane domain is involved in some aspect of Mcc biosynthesis or secretion. A single amino acid substitution in ClbP inactivates the Genotoxic activity but maintains the antagonistic activity. In an in vivo salmonellosis model, this point mutant reduced the clinical signs and the fecal shedding of Salmonella similarly to the wild type strain, whereas the clbP deletion mutant could neither protect nor outcompete the pathogen. The ClbP-dependent antibacterial effect was also observed in vitro with other E. coli strains that carry both a truncated form of the Mcc gene cluster and the pks island. In such strains, siderophore-Mcc synthesis also required the glucosyltransferase IroB involved in salmochelin production. This interplay between colibactin, salmochelin, and siderophore-Mcc biosynthetic pathways suggests that these genomic islands were co-selected and played a role in the evolution of E. coli from phylogroup B2. This co-evolution observed in EcN illustrates the fine margin between pathogenicity and probiotic activity, and the need to address both the effectiveness and safety of probiotics. Decoupling the antagonistic from the Genotoxic activity by specifically inactivating ClbP peptidase domain opens the way to the safe use of EcN.
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The Polyamine Spermidine Modulates the Production of the Bacterial Genotoxin Colibactin
MSphere, 2019Co-Authors: Camille V. Chagneau, Jean-philippe Nougayrède, Christophe Garcie, Nadège Bossuet-greif, Sophie Tronnet, Alexander O. Brachmann, Jörn Piel, Patricia Martin, Eric OswaldAbstract:Colibactin is a polyketide/nonribosomal peptide produced by Escherichia coli strains that harbor the pks island. This toxin induces DNA double-strand breaks and DNA interstrand cross-links in infected eukaryotic cells. Colibactin-producing strains are found associated with colorectal cancer biopsy specimens and promote intestinal tumor progression in various murine models. Polyamines are small polycationic molecules produced by both microorganisms and eukaryotic cells. Their levels are increased in malignancies, where they contribute to disease progression and metastasis. In this study, we demonstrated that the endogenous spermidine synthase SpeE is required for full Genotoxic activity of colibactin-producing E. coli. Supplying spermidine in a ΔspeE pks+ E. coli strain restored Genotoxic activity. Spermidine is involved in the autotoxicity linked to colibactin and is required for direct damaging activity on DNA. The production of the colibactin prodrug motif is impaired in ΔspeE mutants. Therefore, we demonstrated that spermidine has a direct impact on colibactin synthesis. IMPORTANCE Colibactin-producing Escherichia coli strains are associated with cancerous and precancerous colorectal tissues and are suspected of promoting colorectal carcinogenesis. In this study, we describe a new interplay between the synthesis of the genotoxin colibactin and the polyamine spermidine. Polyamines are highly abundant in cancer tissue and are associated with cell proliferation. The need for spermidine in Genotoxic activity provides a new perspective on the role of these metabolites in the pathogenicity of colibactin-producing E. coli strains in colorectal cancer.
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The Enterobacterial Genotoxins: Cytolethal Distending Toxin and Colibactin
EcoSal Plus, 2016Co-Authors: Frederic Taieb, Jean-philippe Nougayrède, Claude Petit, Eric OswaldAbstract:While the DNA damage induced by ionizing radiation and by many chemical compounds and drugs is well characterized, the Genotoxic insults inflicted by bacteria are only scarcely documented. However, accumulating evidence indicates that we are exposed to bacterial genotoxins. The prototypes of such bacterial genotoxins are the Cytolethal Distending Toxins (CDTs) produced by Escherichia coli and Salmonella enterica serovar Typhi. CDTs display the DNase structure fold and activity, and induce DNA strand breaks in the intoxicated host cell nuclei. E. coli and certain other Enterobacteriaceae species synthesize another genotoxin, colibactin. Colibactin is a secondary metabolite, a hybrid polyketide/nonribosomal peptide compound synthesized by a complex biosynthetic machinery. In this review, we summarize the current knowledge on CDT and colibactin produced by E. coli and/or Salmonella Typhi. We describe their prevalence, genetic determinants, modes of action, and impact in infectious diseases or gut colonization, and discuss the possible involvement of these genotoxigenic bacteria in cancer.
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Maternally acquired Genotoxic Escherichia coli alters offspring's intestinal homeostasis
Gut Microbes, 2014Co-Authors: Delphine Payros, T. Secher, Michèle Boury, Camille Brehin, Sandrine Ménard, Christel Salvador-cartier, Gabriel Cuevas-ramos, Claude Watrin, Ingrid Marcq, Jean-philippe NougayrèdeAbstract:The neonatal gut is rapidly colonized by a newly dominant group of commensal Escherichia coli strains among which a large proportion produces a genotoxin called colibactin. In order to analyze the short- and long-term effects resulting from such evolution, we developed a rat model mimicking the natural transmission of E. coli from mothers to neonates. Genotoxic and non-Genotoxic E. coli strains were equally transmitted to the offspring and stably colonized the gut across generations. DNA damage was only detected in neonates colonized with Genotoxic E. coli strains. Signs of Genotoxic stress such as anaphase bridges, higher occurrence of crypt fission and accelerated renewal of the mature epithelium were detected at adulthood. In addition, we observed alterations of secretory cell populations and gut epithelial barrier. Our findings illustrate how critical is the genotype of E. coli strains acquired at birth for gut homeostasis at adulthood.
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Escherichia coli producing colibactin triggers premature and transmissible senescence in mammalian cells
PLoS ONE, 2013Co-Authors: Thomas Secher, Ascel Samba Louaka, Eric Oswald, Jean-philippe NougayrèdeAbstract:Cellular senescence is an irreversible state of proliferation arrest evoked by a myriad of stresses including oncogene activation, telomere shortening/dysfunction and Genotoxic insults. It has been associated with tumor activation, immune suppression and aging, owing to the secretion of proinflammatory mediators. The bacterial genotoxin colibactin, encoded by the pks genomic island is frequently harboured by Escherichia coli strains of the B2 phylogenetic group. Mammalian cells exposed to live pks+ bacteria exhibit DNA-double strand breaks (DSB) and undergo cell-cycle arrest and death. Here we show that cells that survive the acute bacterial infection with pks+ E. coli display hallmarks of cellular senescence: chronic DSB, prolonged cell-cycle arrest, enhanced senescence-associated beta-galactosidase (SA-beta-Gal) activity, expansion of promyelocytic leukemia nuclear foci and senescence-associated heterochromatin foci. This was accompanied by reactive oxygen species production and pro-inflammatory cytokines, chemokines and proteases secretion. These mediators were able to trigger DSB and enhanced SA-beta-Gal activity in bystander recipient cells treated with conditioned medium from senescent cells. Furthermore, these senescent cells promoted the growth of human tumor cells. In conclusion, the present data demonstrated that the E. coli genotoxin colibactin induces cellular senescence and subsequently propel bystander Genotoxic and oncogenic effects.
Hajime Kojima - One of the best experts on this subject based on the ideXlab platform.
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jacvam organized international validation study of the in vivo rodent alkaline comet assay for the detection of Genotoxic carcinogens i summary of pre validation study results
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2015Co-Authors: Hajime Kojima, Takashi Omori, Raffaella Corvi, Masamistu Honma, Leonard M Schechtman, Raymond R Tice, Brian Burlinson, Patricia A Escobar, Andrew R Kraynak, Yuzuki NakagawaAbstract:Abstract The in vivo rodent alkaline comet assay (comet assay) is used internationally to investigate the in vivo Genotoxic potential of test chemicals. This assay, however, has not previously been formally validated. The Japanese Center for the Validation of Alternative Methods (JaCVAM), with the cooperation of the U.S. NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)/the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), the European Centre for the Validation of Alternative Methods (ECVAM), and the Japanese Environmental Mutagen Society/Mammalian Mutagenesis Study Group (JEMS/MMS), organized an international validation study to evaluate the reliability and relevance of the assay for identifying Genotoxic carcinogens, using liver and stomach as target organs. The ultimate goal of this exercise was to establish an Organisation for Economic Co-operation and Development (OECD) test guideline. The study protocol was optimized in the pre-validation studies, and then the definitive (4th phase) validation study was conducted in two steps. In the 1st step, assay reproducibility was confirmed among laboratories using four coded reference chemicals and the positive control ethyl methanesulfonate. In the 2nd step, the predictive capability was investigated using 40 coded chemicals with known Genotoxic and carcinogenic activity (i.e., Genotoxic carcinogens, Genotoxic non-carcinogens, non-Genotoxic carcinogens, and non-Genotoxic non-carcinogens). Based on the results obtained, the in vivo comet assay is concluded to be highly capable of identifying Genotoxic chemicals and therefore can serve as a reliable predictor of rodent carcinogenicity.
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jacvam organized international validation study of the in vivo rodent alkaline comet assay for detection of Genotoxic carcinogens ii summary of definitive validation study results
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2015Co-Authors: Yoshifumi Uno, Hajime Kojima, Takashi Omori, Raffaella Corvi, Masamistu Honma, Leonard M Schechtman, Raymond R Tice, Brian Burlinson, Patricia A Escobar, Andrew R KraynakAbstract:The in vivo rodent alkaline comet assay (comet assay) is used internationally to investigate the in vivo Genotoxic potential of test chemicals. This assay, however, has not previously been formally validated. The Japanese Center for the Validation of Alternative Methods (JaCVAM), with the cooperation of the U.S. NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)/the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), the European Centre for the Validation of Alternative Methods (ECVAM), and the Japanese Environmental Mutagen Society/Mammalian Mutagenesis Study Group (JEMS/MMS), organized an international validation study to evaluate the reliability and relevance of the assay for identifying Genotoxic carcinogens, using liver and stomach as target organs. The ultimate goal of this exercise was to establish an Organisation for Economic Co-operation and Development (OECD) test guideline. The study protocol was optimized in the pre-validation studies, and then the definitive (4th phase) validation study was conducted in two steps. In the 1st step, assay reproducibility was confirmed among laboratories using four coded reference chemicals and the positive control ethyl methanesulfonate. In the 2nd step, the predictive capability was investigated using 40 coded chemicals with known Genotoxic and carcinogenic activity (i.e., Genotoxic carcinogens, Genotoxic non-carcinogens, non-Genotoxic carcinogens, and non-Genotoxic non-carcinogens). Based on the results obtained, the in vivo comet assay is concluded to be highly capable of identifying Genotoxic chemicals and therefore can serve as a reliable predictor of rodent carcinogenicity.
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the jacvam international validation study on the in vivo comet assay selection of test chemicals
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2015Co-Authors: Takeshi Morita, Hajime Kojima, Raffaella Corvi, Raymond R Tice, Masamitsu Honma, Makoto Hayashi, Leonard M SchechtmanAbstract:Abstract The Japanese Center for the Validation of Alternative Methods (JaCVAM) sponsored an international prevalidation and validation study of the in vivo rat alkaline pH comet assay. The main objective of the study was to assess the sensitivity and specificity of the assay for correctly identifying Genotoxic carcinogens, as compared with the traditional rat liver unscheduled DNA synthesis assay. Based on existing carcinogenicity and Genotoxicity data and chemical class information, 90 chemicals were identified as primary candidates for use in the validation study. From these 90 chemicals, 46 secondary candidates and then 40 final chemicals were selected based on a sufficiency of carcinogenic and Genotoxic data, differences in chemical class or Genotoxic or carcinogenic mode of action (MOA), availability, price, and ease of handling. These 40 chemicals included 19 Genotoxic carcinogens, 6 Genotoxic non-carcinogens, 7 non-Genotoxic carcinogens and 8 non-Genotoxic non-carcinogens. “Genotoxicity” was defined as positive in the Ames mutagenicity test or in one of the standard in vivo Genotoxicity tests (primarily the erythrocyte micronucleus assay). These chemicals covered various chemicals classes, MOAs, and Genotoxicity profiles and were considered to be suitable for the purpose of the validation study. General principles of chemical selection for validation studies are discussed.
Raymond R Tice - One of the best experts on this subject based on the ideXlab platform.
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jacvam organized international validation study of the in vivo rodent alkaline comet assay for the detection of Genotoxic carcinogens i summary of pre validation study results
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2015Co-Authors: Hajime Kojima, Takashi Omori, Raffaella Corvi, Masamistu Honma, Leonard M Schechtman, Raymond R Tice, Brian Burlinson, Patricia A Escobar, Andrew R Kraynak, Yuzuki NakagawaAbstract:Abstract The in vivo rodent alkaline comet assay (comet assay) is used internationally to investigate the in vivo Genotoxic potential of test chemicals. This assay, however, has not previously been formally validated. The Japanese Center for the Validation of Alternative Methods (JaCVAM), with the cooperation of the U.S. NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)/the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), the European Centre for the Validation of Alternative Methods (ECVAM), and the Japanese Environmental Mutagen Society/Mammalian Mutagenesis Study Group (JEMS/MMS), organized an international validation study to evaluate the reliability and relevance of the assay for identifying Genotoxic carcinogens, using liver and stomach as target organs. The ultimate goal of this exercise was to establish an Organisation for Economic Co-operation and Development (OECD) test guideline. The study protocol was optimized in the pre-validation studies, and then the definitive (4th phase) validation study was conducted in two steps. In the 1st step, assay reproducibility was confirmed among laboratories using four coded reference chemicals and the positive control ethyl methanesulfonate. In the 2nd step, the predictive capability was investigated using 40 coded chemicals with known Genotoxic and carcinogenic activity (i.e., Genotoxic carcinogens, Genotoxic non-carcinogens, non-Genotoxic carcinogens, and non-Genotoxic non-carcinogens). Based on the results obtained, the in vivo comet assay is concluded to be highly capable of identifying Genotoxic chemicals and therefore can serve as a reliable predictor of rodent carcinogenicity.
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jacvam organized international validation study of the in vivo rodent alkaline comet assay for detection of Genotoxic carcinogens ii summary of definitive validation study results
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2015Co-Authors: Yoshifumi Uno, Hajime Kojima, Takashi Omori, Raffaella Corvi, Masamistu Honma, Leonard M Schechtman, Raymond R Tice, Brian Burlinson, Patricia A Escobar, Andrew R KraynakAbstract:The in vivo rodent alkaline comet assay (comet assay) is used internationally to investigate the in vivo Genotoxic potential of test chemicals. This assay, however, has not previously been formally validated. The Japanese Center for the Validation of Alternative Methods (JaCVAM), with the cooperation of the U.S. NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)/the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), the European Centre for the Validation of Alternative Methods (ECVAM), and the Japanese Environmental Mutagen Society/Mammalian Mutagenesis Study Group (JEMS/MMS), organized an international validation study to evaluate the reliability and relevance of the assay for identifying Genotoxic carcinogens, using liver and stomach as target organs. The ultimate goal of this exercise was to establish an Organisation for Economic Co-operation and Development (OECD) test guideline. The study protocol was optimized in the pre-validation studies, and then the definitive (4th phase) validation study was conducted in two steps. In the 1st step, assay reproducibility was confirmed among laboratories using four coded reference chemicals and the positive control ethyl methanesulfonate. In the 2nd step, the predictive capability was investigated using 40 coded chemicals with known Genotoxic and carcinogenic activity (i.e., Genotoxic carcinogens, Genotoxic non-carcinogens, non-Genotoxic carcinogens, and non-Genotoxic non-carcinogens). Based on the results obtained, the in vivo comet assay is concluded to be highly capable of identifying Genotoxic chemicals and therefore can serve as a reliable predictor of rodent carcinogenicity.
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the jacvam international validation study on the in vivo comet assay selection of test chemicals
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2015Co-Authors: Takeshi Morita, Hajime Kojima, Raffaella Corvi, Raymond R Tice, Masamitsu Honma, Makoto Hayashi, Leonard M SchechtmanAbstract:Abstract The Japanese Center for the Validation of Alternative Methods (JaCVAM) sponsored an international prevalidation and validation study of the in vivo rat alkaline pH comet assay. The main objective of the study was to assess the sensitivity and specificity of the assay for correctly identifying Genotoxic carcinogens, as compared with the traditional rat liver unscheduled DNA synthesis assay. Based on existing carcinogenicity and Genotoxicity data and chemical class information, 90 chemicals were identified as primary candidates for use in the validation study. From these 90 chemicals, 46 secondary candidates and then 40 final chemicals were selected based on a sufficiency of carcinogenic and Genotoxic data, differences in chemical class or Genotoxic or carcinogenic mode of action (MOA), availability, price, and ease of handling. These 40 chemicals included 19 Genotoxic carcinogens, 6 Genotoxic non-carcinogens, 7 non-Genotoxic carcinogens and 8 non-Genotoxic non-carcinogens. “Genotoxicity” was defined as positive in the Ames mutagenicity test or in one of the standard in vivo Genotoxicity tests (primarily the erythrocyte micronucleus assay). These chemicals covered various chemicals classes, MOAs, and Genotoxicity profiles and were considered to be suitable for the purpose of the validation study. General principles of chemical selection for validation studies are discussed.