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Azeddine Elhajouji, Dagmara Vaskova, Rebecca Downing, Stephen D Dertinger, Hansjeorg Martus
No abstract text is available yet for this article.
December 27, 2018: Mutagenesis
Hanns Moshammer, Abdul Wali Khan, Peter Wallner, Michael Poteser, Michael Kundi, Hans-Peter Hutter
Higher rates of nuclear anomalies in buccal cells of coffee workers exposed to pesticides in comparison to their unexposed peers were detected in our field study. Here, we extend our findings by examining other exposure indicators in this sample. Occupational exposure of 38 exposed and 33 non-exposed farmworkers was assessed as exposure days in the last month (0-25 days) and as years of exposure (0-47 years). Genotoxic and cytotoxic markers in buccal cells were analysed following standard procedures for buccal micronucleus cytome assay...
December 26, 2018: Mutagenesis
Shun Matsuda, Sayaka Wanibuchi, Toshihiko Kasahara
Ser139-phosphorylated H2AX (γH2AX) is a functional biomarker of DNA double-strand breaks. However, its conventional detection for in vivo samples relies on immunological methods using anti-γH2AX antibodies, making quantitative analysis difficult. Here, we established an absolute γH2AX quantification in vivo method for multiple organs in mice using liquid chromatography-triple quadrupole tandem mass spectrometry. When applying the method to male Institute of Cancer Research (ICR) mice (8 weeks old), the testes showed the highest γH2AX level (2...
December 24, 2018: Mutagenesis
Weiying Liu, Jing Xi, Yiyi Cao, Xinyue You, Ruixue Chen, Xinyu Zhang, Li Han, Guoyu Pan, Yang Luan
Metabolic activation is essential in standard in vitro genotoxicity test systems. At present, there is a lack of suitable cell models that can express the major characteristics of liver function for predicting substance toxicity in humans. Human-induced hepatocytes (hiHeps), which have been generated from fibroblasts by lentiviral expression of liver transcription factors, can express hepatic gene programs and can be expanded in vitro and display functional characteristics of mature hepatocytes, including cytochrome P450 enzyme activity and biliary drug clearance...
December 24, 2018: Mutagenesis
Yurika Fujita, Hiroshi Honda, Masayuki Yamane, Takeshi Morita, Tomonari Matsuda, Osamu Morita
Genotoxicity evaluation has been widely used to estimate the carcinogenicity of test substances during safety evaluation. However, the latest strategies using genotoxicity tests give more weight to sensitivity; therefore, their accuracy has been very low. For precise carcinogenicity evaluation, we attempted to establish an integrated testing strategy for the tailor-made carcinogenicity evaluation of test materials, considering the relationships among genotoxicity test results (Ames, in vitro mammalian genotoxicity and in vivo micronucleus), carcinogenicity test results and chemical properties (molecular weight, logKow and 179 organic functional groups)...
December 14, 2018: Mutagenesis
Ulf Norinder, Ernst Ahlberg, Lars Carlsson
Valid and predictive models for classifying Ames mutagenicity have been developed using conformal prediction. The models are Random Forest models using signature molecular descriptors. The investigation indicates, on excluding not-strongly mutagenic compounds (class B), that the validity for mutagenic compounds is increased for the predictions based on both public and the Division of Genetics and Mutagenesis, National Institute of Health Sciences of Japan (DGM/NIHS) data while less so when using only the latter data source...
December 12, 2018: Mutagenesis
Srambikkal Nishad, Anu Ghosh
There remain significant uncertainties in estimation of risks with low doses of radiation. The small coastal belt in the southwestern state of Kerala, India, extending from Neendakara in the south to Purakkad in the north is one of the most extensively studied high-level natural background radiation areas (HLNRAs) of the world to address these concerns. The natural radioactivity here is due to occurrence of monazite sand bearing placer deposits along the coastline. In this study, proteomic approach was employed to study the response of human peripheral blood mononuclear cells (PBMCs) from individuals residing in HLNRA (N = 10; mean radiation dose: 15...
November 29, 2018: Mutagenesis
Olgica Mihaljevic, Snezana Zivancevic-Simonovic, Olivera Milosevic-Djordjevic, Predrag Djurdjevic, Danijela Jovanovic, Zeljko Todorovic, Darko Grujicic, Marina Radovic-Jakovljevic, Jovana Tubic, Aleksandra Markovic, Milan Paunovic, Marijana Stanojevic-Pirkovic, Slavica Markovic
As apoptosis and genome instability in children with autoimmune diseases (AIDs) are insufficiently investigated, we aimed to analyse them in peripheral blood lymphocytes (PBLs) of children and adolescents with Hashimoto's thyroiditis (HT), Graves' disease (GD) and type 1 diabetes mellitus (T1DM), including possible factors that could affect their occurrence. The study population included 24 patients and 19 healthy controls. Apoptotic cells were detected using an Annexin V-FITC/7-AAD kit. Genome instability was measured as micronuclei (MNs) frequency using the cytokinesis-block MN assay...
November 27, 2018: Mutagenesis
Petko I Petkov, Terry W Schultz, Masamitsu Honma, Takashi Yamada, Elena Kaloyanova, Ovanes G Mekenyan
This study validates the performance of the TIssue MEtabolism Simulator (TIMES) genotoxicity models with data on pesticide chemicals included in a recently released European Food Safety Authority (EFSA) genotoxicity database. The EFSA database is biased towards negative chemicals. A comparison of substances included in the EFSA database and TIMES genotoxicity databases showed that the majority of the EFSA pesticides is not included in the TIMES genotoxicity databases and, thus, out of the applicability domains of the current TIMES models...
November 16, 2018: Mutagenesis
Masamitsu Honma, Airi Kitazawa, Alex Cayley, Richard V Williams, Chris Barber, Thierry Hanser, Roustem Saiakhov, Suman Chakravarti, Glenn J Myatt, Kevin P Cross, Emilio Benfenati, Giuseppa Raitano, Ovanes Mekenyan, Petko Petkov, Cecilia Bossa, Romualdo Benigni, Chiara Laura Battistelli, Alessandro Giuliani, Olga Tcheremenskaia, Christine DeMeo, Ulf Norinder, Hiromi Koga, Ciloy Jose, Nina Jeliazkova, Nikolay Kochev, Vesselina Paskaleva, Chihae Yang, Pankaj R Daga, Robert D Clark, James Rathman
The International Conference on Harmonization (ICH) M7 guideline allows the use of in silico approaches for predicting Ames mutagenicity for the initial assessment of impurities in pharmaceuticals. This is the first international guideline that addresses the use of quantitative structure-activity relationship (QSAR) models in lieu of actual toxicological studies for human health assessment. Therefore, QSAR models for Ames mutagenicity now require higher predictive power for identifying mutagenic chemicals. To increase the predictive power of QSAR models, larger experimental datasets from reliable sources are required...
October 23, 2018: Mutagenesis
Alex Cayley, Adrian Fowkes, Richard V Williams
While high-level performance metrics generated from the validation of quantitative structure-activity relationship (QSAR) systems can provide valuable information on how well these models perform and where they need to be improved, they require appropriate interpretation. There is no universal performance metric which will answer all of the questions a user might ask relating to a model, and therefore, a combination of metrics should usually be considered. Furthermore, results may vary according to the chemical space being used to validate a model, and, in some cases, it may be the validation data which is lacking or ambiguous rather than the prediction being made...
October 20, 2018: Mutagenesis
Suman K Chakravarti, Roustem D Saiakhov
This article describes a method to generate molecular fingerprints from structural environments of mutagenicity alerts and calculate similarity between them. This approach was used to improve classification accuracy of alerts and for searching structurally similar analogues of an alerting chemical. It builds fingerprints using molecular fragments from the vicinity of the alerts and automatically accounts for the activating and deactivating/mitigating features of alerts needed for accurate predictions. This study also demonstrates the usefulness of transfer learning in which a distributed representation of chemical fragments was first trained on millions of unlabelled chemicals and then used for generating fingerprints and similarity search on smaller data sets labelled with Ames test outcomes...
October 20, 2018: Mutagenesis
Shunlan Yu, Junkang Quan, Xiaozhe Wang, Xiangyu Sun, Xianli Zhang, Yang Liu, Chenying Zhang, Shuguo Zheng
Autosomal-dominant hypocalcification amelogenesis imperfecta (ADHCAI) is characterized by soft enamel that easily disintegrates and exposed dark dentin. ADHCAI is caused by mutations in a gene called family with sequence similarity 83 member H (FAM83H). To investigate the molecular genetics of ADHCAI, a Chinese family in which three generations exhibited ADHCAI was recruited. The enamel ultrastructure was analysed by environmental scanning electron microscopy (ESEM), which showed altered enamel rod (prism) structures in ADHCAI patients compared to the structures in healthy controls...
October 11, 2018: Mutagenesis
Laura E Wohak, Ann-Christin Baranski, Annette M Krais, Heinz H Schmeiser, David H Phillips, Volker M Arlt
The tumour suppressor p53, encoded by TP53, is a key player in a wide network of signalling pathways. We investigated its role in the bioactivation of the environmental carcinogen 3-nitrobenzanthrone (3-NBA)found in diesel exhaust and its metabolites 3-aminobenzanthrone (3-ABA) and N-hydroxy-3-aminobenzanthrone (N-OH-3-ABA) in a panel of isogenic human colorectal HCT116 cells differing only with respect to their TP53 status [i.e. TP53(+/+), TP53(+/-), TP53(-/-), TP53(R248W/+) or TP53(R248W/-)]. As a measure of metabolic competence, DNA adduct formation was determined using 32P-postlabelling...
October 11, 2018: Mutagenesis
Jatin R Verma, Danielle S G Harte, Ume-Kulsoom Shah, Huw Summers, Catherine A Thornton, Shareen H Doak, Gareth J S Jenkins, Paul Rees, John W Wills, George E Johnson
Use of imaging flow cytometry to assess induced DNA damage via the cytokinesis block micronucleus (CBMN) assay has thus far been limited to radiation dosimetry in human lymphocytes using high end, 'ImageStream X' series imaging cytometers. Its potential to enumerate chemically induced DNA damage using in vitro cell lines remains unexplored. In the present manuscript, we investigate the more affordable FlowSight® imaging cytometry platform to assess in vitro micronucleus (MN) induction in the human lymphoblastoid TK6 and metabolically competent MCL-5 cells treated with Methyl Methane Sulfonate (MMS) (0-5 µg/ml), Carbendazim (0-1...
October 11, 2018: Mutagenesis
Antonella Russo, Eugenia Cordelli, Tullia Salvitti, Elisa Palumbo, Francesca Pacchierotti
Rad54 protein is a key player of the homologous recombination pathway, required for deposition and stabilisation of Rad51 foci at double strand breaks. Its role at the meiotic prophase, when double strand breaks are physiologically introduced to allow recombination, is well described. However, the hypothesis that Rad54 deficiency affect chromosome integrity of germ cells in unirradiated and irradiated animals has not been tested yet. In this study, the occurrence of spontaneous and X-ray-induced chromosome aberrations was assessed by analysis of spermatocyte MI spreads or by application of micronucleus assay in early spermatids isolated from wild type and Rad54/Rad54B knockout (KO) mice...
October 11, 2018: Mutagenesis
Fengge Wang, Shuxiong Chen, Yanwen Jiang, Yun Zhao, Liting Sun, Biaobiao Zheng, Lu Chen, Zhuo Liu, Xue Zheng, Kangle Yi, Chunjin Li, Xu Zhou
Ammonia, produced mainly from the deamination of amino acids and glutamine, is one of the major toxic components in blood and tissues that may affect bovine health. However, the physiological and pathological roles of ammonia in the mammary glands are not understood clearly. In the present study, the bovine mammary epithelial cell line (MAC-T) was utilised as an in vitro model to determine the effects of ammonia on bovine mammary gland. We demonstrated that ammonia stimulated the production of intracellular reactive oxygen species, decreased mitochondrial membrane potential, interrupted intracellular calcium ion (Ca2+) homeostasis and induced cell apoptosis...
October 11, 2018: Mutagenesis
Hiroyuki Kamiya, Tetsuaki Makino, Tetsuya Suzuki, Miwako Kobayashi, Ichiro Matsuoka
Reactive oxygen species generate 8-oxo-7,8-dihydroguanine (GO, 8-hydroxyguanine), which induces G:C→T:A transversion mutations. The knockdowns of the protein responsible for Werner syndrome (WRN), a cancer-associated DNA helicase, and DNA polymerase (pol) λ, a WRN-interacting DNA pol, cause untargeted base-substitution mutations (action-at-a-distance mutations). To examine the consequences of the dual reductions of WRN and pol λ for the mutations caused by GO, siRNAs against both proteins were introduced into human U2OS cells...
October 11, 2018: Mutagenesis
Xihan Guo, Han Wang, Juan Ni, Ziqing Liang, Xiayu Wu, Jinglun Xue, Xu Wang
Homeostasis of chromosomal instability (CIN) facilitates the origin and evolution of abnormal karyotypes that are critical for the survival and proliferation of cancer cells, but excessive CIN can result in cellular toxicity. Geraniin is a multifunctional ellagitannin found in some species of Geranium and Phyllanthus. We employed the cytokinesis-block micronucleus cytome assay to evaluate the CIN, nuclear division index (NDI) and apoptosis induced by geraniin in human colorectal adenocarcinoma cells (Colo205 and Colo320) and human colon mucosal epithelial cells (NCM460)...
October 11, 2018: Mutagenesis
Rachael E Tennant, Sébastien J Guesné, Steven Canipa, Alex Cayley, William C Drewe, Masamitsu Honma, Kenichi Masumura, Takeshi Morita, Susanne A Stalford, Richard V Williams
As part of the hazard and risk assessment of chemicals in man, it is important to assess the ability of a chemical to induce mutations in vivo. Because of the commonalities in the molecular initiating event, mutagenicity in vitro can correlate well to the in vivo endpoint for certain compound classes; however, the difficulty lies in identifying when this correlation holds true. In silico alerts for in vitro mutagenicity may therefore be used as the basis for alerts for mutagenicity in vivo where an expert assessment is carried out to establish the relevance of the correlation...
October 3, 2018: Mutagenesis
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