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Azeddine Elhajouji, Dagmara Vaskova, Stephen D Dertinger, Hansjeorg Martus
5-(2-Chloroethyl)-2'-deoxyuridine (CEDU) was developed as an antiviral drug. It has been studied in a number of in vitro and in vivo genotoxicity assays and is considered an unusual nucleoside analogue owing to its potent mutagenic potential, with little to no measurable clastogenic activity. Given this atypical profile, CEDU represented an interesting compound for evaluating the in vivo Pig-a gene mutation assay, a test that is undergoing extensive validation for regulatory safety applications. The current report describes two studies with 7-week-old male Wistar Han rats, one that exposed animals to several dose levels of CEDU for 5 consecutive days, the other for 28 consecutive days...
September 15, 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...
September 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...
September 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...
September 11, 2018: Mutagenesis
Alexander Amberg, Lennart T Anger, Joel Bercu, David Bower, Kevin P Cross, Laura Custer, James S Harvey, Catrin Hasselgren, Masamitsu Honma, Candice Johnson, Robert Jolly, Michelle O Kenyon, Naomi L Kruhlak, Penny Leavitt, Donald P Quigley, Scott Miller, David Snodin, Lidiya Stavitskaya, Andrew Teasdale, Alejandra Trejo-Martin, Angela T White, Joerg Wichard, Glenn J Myatt
(Quantitative) structure-activity relationship or (Q)SAR predictions of DNA-reactive mutagenicity are important to support both the design of new chemicals and the assessment of impurities, degradants, metabolites, extractables and leachables, as well as existing chemicals. Aromatic N-oxides represent a class of compounds that are often considered alerting for mutagenicity yet the scientific rationale of this structural alert is not clear and has been questioned. Because aromatic N-oxide-containing compounds may be encountered as impurities, degradants and metabolites, it is important to accurately predict mutagenicity of this chemical class...
September 5, 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...
September 4, 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...
August 23, 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 Geranuim 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)...
August 6, 2018: Mutagenesis
Romualdo Benigni
Computational toxicology, also called 'in silico toxicology', is based on scientific knowledge gained from different scientific fields and on the premise that the toxicity of a chemical, depending on its intrinsic nature, can be predicted from its molecular structure and inferred from the properties of similar compounds whose activities are known. With the aim of providing faster, more economical, animal-free tools for predicting toxicity, the 'old' and well established science of Structure-Activity Relationships plays a crucial role, with increasing applications to the assessment of chemical genotoxicity and carcinogenicity...
July 30, 2018: Mutagenesis
Takeshi Morita, Yoshiyuki Shigeta, Tomoko Kawamura, Yurika Fujita, Hiroshi Honda, Masamitsu Honma
Two major endpoints for genotoxicity tests are gene mutation and chromosome damage (CD), which includes clastogenicity and aneugenicity detected by chromosomal aberration (CA) test or micronucleus (MN) test. Many in silico prediction systems for bacterial mutagenicity (i.e. Ames test results) have been developed and marketed. They show good performance for prediction of Ames mutagenicity. On the other hand, it seems that in silico prediction of CD does not progress as much as Ames prediction. Reasons for this include different mechanisms and detection methods, many false positives and conflicting test results...
July 28, 2018: Mutagenesis
Huaxiang Zhao, Mengqi Zhang, Wenjie Zhong, Jieni Zhang, Wenbin Huang, Yunfan Zhang, Weiran Li, Peizeng Jia, Taowen Zhang, Zhonghao Liu, Jiuxiang Lin, Feng Chen
Non-syndromic cleft lip with or without cleft palate (NSCLP) is the most common congenital craniofacial malformation, and its harmful influence on affected individuals is apparent. Despite many studies, the causative genes and their mechanisms are not completely clear. We recruited a Han Chinese NSCLP family and explored the causative variant in this pedigree. We performed whole-exome sequencing on two patients. Bioinformatics screening and analysis were used to identify the mutation. We also performed species conservation analysis, mutation function predictions, and homology protein modelling to evaluate the influence of the mutation...
July 20, 2018: Mutagenesis
David J Tweats, George E Johnson, Ivan Scandale, James Whitwell, Dean B Evans
No abstract text is available yet for this article.
July 16, 2018: Mutagenesis
Hunasanahally Puttaswamygowda Gurushankara, Ramamurthy Venu, Venkateshaiah Vasudev
To understand the role of hyperthermia (HT) in adaptive response, methyl methanesulfonate (MMS) adapted meiotic cells of Poecilocerus pictus were used. Poecilocerus pictus were treated with conditioning (L) or challenging (H) dose of MMS and 2-h time lag (TL) between these doses (L-2h-H) (combined) was employed. Different treatment schedules were used to analyse the influence of HT on MMS-induced adaptive response namely pre; inter; post-treatment and cross-adaptation. After each treatment schedules, chromosomal anomalies were analysed...
July 6, 2018: Mutagenesis
Jennifer E May, Craig Donaldson, Liana Gynn, H Ruth Morse
Mesenchymal stem/stromal cells (MSCs) within the bone marrow (BM) are vitally important in forming the micro-environment supporting haematopoiesis after myeloablative chemotherapy. MSCs are known to be damaged phenotypically and functionally by chemotherapy; however, to the best our knowledge, the persistence of genotoxic effects of chemotherapy on the BM micro-environment has not been studied. We therefore aimed to evaluate genotoxic effects of chemotherapy on the BM both in vitro and in vivo, using the comet and micronucleus assays, focussing on the persistence of DNA lesions that may contribute to complications in the patient...
September 17, 2018: Mutagenesis
Priti Singh, Lalit Mohan Aggarwal, Stephen A Parry, Mercy J Raman
Accurate quantification of DNA double strand breaks (DSB) in testicular germ cells is difficult because of cellular heterogeneity and the presence of endogenous γH2AX. Here, we used confocal microscopy to quantify DNA damage and repair kinetics following γ-irradiation (0.5-4 Gy) in three major mouse male germ cell stages, early and late pachytene spermatocytes and round spermatids (RSs), following a defined post irradiation time course. Dose-response curves showing linear best fit validated γH2AX focus as a rapid biodosimetric tool in these substages in response to whole body in vivo exposure...
September 17, 2018: Mutagenesis
Ashutosh Kumar, Mojgan Najafzadeh, Badie K Jacob, Alok Dhawan, Diana Anderson
No abstract text is available yet for this article.
September 17, 2018: Mutagenesis
Ana Cecilia Damiao Gouveia, Astrid Skovman, Annie Jensen, Ismo Kalevi Koponen, Steffen Loft, Martin Roursgaard, Peter Møller
Particles from burning candles contribute to the overall indoor exposure to particulate matter (PM). However, little is known about the effects of indoor sources of particles on cardiovascular disease endpoints. This study investigated the effect of pulmonary exposure to particles from combustion of candles and progression of atherosclerosis. Telomere shortening was assessed in tissues due to its relationship to risk of cardiovascular diseases. The particles were collected from burning candles and used for toxicological studies in cultured endothelial cells and apolipoprotein E (ApoE) knockout mice...
September 17, 2018: Mutagenesis
Héloïse Proquin, Carolina Rodríguez-Ibarra, Carolyn Moonen, Ismael M Urrutia Ortega, Jacob J Briedé, Theo M de Kok, Henk van Loveren, Yolanda Irasema Chirino
No abstract text is available yet for this article.
September 17, 2018: Mutagenesis
Yang Liu, Yixiang Wang, Xiangyu Sun, Xianli Zhang, Xiaozhe Wang, Chenying Zhang, Shuguo Zheng
Disturbed permanent tooth eruption is common in cleidocranial dysplasia (CCD), a skeletal disorder caused by heterozygous mutation of RUNX2, but the mechanism underlying is still unclear. As it is well known that dental follicle cells (DFCs) play a critical role in tooth eruption, the changed biological characteristics of DFCs might give rise to disturbance of permanent tooth eruption in CCD patients. Thus, primary DFCs from one CCD patient and normal controls were collected to investigate the effect of RUNX2 mutation on the bone remodeling activity of DFCs and explore the mechanism of impaired permanent tooth eruption in this disease...
June 26, 2018: Mutagenesis
Rafiqa Eachkoti, Sanah Farooq, Sheikh Imran Syeed, Hilal Ahmed Wani, Sabhiya Majid, Mohd Rafiq Pampori
Molecular studies have implicated mutant B-type Raf kinase (BRAFMut) of MAP-kinase signalling pathway in the pathogenesis of several cancers including colorectal cancer. Recently, the prognostic and therapeutic relevance of the most frequent BRAFV600E mutation also has been highlighted in colorectal carcinomas (CRC). Thus, the aim of this study was to investigate the prevalence of BRAFV600E mutation and to determine the correlation between this mutation and indicators of poor prognosis and outcome in patients with CRCs from Kashmir, North India...
May 23, 2018: Mutagenesis
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