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Environmental and Molecular Mutagenesis

Miroslav Mišík, Armen Nersesyan, Claudia Bolognesi, Michael Kundi, Franziska Ferk, Siegfried Knasmueller
One of the main problems of in vitro genotoxicity tests is the inadequate representation of drug metabolizing enzymes in most indicator cell lines which are currently used. We identified recently a human derived liver cell line (Huh6) which detected induction of DNA damage by representatives of different groups of promutagens without enzyme mix and showed that these cells are more suitable in terms of reproducibility and sensitivity as other currently used liver derived lines. We developed a protocol for micronucleus (MN) cytome assays with these cells and validated the procedure in experiments with representatives of different groups of directly and indirectly acting genotoxic carcinogens (MMS, cisplatin, PhIP, IQ, NDMA, B(a)P, AFB1, etoposide, and H2 O2 )...
November 8, 2018: Environmental and Molecular Mutagenesis
Xihan Guo, Xueqin Dai, Juan Ni, Xiaoling Ma, Jinglun Xue, Xu Wang
Geraniin has been reported to specifically induce apoptosis in multiple human cancers, but the underlying mechanism is poorly defined. The spindle assembly checkpoint (SAC) is a surveillance system to ensure high-fidelity chromosome segregation during mitosis. Weakening of SAC to enhance chromosome instability (CIN) can be therapeutic because very high levels of CIN are lethal. In this study, we have investigated the effects of geraniin on the SAC of colorectal cancer HCT116 cells and noncancerous colon epithelial CCD841 cells...
November 7, 2018: Environmental and Molecular Mutagenesis
Bhawana Bariar, C Greer Vestal, Bradley Deem, Donna Goodenow, Mimi Ughetta, R Warren Engledove, Mark Sahyouni, Christine Richardson
Infant acute leukemias are aggressive and characterized by rapid onset after birth. The majority harbor translocations involving the MLL gene with AF9 as one of its most common fusion partners. MLL and AF9 loci contain breakpoint cluster regions (bcrs) with sequences hypothesized to be targets of topoisomerase II inhibitors that promote translocation formation. Overlap of MLL bcr sequences associated with both infant acute leukemia and therapy-related leukemia following exposure to the topoisomerase II inhibitor etoposide led to the hypothesis that exposure during pregnancy to biochemically similar compounds may promote infant acute leukemia...
November 2, 2018: Environmental and Molecular Mutagenesis
Guifang Jin, Lu Cai, Keqi Hu, Yuyi Luo, Yuting Chen, Hansruedi Glatt, Yungang Liu
Human CYP2E1 metabolizes many xenobiotics of low molecular weight, thereby activating various promutagens/procarcinogens. In toxicological studies in vitro, dimethylsulfoxide (DMSO) is a common vehicle for organic compounds. However, it was observed to potently inhibit CYP2E1 activity. We were interested in whether it affects CYP2E1-dependent mutagenic responses. In this study, N-nitrosodiethylamine (NDEA), which is soluble in both water and DMSO, was used as a model promutagen. It induced Hprt gene mutations and micronuclei in a Chinese hamster V79-derived cell line expressing both human CYP2E1 and sulfotransferase (SULT) 1A1 (V79-hCYP2E1-hSULT1A1) even at low micromolar concentrations, but was inactive in parental V79 cells...
November 1, 2018: Environmental and Molecular Mutagenesis
Maria Michela Pallotta, Vincenza Barbato, Alain Pinton, Hervè Acloque, Roberto Gualtieri, Riccardo Talevi, Hèléne Jammes, Teresa Capriglione
Several studies have demonstrated that overexposure to pesticides can reduce mammalian sperm quality, impairing male fertility. Chlorpyrifos (CPF), a widely used organophosphate pesticide, was shown to impair spermatogenesis by inducing the formation of highly reactive toxic intermediates. To gain further insight into the mechanisms underlying the cytotoxicity and genotoxicity of CPF, bovine spermatozoa were exposed in vitro to environmental CPF concentrations and the motility, in vitro fertilization rates, DNA fragmentation, chromatin alterations, and methylation patterns were assessed...
October 26, 2018: Environmental and Molecular Mutagenesis
M R Schisler, B B Gollapudi, M M Moore
The forward gene mutation mouse lymphoma assay (MLA) is widely used, as part of a regulatory test battery, to identify the genotoxic potential of chemicals. It identifies mutagens capable of inducing a variety of genetic events. During the 1980s and early 1990s, the U.S. National Toxicology Program (NTP) developed a publicly available database ( of MLA results. This database is used to define the mutagenic potential of chemicals, to develop structure-activity relationships (SAR), and to draw correlations to animal carcinogenicity findings...
October 25, 2018: Environmental and Molecular Mutagenesis
Mohamed Alaraby, Sara Romero, Alba Hernández, Ricard Marcos
The in vivo model Drosophila melanogaster was used here to determine the detrimental effects induced by silver nanoparticles (AgNPs) exposure. The main aim was to explore its interaction with the intestinal barrier and the genotoxic effects induced in hemocytes. The observed effects were compared with those obtained by silver nitrate, as an agent acting via the release of silver ions. Larvae were fed in food media containing both forms of silver. Results indicated that silver nitrate was more toxic than AgNPs when the viability "egg-to-adult" was determined...
October 24, 2018: Environmental and Molecular Mutagenesis
Ulrike Luderer, Matthew J Meier, Gregory W Lawson, Marc A Beal, Carole L Yauk, Francesco Marchetti
Polycyclic aromatic hydrocarbons (PAHs) like benzo[a]pyrene (BaP) are ubiquitous environmental contaminants formed during incomplete combustion of organic materials. Our prior work showed that transplacental exposure to BaP depletes ovarian follicles and increases prevalence of epithelial ovarian tumors later in life. We used the MutaMouse transgenic rodent model to address the hypothesis that ovarian mutations play a role in tumorigenesis caused by prenatal exposure to BaP. Pregnant MutaMouse females were treated with 0, 10, 20, or 40 mg/kg/day BaP orally on gestational days 7-16, covering critical windows of ovarian development...
October 24, 2018: Environmental and Molecular Mutagenesis
Zhiying Ji, Raja S Settivari, Matthew J LeBaron
The Pig-a assay is an emerging and promising in vivo method to determine mutagenic potential of chemicals. Since its development in 2008, remarkable progress has been made in harmonizing and characterizing the test procedures, primarily using known mutagenic chemicals. The purpose of the present study was to evaluate specificity of the Pig-a assay using two nongenotoxic and well-characterized rodent liver carcinogens, phenobarbital and clofibrate, in male F344/DuCrl rats. Daily oral administration of phenobarbital or clofibrate at established hepatotoxic doses for 28 days resulted in substantial hepatic alterations, however, did not increase the frequency of Pig-a mutation markers (RETCD59- and RBCCD59- ) compared to vehicle control or pre-exposure (Day -5) mutant frequencies...
October 19, 2018: Environmental and Molecular Mutagenesis
J Christopher Corton, Andrew Williams, Carole L Yauk
High-throughput transcriptomic technologies are increasingly being used to screen environmental chemicals in vitro to provide mechanistic context for regulatory testing. The TGx-DDI biomarker is a 64-gene expression profile generated from testing 28 model chemicals or treatments (13 that cause DNA damage and 15 that do not) in human TK6 cells. While the biomarker is very accurate at predicting DNA damage inducing (DDI) potential using the nearest shrunken centroid method, the broad utility of the biomarker using other computational methods is not fully known...
October 17, 2018: Environmental and Molecular Mutagenesis
Miriam C Poirier, Stéphane Lair, Robert Michaud, Elena E Hernández-Ramon, Kathyayini V Divi, Jennifer E Dwyer, Corbin D Ester, Nancy N Si, Mehnaz Ali, Lisa L Loseto, Stephen A Raverty, Judith A St Leger, William G Van Bonn, Kathleen Colegrove, Kathleen A Burek-Huntington, Robert Suydam, Raphaela Stimmelmayr, John Pierce Wise, Sandra S Wise, Guy Beauchamp, Daniel Martineau
Carcinogenic polycyclic aromatic hydrocarbons (PAHs) were disposed directly into the Saguenay River of the St. Lawrence Estuary (SLE) by local aluminum smelters (Quebec, Canada) for 50 years (1926-1976). PAHs in the river sediments are likely etiologically related to gastrointestinal epithelial cancers observed in 7% of 156 mature (>19-year old) adult beluga found dead along the shorelines. Because DNA adduct formation provides a critical link between exposure and cancer induction, and because PAH-DNA adducts are chemically stable, we hypothesized that SLE beluga intestine would contain PAH-DNA adducts...
October 11, 2018: Environmental and Molecular Mutagenesis
Ulla Plappert-Helbig, Silvana Libertini, Wilfried Frieauff, Diethilde Theil, Hans-Jörg Martus
The phosphorylation of histone H2AX in Serine 139 (gamma-H2AX) marks regions of DNA double strand breaks and contributes to the recruitment of DNA repair factors to the site of DNA damage. Gamma-H2AX is used widely as DNA damage marker in vitro, but its use for genotoxicity assessment in vivo has not been extensively investigated. Here, we developed an image analysis system for the precise quantification of the gamma-H2AX signal, which we used to monitor DNA damage in animals treated with known genotoxicants (EMS, ENU and doxorubicin)...
October 11, 2018: Environmental and Molecular Mutagenesis
Axel J Berky, Ian T Ryde, Beth Feingold, Ernesto J Ortiz, Lauren H Wyatt, Caren Weinhouse, Heileen Hsu-Kim, Joel N Meyer, William K Pan
Mitochondrial DNA (mtDNA) copy number (CN) and damage in circulating white blood cells have been proposed as effect biomarkers for pollutant exposures. Studies have shown that mercury accumulates in mitochondria and affects mitochondrial function and integrity; however, these data are derived largely from experiments in model systems, rather than human population studies that evaluate the potential utility of mitochondrial exposure biomarkers. We measured mtDNA CN and damage in white blood cells (WBCs) from 83 residents of nine communities in the Madre de Dios region of the Peruvian Amazon that vary in proximity to artisanal and small-scale gold mining...
October 5, 2018: Environmental and Molecular Mutagenesis
Felicidad Espinoza, Lluis Cecchini, Juan Morote, Ricard Marcos, Susana Pastor
It has been suggested that the frequency of micronuclei (MN) in defoliated urothelial cells could be used as a biomarker for both the potential risk of bladder cancer (BC) and its progression. To prove this we have carried out a large study evaluating the MN frequency in a group of 383 hospital patients submitted to cystoscopy. From them, 77 were negative in their first cystoscopy, and were considered as a reference group; 79 were positive and were classified as patients with tumor; and 227 with previous bladder cancer submitted to follow-up monitoring were negative and classified as BC patients without tumor...
October 4, 2018: Environmental and Molecular Mutagenesis
Yasmeen Niazi, Hauke Thomsen, Bozena Smolkova, Ludmila Vodickova, Sona Vodenkova, Michal Kroupa, Veronika Vymetalkova, Alena Kazimirova, Magdalena Barancokova, Katarina Volkovova, Marta Staruchova, Per Hoffmann, Markus M Nöthen, Maria Dušinská, Ludovit Musak, Pavel Vodicka, Kari Hemminki, Asta Försti
Chromosomal aberrations (CAs) in human peripheral blood lymphocytes (PBL) measured with the conventional cytogenetic assay have been used for human biomonitoring of genotoxic exposure for decades. CA frequency in peripheral blood is a marker of cancer susceptibility. Previous studies have shown associations between genetic variants in metabolic pathway, DNA repair and major mitotic checkpoint genes and CAs. We conducted a genome-wide association study on 576 individuals from the Czech Republic and Slovakia followed by a replication in two different sample sets of 482 (replication 1) and 1288 (replication 2) samples...
October 3, 2018: Environmental and Molecular Mutagenesis
Yi Zhao, Guili Song, Jing Ren, Qing Li, Shan Zhong, Zongbin Cui
Saturation mutagenesis of all endogenous genes within the mouse genome remains a challenging task, although a plenty of gene-editing approaches are available for this purpose. Here, a poly(A)-trap vector was generated for insertion mutagenesis in mouse embryonic stem (mES) cells. This vector contains an expression cassette of neomycin (Neo)-resistant gene lacking a poly(A) signal and flanked by two inverted terminal repeats of the Sleeping Beauty (SB) transposon. The whole poly(A)-trap cassette can transpose into target TA dinucleotides, properly splice with endogenous genes and effectively interrupt the transcription of trapped genes in mES cells after transient induction of SB expression by doxycycline (DOX)-treatment at 1 μg/ml, leading to the formation of multiple geneticin (G418)-resistant cell clones...
October 2, 2018: Environmental and Molecular Mutagenesis
Svetlana L Avlasevich, Dorothea K Torous, Jeffrey C Bemis, Javed A Bhalli, Cameron C Tebbe, Jessica Noteboom, Demetria Thomas, Daniel J Roberts, Matthew Barragato, Brett Schneider, John Prattico, Mary Richardson, B Bhaskar Gollapudi, Stephen D Dertinger
The rodent blood Pig-a assay has been undergoing international validation for use as an in vivo hematopoietic cell gene mutation assay, and given the promising results an Organization for Economic Co-operation and Development (OECD) Test Guideline is currently under development. Enthusiasm for the assay stems in part from its alignment with 3Rs principles permitting combination with other genotoxicity endpoint(s) and integration into repeat-dose toxicology studies. One logistical requirement and experimental design limitation has been that blood samples required antibody labeling and flow cytometric analysis within one week of collection...
September 27, 2018: Environmental and Molecular Mutagenesis
Varinderpal S Dhillon, Eric Yeoh, Carolyn Salisbury, Julie Butters, Addolorata Di Matteo, Ian Olver, Michael Fenech
Prostate cancer (PC) is commonly diagnosed cancer in men but only a few risk factors, such as family history, ethnicity, and age have been established. Chromosomal instability is another possible risk factor but this has not been adequately explained previously. In this study, we tested the hypotheses that peripheral blood lymphocytes (PBL) of PC patients have (1) an abnormally high level of chromosomal instability; (2) that they are hypersensitive to ionizing radiation-induced DNA damage; and (3) that these phenotypes are affected by hOGG1 (C1245G) polymorphism...
September 27, 2018: Environmental and Molecular Mutagenesis
Vedran Mužinić, Snježana Ramić, Davor Želježić
Chlorpyrifos, imidacloprid, and α-cypermethrin are some of the most widely used insecticides in contemporary agriculture. However, their low-dose, nontarget genotoxic effects have not been extensively assayed. As one of the most relevant cancer biomarkers, we aimed to assess the aneuploidy due to chromosome missegregation during mitosis. To aim it we treated human lymphocytes in vitro with three concentrations of insecticides equivalents relevant for real scenario exposure assessed by regulatory agencies. We focused on chlorpyrifos as conventional and imidacloprid and α-cypermethrin as sustainable use insecticides...
September 27, 2018: Environmental and Molecular Mutagenesis
Page B McKinzie, Karen L McKim, Mason G Pearce, Michelle E Bishop, Barbara L Parsons
Somatic mutations accumulate in the human genome and are correlated with increased cancer incidence as humans age. The standard model for studying the carcinogenic effects of exposures for human risk assessment is the rodent 2-year carcinogenicity assay. However, there is little information regarding the effect of age on cancer-driver gene mutations in these models. The mutant fraction (MF) of Kras codon 12 GGT to GAT and GGT to GTT mutations, oncogenic mutations orthologous between humans and rodents, was quantified over the lifespan of B6C3F1 mice...
September 26, 2018: Environmental and Molecular Mutagenesis
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