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Genotoxicity evaluation of gene therapies: A report from the International Workshop on Genotoxicity Testing (IWGT) 2022 Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-09-20 S. Libertini, J. K. Jadlowsky, T. A. Lanz, L. M. Mihalcik, D. M. Pizzurro
At the 8th International Workshop on Genotoxicity Testing meeting in Ottawa, in August 2022, a plenary session was dedicated to the genotoxicity risk evaluation of gene therapies, including insertional oncogenesis and off‐target genome editing. This brief communication summarizes the topics of discussion and the main insights from the speakers. Common themes included recommendations to conduct tailored
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Power analyses to inform Duplex Sequencing study designs for MutaMouse liver and bone marrow Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-09-13 Elena Esina, Annette E. Dodge, Andrew Williams, David M. Schuster, Danielle P. M. LeBlanc, Francesco Marchetti, Carole L. Yauk
Regulatory genetic toxicology testing is essential for identifying potentially mutagenic hazards. Duplex Sequencing (DS) is an error‐corrected next‐generation sequencing technology that provides substantial advantages for mutation analysis over conventional mutagenicity assays including: improved accuracy of mutation detection, ability to measure changes in mutation spectrum, and applicability across
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High frequency of silent mutations in gyrA gene of Mycobacterium tuberculosis in Indian isolates Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-09-12 Anamika Gupta, Sudhir K. Pal, Vijay Nema
Reporting any uncommon or untapped changes in bacterial genetics or physiology would be of great importance to support the drug development process. We studied 120 Mycobacterium tuberculosis clinical isolates with different geographical origin within India and their resistance profile and found a significant number of isolates (109) harboring the polymorphism at nucleotide positions 61 and 284 of the
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Mutagenicity of the agriculture pesticide chlorothalonil assessed by somatic mutation and recombination test in Drosophila melanogaster Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-09-12 Bruno Veber, Mariana do Amaral Flores, Mauricio Lehmann, Carlos Eduardo da Rosa, Mariana Leivas Müller Hoff
Chlorothalonil (CTL) is a pesticide widely used in Brazil, yet its mutagenic potential is not fully determined. Thus, we assessed the mutagenicity of CTL and its bioactivation metabolites using the somatic mutation and recombination test (SMART) in Drosophila melanogaster, by exposing individuals, with basal and high bioactivation capacities (standard and high bioactivation cross offspring, respectively)
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Epigenotoxicity: Decoding the epigenetic imprints of genotoxic agents and their implications for regulatory genetic toxicology Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-09-12 Roger Godschalk, Christopher Faulk, Jessica LaRocca, Jan van Benthem, Francesco Marchetti
Regulatory genetic toxicology focuses on DNA damage and subsequent gene mutations. However, genotoxic agents can also affect epigenetic marks, and incorporation of epigenetic data into the regulatory framework may thus enhance the accuracy of risk assessment. Additionally, epigenetic alterations may identify non‐genotoxic carcinogens that are not captured with the current battery of tests. Epigenetic
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Correction to “Mutation spectra of the BRCA1/2 genes in human breast and ovarian cancer and germline” Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-09-09
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Assessment of genotoxic potential of fragrance materials in the chicken egg assays Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-09-09 Yax Thakkar, Tetyana Kobets, Anne Marie Api, Jian‐Dong Duan, Gary M. Williams
The genotoxic and clastogenic/aneugeneic potentials of four α,β‐unsaturated aldehydes, 2‐phenyl‐2‐butenal, nona‐2‐trans‐6‐cis‐dienal, 2‐methyl‐2‐pentenal, and p‐methoxy cinnamaldehyde, which are used as fragrance materials, were assessed using the Chicken Egg Genotoxicity Assay (CEGA) and the Hen's egg micronucleus (HET‐MN) assay, respectively. Selection of materials was based on their chemical structures
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AOP report: Development of an adverse outcome pathway for deposition of energy leading to learning and memory impairment Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-09-04 Ahmad Sleiman, Kathleen B. Miller, Danicia Flores, Jaqueline Kuan, Kaitlyn Altwasser, Benjamin J. Smith, Tatiana Kozbenko, Robyn Hocking, Scott J. Wood, Janice Huff, Christelle Adam‐Guillermin, Nobuyuki Hamada, Carole Yauk, Ruth Wilkins, Vinita Chauhan
Understanding radiation‐induced non‐cancer effects on the central nervous system (CNS) is essential for the risk assessment of medical (e.g., radiotherapy) and occupational (e.g., nuclear workers and astronauts) exposures. Herein, the adverse outcome pathway (AOP) approach was used to consolidate relevant studies in the area of cognitive decline for identification of research gaps, countermeasure development
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Poly‐ADP‐ribosylation dynamics, signaling, and analysis Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-09-02 Rasha Q. Al‐Rahahleh, Robert W. Sobol
ADP‐ribosylation is a reversible post‐translational modification that plays a role as a signaling mechanism in various cellular processes. This modification is characterized by its structural diversity, highly dynamic nature, and short half‐life. Hence, it is tightly regulated at many levels by cellular factors that fine‐tune its formation, downstream signaling, and degradation that together impacts
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Evaluation of the nitrosamine impurities of ACE inhibitors using computational, in vitro, and in vivo methods demonstrate no genotoxic potential Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-08-24 Jennifer Cheung, Krista Dobo, Shaofei Zhang, Raphael Nudelman, Friedemann Schmidt, Jan Wenzel, Andreas Czich, Maik Schuler
Evaluation and mitigation of the potential carcinogenic risks associated with nitrosamines in marketed pharmaceutical products are areas of interest for pharmaceutical companies and health authorities alike. Significant progress has been made to establish acceptable intake (AI) levels for N‐nitrosamine drug substance‐related impurities (NDSRIs) using SAR, however some compounds require experimental
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Assessing the genotoxicity of N‐nitrosodiethylamine with three in vivo endpoints in male Big Blue® transgenic and wild‐type C57BL/6N mice Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-07-16 Shaofei Zhang, Stephanie L. Coffing, William C. Gunther, Michael L. Homiski, Richard A. Spellman, Phu Van, Maik Schuler
The detection of N‐nitrosamines in drug products has raised global regulatory interest in recent years due to the carcinogenic potential of some nitrosamines in animals and a need to identify a testing strategy has emerged. Ideally, methods used would allow for the use of quantitative analysis of dose–response data from in vivo genotoxicity assays to determine a compound‐specific acceptable intake
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Mutagenicity evaluation of methyl tertiary‐ butyl ether in multiple tissues of transgenic rats following whole body inhalation exposure Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-07-16 B. Bhaskar Gollapudi, Erik K. Rushton
Methyl tertiary‐butyl ether (MTBE) is used as a component of motor vehicle fuel to enhance combustion efficiency and to reduce emissions of carbon monoxide and nitrogen oxides. Although MTBE was largely negative in the in vitro and in vivo genotoxicity studies, isolated reports of positive findings along with the observation of tumors in the rat cancer bioassays raised concern for its in vivo mutagenic
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Mutation spectra of the BRCA1/2 genes in human breast and ovarian cancer and germline. Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-06-11 Yumiko Koi,Arisa Watanabe,Akari Kawasaki,Satomi Ideo,Nao Matsutani,Kaname Miyashita,Seijiro Shioi,Eriko Tokunaga,Mototsugu Shimokawa,Yoshimichi Nakatsu,Isao Kuraoka,Shinya Oda
Annotating genomic sequence alterations is sometimes a difficult decision, particularly in missense variants with uncertain pathogenic significance and also in those presumed as germline pathogenic variants. We here suggest that mutation spectrum may also be useful for judging them. From the public databases, 982 BRCA1/1861 BRCA2 germline missense variants and 294 BRCA1/420 BRCA2 somatic missense variants
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Severity of effect considerations regarding the use of mutation as a toxicological endpoint for risk assessment: A report from the 8th International Workshop on Genotoxicity Testing (IWGT). Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-06-03 Barbara L Parsons,Marc A Beal,Kerry L Dearfield,George R Douglas,Min Gi,B Bhaskar Gollapudi,Robert H Heflich,Katsuyoshi Horibata,Michelle Kenyon,Alexandra S Long,David P Lovell,Anthony M Lynch,Meagan B Myers,Stefan Pfuhler,Alisa Vespa,Andreas Zeller,George E Johnson,Paul A White
Exposure levels without appreciable human health risk may be determined by dividing a point of departure on a dose-response curve (e.g., benchmark dose) by a composite adjustment factor (AF). An "effect severity" AF (ESAF) is employed in some regulatory contexts. An ESAF of 10 may be incorporated in the derivation of a health-based guidance value (HBGV) when a "severe" toxicological endpoint, such
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Establishment of a nonradioactive DNA ligation assay and its applications in murine tissues Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-05-20 Sharleen Friese, Tom Heinze, Franziska Ebert, Tanja Schwerdtle
As final process of every DNA repair pathway, DNA ligation is crucial for maintaining genomic stability and preventing DNA strand breaks to accumulate. Therefore, a method reliably assessing DNA ligation capacity in protein extracts from murine tissues was aimed to establish. To optimize applicability, the use of radioactively labeled substrates was avoided and replaced by fluorescently labeled oligonucleotides
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Visualization strategies to aid interpretation of high‐dimensional genotoxicity data Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-05-17 Stephen D. Dertinger, Erica Briggs, Yusuf Hussien, Steven M. Bryce, Svetlana L. Avlasevich, Adam Conrad, George E. Johnson, Andrew Williams, Jeffrey C. Bemis
This article describes a range of high‐dimensional data visualization strategies that we have explored for their ability to complement machine learning algorithm predictions derived from MultiFlow® assay results. For this exercise, we focused on seven biomarker responses resulting from the exposure of TK6 cells to each of 126 diverse chemicals over a range of concentrations. Obviously, challenges associated
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Assessment of the genotoxicity of tert‐butyl alcohol in an in vivo thyroid comet assay Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-05-08 Chad M. Thompson, Nicole Dewhurst, Dmitri Moundous, Susan J. Borghoff, Laurie C. Haws, Marie Z. Vasquez
Chronic exposure to high (20,000 ppm) concentrations of tert‐butyl alcohol (TBA) in drinking water, equivalent to ~2100 mg/kg bodyweight per day, is associated with slight increases in the incidence of thyroid follicular cell adenomas and carcinomas in mice, with no other indications of carcinogenicity. In a recent toxicological review of TBA, the U.S. EPA determined that the genotoxic potential of
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Comparison between inhalational anesthetics in terms of DNA damage and immunological markers Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-04-29 Mariana G. Braz, Mariane A. P. Silva, Carlos E. Scorza, Juliana R. Lara, José Reinaldo C. Braz, Leandro G. Braz
This study compared genetic damage and immunological markers between surgical patients who underwent inhalational anesthesia with isoflurane or sevoflurane. Blood samples were collected from surgical patients (n = 18 in the isoflurane group and n = 17 in the sevoflurane group) at baseline (before the anesthesia procedure) and the day after anesthesia. DNA damage was detected using an alkaline comet
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Within‐laboratory reproducibility of Ames test results: Are repeat tests necessary? Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-04-23 Errol Zeiger, Constance A. Mitchell, Stefan Pfuhler, Yang Liao, Kristine L. Witt
The Ames test is required by regulatory agencies worldwide for assessing the mutagenic and carcinogenic potential of chemical compounds. This test uses several strains of bacteria to evaluate mutation induction: positive results in the assay are predictive of rodent carcinogenicity. As an initial step to understanding how well the assay may detect mutagens present as constituents of complex mixtures
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AOP report: Development of an adverse outcome pathway for deposition of energy leading to cataracts Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-04-22 Emma Carrothers, Meghan Appleby, Vita Lai, Tatiana Kozbenko, Dalya Alomar, Benjamin J. Smith, Nobuyuki Hamada, Patricia Hinton, Elizabeth A. Ainsbury, Robyn Hocking, Carole Yauk, Ruth C. Wilkins, Vinita Chauhan
Cataracts are one of the leading causes of blindness, with an estimated 95 million people affected worldwide. A hallmark of cataract development is lens opacification, typically associated not only with aging but also radiation exposure as encountered by interventional radiologists and astronauts during the long‐term space mission. To better understand radiation‐induced cataracts, the adverse outcome
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Mouse models to explore the biological and organismic role of DNA polymerase beta Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-04-15 Robert W. Sobol
Gene knock‐out (KO) mouse models for DNA polymerase beta (Polβ) revealed that loss of Polβ leads to neonatal lethality, highlighting the critical organismic role for this DNA polymerase. While biochemical analysis and gene KO cell lines have confirmed its biochemical role in base excision repair and in TET‐mediated demethylation, more long‐lived mouse models continue to be developed to further define
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Inspiring basic and applied research in genome integrity mechanisms: Dedication to Samuel H. Wilson Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-04-15 Shan Yan, Shobhan Gaddameedhi, Robert W. Sobol
This Special Issue (SI) of Environmental and Molecular Mutagenesis (EMM), entitled “Inspiring Basic and Applied Research in Genome Integrity Mechanisms,” is to update the community on recent findings and advances on genome integrity mechanisms with emphasis on their importance for basic and environmental health sciences. This SI includes two research articles, one brief research communication, and
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Interlaboratory validation of the ToxTracker assay: An in vitro reporter assay for mechanistic genotoxicity assessment Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-03-28 Giel Hendriks, Els Adriaens, Ashley Allemang, Julie Clements, Gabrielle Cole, Remco Derr, Maria Engel, Annie Hamel, Darren Kidd, Stephanie Kellum, Tomomi Kiyota, Abby Myhre, Valerie Naëssens, Stefan Pfuhler, Marise Roy, Raja Settivari, Maik Schuler, Andreas Zeller, Jan van Benthem, Philippe Vanparys, David Kirkland
ToxTracker is a mammalian cell reporter assay that predicts the genotoxic properties of compounds with high accuracy. By evaluating induction of various reporter genes that play a key role in relevant cellular pathways, it provides insight into chemical mode-of-action (MoA), thereby supporting discrimination of direct-acting genotoxicants and cytotoxic chemicals. A comprehensive interlaboratory validation
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Qualitative and quantitative changes in mitochondrial DNA associated with cervical cancer: A comprehensive review Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-03-25 Isadora Oliveira Ansaloni Pereira, Nayara Nascimento Toledo Silva, Angelica Alves Lima, Glenda Nicioli da Silva
Cervical cancer is the fourth most commonly diagnosed cancer in women and is considered a preventable disease, as vaccination and screening programs effectively reduce its incidence and mortality rates. Disease physiopathology and malignant cell transformation is a complex process, but it is widely known that high‐risk HPV (hrHPV) infection is a necessary risk factor for cancer development. Mitochondria
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Investigations on the genotoxic potential of styrene in Fischer 344 rats using multiple endpoints Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-03-25 B. Bhaskar Gollapudi
Genotoxicity of styrene monomer was evaluated in male Fischer 344 rats using the alkaline comet assay for DNA damage, micronucleus assay for cytogenetic damage and the Pig-a assay for gene mutations. In a dose range finding (DRF) study, styrene was administered by oral gavage in corn oil for 28 consecutive days at 0, 100, 500, and 1000 mg/kg/day. The bioavailability of styrene was confirmed in the
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Firefighting, per- and polyfluoroalkyl substances, and DNA methylation of genes associated with prostate cancer risk Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-03-24 Margaret Quaid, Jaclyn M. Goodrich, Miriam M. Calkins, Judith M. Graber, Derek Urwin, Jamie Gabriel, Alberto J. Caban-Martinez, Rebekah L. Petroff, Casey Grant, Shawn C. Beitel, Sally Littau, John J. Gulotta, Darin Wallentine, Jeff Hughes, Jefferey L. Burgess
Prostate cancer is the leading incident cancer among men in the United States. Firefighters are diagnosed with this disease at a rate 1.21 times higher than the average population. This increased risk may result from occupational exposures to many toxicants, including per- and polyfluoroalkyl substances (PFAS). This study assessed the association between firefighting as an occupation in general or
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Urinary mutagenicity and bladder cancer risk in northern New England Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-03-11 Jason Y. Y. Wong, Alexander H. Fischer, Dalsu Baris, Laura E. Beane Freeman, Margaret R. Karagas, Molly Schwenn, Alison Johnson, Peggy P. Matthews, Adam E. Swank, G. Monawar Hosain, Stella Koutros, Debra T. Silverman, David M. DeMarini, Nathaniel Rothman
The etiology of bladder cancer among never smokers without occupational or environmental exposure to established urothelial carcinogens remains unclear. Urinary mutagenicity is an integrative measure that reflects recent exposure to genotoxic agents. Here, we investigated its potential association with bladder cancer in rural northern New England. We analyzed 156 bladder cancer cases and 247 cancer-free
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Genotoxicity in humans exposed to arsenic, lithium, and boron in drinking water in the Bolivian Andes—A cross sectional study Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-02-22 Noemi Tirado, Josué Mamani, Jessica De Loma, Franz Ascui, Karin Broberg, Jacques Gardon
Elevated concentrations of arsenic, lithium and boron in drinking water have already been reported in Bolivia. Arsenic is known to cause genotoxicity but that caused by lithium and boron is less well known. The aim of the present cross‐sectional study was to evaluate potential genotoxic effects of exposure to arsenic, while considering exposure to lithium and boron and genetic susceptibility. Women
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Cytogenotoxicity effects in addicts with multidrug consumption Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-02-14 Ana Elizabeth González-Santiago, Alejandro Salvador Gómez-Cabrera, Raúl Cuauhtémoc Baptista-Rosas, Guillermo Moisés Zúñiga-González, Belinda Claudia Gómez-Meda, Ana Alondra Sobrevilla Navarro, María Guadalupe Sánchez-Parada
Drug abuse is considered a global health problem with serious social impact. In recent decades, changes in drug consumption patterns have shown a clear rising trend in the use of multiple drugs. Although the buccal micronucleus cytome (BMCyt) assay has evaluated cytotoxicity in drug abuse, there has not been an approach that takes into account this pattern of multiple drug use. Therefore, in this study
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Comparative analysis of micronucleus induction and DNA damage biomarkers in TK6 and A375 cells using flow cytometry Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-02-09 Xiaowen Sun, Richard A. Spellman, Maria Engel, Elizabeth Rubitski, Maik Schuler
Previously, we introduced an alternative adherent A375 cell line for clastogenicity and aneugenicity testing using a high content imaging platform. To further characterize the performance of A375 cells, we investigated the sensitivity and specificity of A375 and TK6 cells by directly comparing micronucleus (MN) induction, cytotoxicity (relative cell counts, viability, and apoptosis), clastogenicity
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Veterinarians exposed to inhaled anesthetic present chromosome damage, apoptosis and cell cycle changes Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-02-09 Mariana G. Braz, Drielle B. S. Figueiredo, Marjorie A. Golim, Tony F. Grassi, Bruno R. B. da Costa, Bruno S. De Martinis, Leandro G. Braz
This cross-sectional study evaluated, for the first time, DNA damage, viability, and cell death of lymphocytes and cell cycle phases of mononuclear and polymorphonuclear cells in veterinarians exposed to the volatile anesthetic isoflurane. Veterinarians who were occupationally exposed to isoflurane (exposed group; n = 20) and matched-unexposed individuals (volunteers without occupational exposure;
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Effect of smoking on methylation and semen parameters Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2024-02-01 Nasim Naeimi, Homa Mohseni Kouchesfehani, Zahra Heidari, Hamidreza Mahmoudzadeh-Sagheb
One type of epigenetic modification is genomic DNA methylation, which is induced by smoking, and both are associated with male infertility. In this study, the relationship between smoking and CHD5 gene methylation and semen parameters in infertile men was determined. After the MS-PCR of blood in 224 samples, 103 infertile patients (62 smokers and 41 non-smokers) and 121 fertile men, methylation level
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Interpretation of in vitro concentration-response data for risk assessment and regulatory decision-making: Report from the 2022 IWGT quantitative analysis expert working group meeting Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2023-12-19 Marc A. Beal, Guangchao Chen, Kerry L. Dearfield, Min Gi, Bhaskar Gollapudi, Robert H. Heflich, Katsuyoshi Horibata, Alexandra S. Long, David P. Lovell, Barbara L. Parsons, Stefan Pfuhler, John Wills, Andreas Zeller, George Johnson, Paul A. White
Quantitative risk assessments of chemicals are routinely performed using in vivo data from rodents; however, there is growing recognition that non-animal approaches can be human-relevant alternatives. There is an urgent need to build confidence in non-animal alternatives given the international support to reduce the use of animals in toxicity testing where possible. In order for scientists and risk
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The aryl hydrocarbon receptor (AhR) activation mediates benzo(a)pyrene-induced overexpression of AQP3 and Notch1 in HaCaT cells Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2023-11-20 Claudia I. Almendarez-Reyna, Carlos Gabriel de la Trinidad Chacón, Ángeles C. Ochoa-Martínez, Luis A. Rico-Guerrero, Iván N. Pérez-Maldonado
The aim of this study was twofold: (1) evaluate the effect of benzo[a]pyrene (BaP) on expression levels of AQP3 and Notch1 genes in HaCaT cells exposed “in vitro” and (2) investigate the possible biological role of assessed genes by bioinformatics methods. Cells were exposed to increasing concentrations of BaP (0.0–4.0 μM) for 1–4 days. After treatments, cell viability and expression levels of AhR
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Clonality, trafficking, and molecular alterations among Hprt mutant T lymphocytes isolated from control mice versus mice treated with N-ethyl-N-nitrosourea Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2023-11-13 Stephen A. Judice, Hillary E. Sussman, Dale M. Walker, J. Patrick O'Neill, Richard J. Albertini, Vernon E. Walker
Mutations in T lymphocytes (T-cells) are informative quantitative markers for environmental mutagen exposures, but risk extrapolations from rodent models to humans also require an understanding of how T-cell development and proliferation kinetics impact mutagenic outcomes. Rodent studies have shown that patterns in chemical-induced mutations in the hypoxanthine-guanine phosphoribosyltransferase (Hprt)
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In vivo genotoxicity testing strategies: Report from the 8th International Workshop on Genotoxicity Testing (IWGT) Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2023-11-09 Carol Beevers, Yoshifumi Uno, Krista Meurer, Shuichi Hamada, Kiyohiro Hashimoto, David Kirkland, Matthew J. LeBaron, Frank Le Curieux, Ludovic Le Hegarat, Hans-Joerg Martus, Kenichi Masumura, Wakako Ohyama, Daniel J. Roberts, Marie Vasquez, James Whitwell, Kristine L. Witt
The in vivo working group (WG) considered three topics: acceptable maximum doses for negative erythrocyte micronucleus (MN) tests, validation status of MN assays in non-hematopoietic tissues, and nuisance factors in the comet assay. The WG reached agreement on many issues, including: negative erythrocyte MN studies should be acceptable if dosing is conducted to Organisation for Economic Co-operation
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The PIG-A gene mutation assay in human biomonitoring and disease Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2023-11-05 Rachel Lawrence, Kathryn Munn, Hamsa Naser, Laura Thomas, Hasan Haboubi, Lisa Williams, Shareen Doak, Gareth Jenkins
The blood cell phosphatidylinositol glycan class A (PIG-A) gene mutation assay has been extensively researched in rodents for in vivo mutagenicity testing and is now being investigated in humans. The PIG-A gene is involved in glycosyl phosphatidylinositol (GPI)-anchor biosynthesis. A single mutation in this X-linked gene can lead to loss of membrane-bound GPI anchors, which can be enumerated via corresponding
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Assessment of the in vivo genotoxic potential of three smoke flavoring primary product mixtures Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2023-11-02 Chad M. Thompson, Gregory Brorby, Zena Keig-Shevlin, Robert Smith, Allison Franzen, Kristina Ulrich, Alexander D. Blanchette, Candace Doepker
Smoke flavorings are mixtures generated from wood pyrolysis that are filtered to remove tar and are often considered healthier alternatives to conventional smoking processes. While the latter is mostly unregulated, smoke-flavoring primary products (SFPPs) are undergoing the 10-year required re-evaluation in the European Union (EU). To comply with recent smoke flavor guidance, in vivo micronucleus studies
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Genotoxicity assessment in HepaRG™ cells as a new approach methodology follow up to a positive response in the human TK6 cell micronucleus assay: Naphthalene case study Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2023-09-13 Leslie Recio, Jasmine Fowler, Lincoln Martin, Carol Swartz
We are evaluating the use of metabolically competent HepaRG™ cells combined with CometChip® for DNA damage and the micronucleus (MN) assay as a New Approach Methodology (NAM) alternative to animals for follow up genotoxicity assessment to in vitro positive genotoxic response. Naphthalene is genotoxic in human TK6 cells inducing a nonlinear dose–response for the induction of micronuclei in the presence
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The association of epidermal growth factor variant with oral squamous cell carcinoma Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2023-09-02 Baris Ertugrul, Amal Mohammed, Goksu Kasarci, Sinem Bireller, Murat Ulusan, Bedia Cakmakoglu
In this study, our aim was to investigate the epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) gene polymorphisms in oral squamous cell carcinoma (OSCC) patients and non-OSCC healthy controls. This case–control study comprised 89 OSCC and 107 healthy controls by using polymerase chain reaction (PCR) and restriction fragment length polymorphism methods, the genotypes for EGF + 61
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Oxidative DNA damage on the VEGF G-quadruplex forming promoter is repaired via long-patch BER Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2023-08-22 Adil S. Hussen, Haley L. Kravitz, Bret D. Freudenthal, Amy M. Whitaker
In response to oxidative damage, base excision repair (BER) enzymes perturb the structural equilibrium of the VEGF promoter between B-form and G4 DNA conformations, resulting in epigenetic-like modifications of gene expression. However, the mechanistic details remain enigmatic, including the activity and coordination of BER enzymes on the damaged G4 promoter. To address this, we investigated the ability
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Genome-wide impact of cytosine methylation and DNA sequence context on UV-induced CPD formation Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2023-08-09 Hannah E. Wilson, John J. Wyrick
Exposure to ultraviolet (UV) light is the primary etiological agent for skin cancers because UV damages cellular DNA. The most frequent form of UV damage is the cyclobutane pyrimidine dimer (CPD), which consists of covalent linkages between neighboring pyrimidine bases in DNA. In human cells, the 5′ position of cytosine bases in CG dinucleotides is frequently methylated, and methylated cytosines in
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The role of Transcription Factor IIH complex in nucleotide excision repair Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2023-08-06 Allyson Hoag, Mingrui Duan, Peng Mao
DNA damage occurs throughout life from a variety of sources, and it is imperative to repair damage in a timely manner to maintain genome stability. Thus, DNA repair mechanisms are a fundamental part of life. Nucleotide excision repair (NER) plays an important role in the removal of bulky DNA adducts, such as cyclobutane pyrimidine dimers from ultraviolet light or DNA crosslinking damage from platinum-based
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Impact of individual factors on DNA methylation of drug metabolism genes: A systematic review Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2023-07-31 Jialu Bian, Jinxia Zhao, Yinyu Zhao, Xu Hao, Shiyu He, Yuanyuan Li, Lin Huang
Individual differences in drug response have always existed in clinical treatment. Many non-genetic factors show non-negligible impacts on personalized medicine. Emerging studies have demonstrated epigenetic could connect non-genetic factors and individual treatment differences. We used systematic retrieval methods and reviewed studies that showed individual factors’ impact on DNA methylation of drug
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Unbiased whole genome detection of ultrarare off-target mutations in genome-edited cell populations by HiFi sequencing Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2023-07-24 Jaime A. Miranda, Kristina Fenner, Page B. McKinzie, Vasily N. Dobrovolsky, Javier R. Revollo
DNA base editors (BEs) composed of a nuclease-deficient Cas9 fused to a DNA-modifying enzyme can achieve on-target mutagenesis without creating double-strand DNA breaks (DSBs). As a result, BEs generate far less DNA damage than traditional nuclease-proficient Cas9 systems, which do rely on the creation of DSBs to achieve on-target mutagenesis. The inability of BEs to create DSBs makes the detection
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Cadmium exposure induces necroptosis of porcine spleen via ROS-mediated activation of STAT1/RIPK3 signaling pathway Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2023-07-15 Yu Xia, Yiming Zhang, Jintao Zhang, Yongzhen Du, Yixuan Wang, Anqi Xu, Shu Li
Cadmium (Cd), a heavy metal, is used in a wide range of applications, such as plastics, electroplating process, electronics, and so forth. Due to its bioaccumulation ability, Cd can contaminate soil, water, air and food. To determine the effect of Cd exposure on the necroptosis in pig spleen and its mechanistic investigation, we constructed a model in pigs by feeding them food containing 20 mg/kg Cd
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Templated insertions—DNA repair gets acrobatic Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2023-07-12 Susanna Stroik, Adam J. Luthman, Dale A. Ramsden
Deletions associated with the repair of DNA double-strand breaks is a source of genetic alternation and a recognized source of disease-causing mutagenesis. Theta-mediated end joining is a DNA repair mechanism, which guarantees deletions by its employment of microhomology (MH) alignment to facilitate end joining. A lesser-characterized templated insertion ability of this pathway, on the other hand,
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Kinetics of the in vivo genotoxic and radioprotective effects of methyl gallate and epigallocatechin gallate Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2023-07-10 Virginia Cruz-Vallejo, Anaís Zarco-Mendoza, Pedro Morales-Ramírez
The aim of this study was to compare the kinetics of the in vivo action of equimolar doses of methyl gallate (MG) and epigallocatechin gallate (EGCG) on their capacity to induce DNA damage and to protect against DNA damage induced by 60Co gamma rays. DNA-damaged cells were determined by single-cell gel electrophoresis (comets) in murine peripheral blood leukocytes. The maximum radioprotective effects
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Chromosome damage in regions with different levels of air pollution Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2023-07-08 Petra Musilova, Dita Kadlcikova, Hana Hradska, Miluse Vozdova, Iveta Selingerova, Halina Cernohorska, Dusan Salat, Jiri Rubes
Air pollution is an important environmental factor influencing human health. In this study, we compared chromosome damage in city policemen from three cities in the Czech Republic: industrial Ostrava characterized by high levels of benzo[a]pyrene, Prague with heavy traffic emitting nitrogen oxides, and relatively clean Ceske Budejovice located in an area with predominantly agricultural activity. Chromosomal
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Toxicity and mutagenicity studies of 6PPD-quinone in a marine invertebrate species and bacteria Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2023-07-04 Marina Tenório Botelho, Gabriely Groto Militão, Markus Brinkmann, Gisela de Aragão Umbuzeiro
N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone (6PPD-quinone), an oxidation product of the tire additive, 6PPD, has been associated with high mortality of salmonids (0.1 μg/L). The objective of this study was to determine the acute toxicity using neonates and mutagenicity (micronuclei in hemolymph of exposed adults) of 6PPD-quinone in the marine amphipod Parhyale hawaiensis. Also, we studied
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Downregulation of circular RNA hsa_circ_0087856 sensitizes bladder cancer cells to cisplatin through targeting miR-1184/CITED2 signaling Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2023-07-01 Min Ju, Weiwei Wu, Jingkun Qu, Yang Sun, Jun Li
CircRNAs are considered as one of the potential therapeutic targets of multiple cancers. According to accumulating evidence, circRNA regulates cancer progression by acting as a miRNA sponge. In the current work, our data discovered that hsa_circ_0087856 and CITED2 expression was increased, while miR-1184 expression was decreased in BC cell lines and tissues. Hsa_circ_0087856 expression negatively correlated
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Circ_0000033 up-regulates NUAK2 by sequestering miR-378a-3p to promote breast tumorigenesis Environ. Mol. Mutagen. (IF 2.3) Pub Date : 2023-06-25 Yijun Dai, Wenjian Shi, Yanru Qiu, Tianwen Xu, Jianguang Lin, Yunxia Su
Circular RNAs (circRNAs), including circ_0000033, were shown to be abnormally expressed in breast cancer (BC) and play an important regulatory function in the development of this cancer. This study aimed to investigate the action and mechanism of circ_0000033 in BC carcinogenesis. Specifically, levels of genes and proteins were analyzed using quantitative real-time PCR (qRT-PCR) and western blotting