Environmental and Molecular Mutagenesis最新文献

{"title":"Bruce Nathan Ames, 1928-2024: A meaningful scientific life.","authors":"Errol Zeiger","doi":"10.1002/em.22641","DOIUrl":"https://doi.org/10.1002/em.22641","url":null,"abstract":"","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of mutagenicity of styrene in tumor target and non-target tissues of transgenic Big Blue® mice.","authors":"B Bhaskar Gollapudi, Karen Philp, Jeffrey T Weinberg","doi":"10.1002/em.22638","DOIUrl":"10.1002/em.22638","url":null,"abstract":"<p><p>Styrene has been shown to induce lung tumors in mice, but not in rats. The current study investigated the potential role of genotoxicity as an initial key event in the mode of action for styrene-induced lung tumors in mice. Transgenic male B6C3F1 Big Blue® mice were treated by oral gavage for 28 consecutive days with 0 (corn oil), 75, 150, or 300 mg/kg/day of styrene. The 300 mg/kg/day represented the tumorigenic dose in the oral gavage carcinogenicity study conducted in B6C3F1 mice. Following a 28-day expression period, mutant frequencies were assessed at the cII locus of the transgene in the tumor target (lung) and non-target tissues (liver, glandular stomach, and duodenum). Mice treated with N-ethyl-N-nitrosourea (40 mg/kg/day) by oral gavage on Days 1, 2, and 3 of the study and sacrificed on Day 56 served as the positive control group. Genomic DNA was extracted from the selected tissues, processed for the recovery of the transgene into infectious phage, plated onto Escherichia coli strain G1250, and incubated at 37°C for titer determination or at 24°C for the selection of mutant plaques. There were no treatment-related increases in mutant frequency in any of the tissues. The positive control group had a significant increase in the frequency of cII mutants assuring the adequacy of the experimental conditions to detect induced mutations. To conclude, mutagenicity is not considered a plausible initial key event in the mode of action for styrene-induced mouse lung tumors as these data support that styrene is not an in vivo mutagen.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AOP report: Development of an adverse outcome pathway for deposition of energy leading to abnormal vascular remodeling","authors":"Tatiana Kozbenko,&nbsp;Nadine Adam,&nbsp;Veronica S. Grybas,&nbsp;Benjamin J. Smith,&nbsp;Dalya Alomar,&nbsp;Robyn Hocking,&nbsp;Janna Abdelaziz,&nbsp;Amanda Pace,&nbsp;Marjan Boerma,&nbsp;Omid Azimzadeh,&nbsp;Steve Blattnig,&nbsp;Nobuyuki Hamada,&nbsp;Carole Yauk,&nbsp;Ruth Wilkins,&nbsp;Vinita Chauhan","doi":"10.1002/em.22636","DOIUrl":"10.1002/em.22636","url":null,"abstract":"<p>Cardiovascular diseases (CVDs) are complex, encompassing many types of heart pathophysiologies and associated etiologies. Radiotherapy studies have shown that fractionated radiation exposure at high doses (3–17 Gy) to the heart increases the incidence of CVD. However, the effects of low doses of radiation on the cardiovascular system or the effects from space travel, where radiation and microgravity are important contributors to damage, are not clearly understood. Herein, the adverse outcome pathway (AOP) framework was applied to develop an AOP to abnormal vascular remodeling from the deposition of energy. Following the creation of a preliminary pathway with the guidance of field experts and authoritative reviews, a scoping review was conducted that informed final key event (KE) selection and evaluation of the Bradford Hill criteria for the KE relationships (KERs). The AOP begins with a molecular initiating event of deposition of energy; ionization events increase oxidative stress, which when persistent concurrently causes the release of pro-inflammatory mediators, suppresses anti-inflammatory mechanisms and alters stress response signaling pathways. These KEs alter nitric oxide levels leading to endothelial dysfunction, and subsequent abnormal vascular remodeling (the adverse outcome). The work identifies evidence needed to strengthen understanding of the causal associations for the KERs, emphasizing where there are knowledge gaps and uncertainties in both qualitative and quantitative understanding. The AOP is anticipated to direct future research to better understand the effects of space on the human body and potentially develop countermeasures to better protect future space travelers.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 S3","pages":"4-30"},"PeriodicalIF":2.3,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22636","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Absence of genotoxicity following pulmonary exposure to metal oxides of copper, tin, aluminum, zinc, and titanium in mice","authors":"Claudia Torero Gutierrez,&nbsp;Niels Hadrup,&nbsp;Charis Loizides,&nbsp;Iosif Hafez,&nbsp;George Biskos,&nbsp;Martin Roursgaard,&nbsp;Anne Thoustrup Saber,&nbsp;Peter Møller,&nbsp;Ulla Vogel","doi":"10.1002/em.22634","DOIUrl":"10.1002/em.22634","url":null,"abstract":"<p>Inhalation of nanosized metal oxides may occur at the workplace. Thus, information on potential hazardous effects is needed for risk assessment. We report an investigation of the genotoxic potential of different metal oxide nanomaterials. Acellular and intracellular reactive oxygen species (ROS) production were determined for all the studied nanomaterials. Moreover, mice were exposed by intratracheal instillation to copper oxide (CuO) at 2, 6, and 12 μg/mouse, tin oxide (SnO₂) at 54 and 162 μg/mouse, aluminum oxide (Al₂O₃) at 18 and 54 μg/mouse, zinc oxide (ZnO) at 0.7 and 2 μg/mouse, titanium dioxide (TiO₂) and the benchmark carbon black at 162 μg/mouse. The doses were selected based on pilot studies. Post-exposure time points were 1 or 28 days. Genotoxicity, assessed as DNA strand breaks by the comet assay, was measured in lung and liver tissue. The acellular and intracellular ROS measurements were fairly consistent. The CuO and the carbon black bench mark particle were potent ROS generators in both assays, followed by TiO₂. Al₂O₃, ZnO, and SnO₂ generated low levels of ROS. We detected no increased genotoxicity in this study using occupationally relevant dose levels of metal oxide nanomaterials after pulmonary exposure in mice, except for a slight increase in DNA damage in liver tissue at the highest dose of CuO. The present data add to the body of evidence for risk assessment of these metal oxides.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 8","pages":"251-260"},"PeriodicalIF":2.3,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22634","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AOP Report: Development of an adverse outcome pathway for deposition of energy leading to bone loss","authors":"Snehpal Sandhu,&nbsp;Mitchell Keyworth,&nbsp;Syna Karimi-Jashni,&nbsp;Dalya Alomar,&nbsp;Benjamin J. Smith,&nbsp;Tatiana Kozbenko,&nbsp;Stephen Doty,&nbsp;Robyn Hocking,&nbsp;Nobuyuki Hamada,&nbsp;Robert J. Reynolds,&nbsp;Ryan T. Scott,&nbsp;Sylvain V. Costes,&nbsp;Afshin Beheshti,&nbsp;Carole Yauk,&nbsp;Ruth C. Wilkins,&nbsp;Vinita Chauhan","doi":"10.1002/em.22631","DOIUrl":"10.1002/em.22631","url":null,"abstract":"<p>Bone loss, commonly seen in osteoporosis, is a condition that entails a progressive decline of bone mineral density and microarchitecture, often seen in post-menopausal women. Bone loss has also been widely reported in astronauts exposed to a plethora of stressors and in patients with osteoporosis following radiotherapy for cancer. Studies on mechanisms are well documented but the causal connectivity of events to bone loss development remains incompletely understood. Herein, the adverse outcome pathway (AOP) framework was used to organize data and develop a qualitative AOP beginning from deposition of energy (the molecular initiating event) to bone loss (the adverse outcome). This qualitative AOP was developed in collaboration with bone loss research experts to aggregate relevant findings, supporting ongoing efforts to understand and mitigate human system risks associated with radiation exposures. A literature review was conducted to compile and evaluate the state of knowledge based on the modified Bradford Hill criteria. Following review of 2029 studies, an empirically supported AOP was developed, showing the progression to bone loss through many factors affecting the activities of bone-forming osteoblasts and bone-resorbing osteoclasts. The structural, functional, and quantitative basis of each proposed relationship was defined, for inference of causal changes between key events. Current knowledge and its gaps relating to dose-, time- and incidence-concordance across the key events were identified, as well as modulating factors that influence linkages. The new priorities for research informed by the AOP highlight areas for improvement to enable development of a quantitative AOP used to support risk assessment strategies for space travel or cancer radiotherapy.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 S3","pages":"85-111"},"PeriodicalIF":2.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22631","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anatomy of a hotspot: Cisplatin hotspots in the tdk gene of Escherichia coli.","authors":"Courtney Young, Mackenzie Lee, Zoe Ge, Jeana Shin, Bella Bursulaya, Dana Sorensen, Arnav Saud, Ananya Sridharan, Ava Gonick, Nhu Phi, Kelly Nguyen, Shawal Bhalli, Jyotsna Hiranandani, Jeffrey H Miller","doi":"10.1002/em.22635","DOIUrl":"https://doi.org/10.1002/em.22635","url":null,"abstract":"<p><p>We previously reported that certain sub-regions of the thyA gene of Escherichia coli are more mutable than others when many different mutagens and mutators are analyzed (Mashiach et al., Mutation Research Fundamental Molecular Mechansims of Mutagenesis, 821: 111702, 2021). In this study, we focus on a single mutagen, cisplatin and verify that mutations occur preferentially at specific 3 bp sequences, but only when they appear in certain subregions of the gene. Moreover, we show that hotspots for some premutational lesions are camouflaged by the preferential repair effected by the uvrA,B,C-encoded excision repair system, even when they appear on the same strand. We do this by using a novel reporter gene in E. coli, the tdk gene that codes for thymidine deoxykinase, and we describe some of the advantages of utilizing this detection system.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Artificial targeting of the NEIL1 DNA glycosylase to the mitochondria","authors":"Marlo K. Thompson,&nbsp;Mark H. Eggers,&nbsp;Ryan G. Benton,&nbsp;Tom Johnsten,&nbsp;Aishwarya Prakash","doi":"10.1002/em.22632","DOIUrl":"10.1002/em.22632","url":null,"abstract":"<p>The human NEIL1 DNA glycosylase is one of 11 mammalian glycosylases that initiate base excision repair. While substrate preference, catalytic mechanism, and structural information of NEIL1's ordered residues are available, limited information on its subcellular localization, compounded by relatively low endogenous expression levels, have impeded our understanding of NEIL1. Here, we employed a previously developed computational framework to optimize the mitochondrial localization signal of NEIL1, enabling the visualization of its specific targeting to the mitochondrion via confocal microscopy. While we observed clear mitochondrial localization and increased glycosylase/lyase activity in mitochondrial extracts from low-moderate NEIL1 expression, high NEIL1 mitochondrial expression levels proved harmful, potentially leading to cell death.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 8","pages":"243-250"},"PeriodicalIF":2.3,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotoxicity evaluation of gene therapies: A report from the International Workshop on Genotoxicity Testing (IWGT) 2022.","authors":"S Libertini, J K Jadlowsky, T A Lanz, L M Mihalcik, D M Pizzurro","doi":"10.1002/em.22633","DOIUrl":"https://doi.org/10.1002/em.22633","url":null,"abstract":"<p><p>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 risk assessments based on a weight-of-evidence approach, to promote data sharing, transparency, and cooperation between stakeholders, and to develop state-of-the-art validated tests relevant to clinical scenarios.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutagenicity of the agriculture pesticide chlorothalonil assessed by somatic mutation and recombination test in Drosophila melanogaster","authors":"Bruno Veber,&nbsp;Mariana do Amaral Flores,&nbsp;Mauricio Lehmann,&nbsp;Carlos Eduardo da Rosa,&nbsp;Mariana Leivas Müller Hoff","doi":"10.1002/em.22630","DOIUrl":"10.1002/em.22630","url":null,"abstract":"<p>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 <i>Drosophila melanogaster</i>, by exposing individuals, with basal and high bioactivation capacities (standard and high bioactivation cross offspring, respectively), from third instar larval to early adult fly stages, to CTL-contaminated substrate (0.25, 1, 10 or 20 μM). This substrate served as food and as physical medium. Increased frequency of large single spots in standard cross flies' wings exposed to 0.25 μM indicates that, if CTL is genotoxic, it may affect <i>Drosophila</i> at early life stages. Since the total spot frequency did not change, CTL cannot be considered mutagenic in SMART. The same long-term exposure design was performed to test whether CTL induces oxidative imbalance in flies with basal (wild-type, WT) or high bioactivation (ORR strain) levels. CTL did not alter reactive oxygen species and antioxidant capacity against peroxyl radicals levels in adult flies. However, lipid peroxidation (LPO) levels were increased in WT male flies exposed to 1 μM CTL. SMART and LPO alterations were observed only in flies with basal bioactivation levels, pointing to direct CTL toxicity to DNA and lipids. Survival, emergence and locomotor behavior were not affected, indicating no bias due to lethality, developmental and behavioral impairment. We suggest that, if related to CTL exposure, DNA and lipid damages may be residual damage of earlier life stages of <i>D. melanogaster</i>.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 8","pages":"275-288"},"PeriodicalIF":2.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142217656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High frequency of silent mutations in gyrA gene of Mycobacterium tuberculosis in Indian isolates","authors":"Anamika Gupta,&nbsp;Sudhir K. Pal,&nbsp;Vijay Nema","doi":"10.1002/em.22629","DOIUrl":"10.1002/em.22629","url":null,"abstract":"<p>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 <i>Mycobacterium tuberculosis</i> 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 <i>gyrA</i> gene. Bioinformatics analysis of these changes for drug binding suggested no significant change in the binding of the drug but have lower binding energies as compared with the wild-type proteins. Although functionally silent for the <i>gyrA</i> gene, these changes are indicating a silent geographical and evolutionary change that needs to be further studied for drug discovery and bacterial fitness.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 8","pages":"289-293"},"PeriodicalIF":2.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142217659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}