Mutagenesis最新文献

{"title":"Retraction to: Divergent molecular profile of PIK3CA gene in arsenic-associated bladder carcinoma.","authors":"","doi":"10.1093/mutage/geaf017","DOIUrl":"https://doi.org/10.1093/mutage/geaf017","url":null,"abstract":"","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961856","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":"The Micronucleus Assay in Exfoliated Buccal Cells for Occupational Exposure Studies: An Overview.","authors":"G Wultsch, A Nersesyan, M Mišík, F Ferk, K Schelch, M Scharnagl, M Grusch, S Knasmüller","doi":"10.1093/mutage/geaf018","DOIUrl":"https://doi.org/10.1093/mutage/geaf018","url":null,"abstract":"<p><p>This review describes the use of the micronucleus (MN) assay with exfoliated cells from the oral mucosa in occupational studies. The molecular mechanisms leading to formation of MN (chromosomal breakage and aneuploidy) are well known. In total, 222 articles have been published since the method was developed in 1982. The majority of investigations was realized with agricultural workers, followed by petrol station attendants, painters, pathology/anatomy lab workers and miners. Positive results were reported in the majority of studies (86%); Brazil, Italy, Mexico and Turkey being the most productive countries. The use of this technique increased substantially in the last years and a recent correlation analyses with data from MN studies with lymphocytes indicate that the method is useful for the prediction of the cancer risks of chemically- and radiation-exposed workers. The methodological quality of the studies increased in recent years since standardized and validated guidelines have been published. However, major shortcomings are still the lack of adequate matching (in particular in regard to nutrition and intake of dietary supplements), the lack of chemical exposure measurements and the use of inadequate (DNA-non-specific) stains. The most pronounced effects were seen in metal production workers, miners, petrol station attendants, agricultural workers and pathologists. The sampling of the cells from the oral cavity is non-invasive and no cultivation under sterile conditions is required. The currently available data indicate that this fast and easy to perform procedure provides valuable information about combined effects of chemical exposures and about the efficiency of safety measurements. Therefore, it should be used in the future for the routine surveillance of workers.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874211","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":"Harnessing the power of an advanced in vitro 3D liver model and error-corrected duplex sequencing for the detection of mutational signatures.","authors":"Gillian E Conway, Bérénice Chavanel, François Virard, Ume-Kulsoom Shah, Michael J Burgum, Stephen J Evans, Michael Korenjak, Laura E Thomas, Gareth J Jenkins, Jiri Zavadil, Shareen H Doak","doi":"10.1093/mutage/geaf015","DOIUrl":"https://doi.org/10.1093/mutage/geaf015","url":null,"abstract":"<p><p>Genotoxicity testing plays a crucial role in evaluating the hazards posed by various chemicals. Traditional methods, such as the Ames test, mammalian cell mutation assays and the transgenic rodent assay have certain limitations including laborious procedures and/or reliance on animal models. The aim of this study was to determine the potential of using error-corrected next-generation sequencing (ecNGS), specifically duplex sequencing (DS), as an alternative method for the detection of point mutations in conjunction with advanced in vitro models. This study establishes an easy to use, adaptable in vitro 3D HepG2 model, that shows good viability, and liver functionality over 14 days. 3D HepG2 spheroids were exposed to aristolochic acid in a repeated dose regime over 4 days. This was shown to significantly induce micronucleus formation, indicative of fixed DNA damage, in a dose dependent fashion. DS coupled with mutational signature analyses revealed a predominant treatment-specific T:A > A:T-enriched mutational signature explained by COSMIC signature SBS22 derived from human cancers associated with aristolochic acid exposure. De novo extraction provided a stable signature, of which more than 40% were unambiguously explained by SBS22 These results demonstrate that the presented 3D HepG2 spheroid model is appropriate for assessing chemically induced fixed DNA damage. Additionally, we provide evidence that DS applied to the studied in vitro 3D model has the capacity to reveal specific mutational signatures of mutagenic exposures. The modern integrative approach will improve the understanding of mechanisms of carcinogenesis related to chemical exposures by providing a cost-effective and efficient means to assess genotoxicity and mutagenicity. With the inclusion of mutational signature analyses, this approach would see a reduction in reliance on animal models and enhancement of hazard assessment accuracy.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835782","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":"\"Computational Prediction of Mutagenicity Through Comprehensive Cell Painting Analysis\".","authors":"Natacha Cerisier, Emily Truong, Taku Watanabe, Taro Oshiro, Tomohiro Takahashi, Shigeaki Ito, Olivier Taboureau","doi":"10.1093/mutage/geaf014","DOIUrl":"https://doi.org/10.1093/mutage/geaf014","url":null,"abstract":"<p><p>The mutagenicity of chemical compounds is a key consideration in toxicology, drug development, and environmental safety. Traditional methods such as the Ames test, while reliable, are time-intensive and costly. With advances in imaging and machine learning, high-content assays like Cell Painting offer new opportunities for predictive toxicology. Cell Painting captures extensive morphological features of cells, which can correlate with chemical bioactivity. In this study, we leveraged Cell Painting data to develop machine learning models for predicting mutagenicity and compared their performance with structure-based models. We used two datasets: a Broad Institute dataset containing profiles of over 30,000 molecules and a US-EPA dataset with images of 1,200 chemicals tested at multiple concentrations. By integrating these datasets, we aimed to improve the robustness of our models. Among three algorithms tested - Random Forest, Support Vector Machine, and Extreme Gradient Boosting - the third showed the best performance for both datasets. Notably, selecting the most relevant concentration per compound, the Phenotypic Altering Concentration, significantly improved prediction accuracy. Our models outperformed traditional QSAR tools such as VEGA and the CompTox Dashboard for the majority of compounds, demonstrating the utility of Cell Painting features. The Cell Painting-based models revealed morphological changes related to DNA/RNA and ER perturbation, especially in mitochondria and nuclei, aligning with mutagenicity mechanisms. Despite this, certain compounds remained challenging to predict due to inherent dataset limitations and inter-laboratory variability in Cell Painting technology. The findings highlight the potential of Cell Painting in mutagenicity prediction, offering a complementary perspective to chemical structure-based models. Future work could involve harmonizing Cell Painting methodologies across datasets and exploring deep learning techniques to enhance predictive accuracy. Ultimately, integrating Cell Painting data with QSAR descriptors in hybrid models may unlock novel insights into chemical mutagenicity.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775848","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":"Re: Rather et al. Carcinogenic parasites: Insights into the epidemiology and possible mechanisms of cancer. Mutagenesis.","authors":"Armen Nersesyan","doi":"10.1093/mutage/geaf016","DOIUrl":"10.1093/mutage/geaf016","url":null,"abstract":"","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775849","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":"Understanding the cellular uptake and genotoxic potential of industrial relevant nanomaterials utilising electron microscopy and the ToxTracker assay in vitro.","authors":"Stephen J Evans, Nynke Moelijker, Inger Brandsma, Michael J Burgum, Rosalie Elespuru, Giel Hendriks, Shareen H Doak","doi":"10.1093/mutage/geaf013","DOIUrl":"https://doi.org/10.1093/mutage/geaf013","url":null,"abstract":"<p><p>Evaluating genotoxic potential of nanomaterials presents unique challenges not associated with traditional toxicological assessment. The exceptional properties and complexities of these nanomaterials require additional considerations and protocol modifications to assess and fully interpret genotoxicity potential. A key question in any nanomaterial focused toxicity study is whether the material has reached the target cell and what its subsequent sub-cellular localisation is. This current study aimed to assess the potential of a panel of industrial relevant nanomaterials; TiO2-NM102, TiO2-NM105, TiO2-E171, silica, polyethylene, polystyrene, carbon black, Gold nanorods, tungsten carbide/cobalt and tungsten carbide, to undergo cellular uptake in mouse embryonic stem cells (mES) that are applied in the ToxTracker genotoxicity assay. Ultrastructural cellular analysis by transmission electron microscopy (TEM) was undertaken following 100 μg/ml treatment with the test nanomaterials for 24 h, any observed uptake was confirmed by energy dispersive X-ray spectroscopy. Induction of DNA damage, cytotoxicity, p53 activation, protein stress, and oxidative stress was evaluated by the ToxTracker assay following 24 h treatment with the test nanomaterials (0-100 μg/ml) in the absence of S9. TiO2-NM105, silica, polystyrene carbon black and tungsten carbide were all shown to undergo cellular uptake, localised in membrane bound vesicles within the cytoplasm. None of the internalised nanomaterials promoted a genotoxic response in ToxTracker, similarly no DNA damage was observed by the materials not internalised. Interestingly, of the internalised nanomaterials only polystyrene caused a slight cytotoxic response at 100 μg/ml treatment (10% loss in cell viability). Of the nanomaterials not internalised, cytotoxicity was observed in mES cells treated with 100 μg/ml TiO2-NM102 (15%), polyethylene (15%), Gold nanorods (35%) and tungsten carbide/cobalt (45%). In summary this study demonstrated that TiO2-NM105, silica, polystyrene carbon black and tungsten carbide are non-genotoxic in vitro despite undergoing cell uptake in the ToxTracker cells. A continued focus is needed to supplement nanomaterial genotoxicity studies with cellular uptake analysis.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649874","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":"Polystyrene microplastics induces the injury of human corneal epithelial cells through ROS-mediated p53 pathway.","authors":"Jianfeng Long, Limin Deng, Jian Liu, Kang Zhou, Shijie He","doi":"10.1093/mutage/geaf011","DOIUrl":"https://doi.org/10.1093/mutage/geaf011","url":null,"abstract":"<p><strong>Objective: </strong>To investigate the effects of polystyrene microplastics (PS-MPs) on human corneal epithelial cells (HCEP).</p><p><strong>Methods: </strong>The cytotoxicity of PS-MPs on HCEP cells was evaluated using a CCK-8 assay to measure cell viability, flow cytometry to analyze cell cycle and status, immunofluorescence to detect reactive oxygen species (ROS) and γ-H2AX levels, and western blotting to assess protein expression.</p><p><strong>Results: </strong>The effects of PS-MPs on HCEP cell morphology and viability were particle size- and concentration-dependent. Smaller particle sizes and higher concentrations of PS-MPs were associated with greater cytotoxicity. PS-MP exposure induced cell cycle arrest, necrosis, and apoptosis in HCEP cells, along with excessive ROS production and DNA damage. Furthermore, ROS scavengers significantly reduced PS-MP-induced ROS overproduction and DNA damage, thereby alleviating PS-MP-induced cell cycle arrest, necrosis, and apoptosis. At the molecular level, ROS scavengers reversed the PS-MP-induced changes in the expression of γ-H2AX, P53, cell cycle-related proteins (cyclin D1, CDK2, and CDK4), necrosis-related proteins (CypD, PARP-1, and SRX), and apoptosis-related proteins (Cyt C, AIF, and cleaved-caspase 3).</p><p><strong>Conclusion: </strong>PS-MP exposure leads to cell cycle arrest, necrosis, and apoptosis in HCEP cells, which is associated with ROS overproduction and activation of the P53 pathway.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275441","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":"Genotoxic effects of aristolochic acid I on functional human-induced hepatocyte-like cells.","authors":"Yushi Hu, Yuyang Lei, Zhenna Gao, Yiyi Cao, Jing Xi, Yuning Ma, Qinwen Gao, Jian Fu, Xinyu Zhang, Yang Luan","doi":"10.1093/mutage/geaf012","DOIUrl":"https://doi.org/10.1093/mutage/geaf012","url":null,"abstract":"<p><p>Aristolochic acid I (AAI) is a carcinogen associated with various human cancers. However, its causal relationship with hepatocellular carcinoma remains controversial, and inconsistent results from rodent studies have suggested species-specific differences. Here we evaluated AAI genotoxicity using functional human-induced hepatocyte-like cells (hiHep cells), a model that closely mimics primary human hepatocytes in gene expression and function, thereby shedding light on its potential hepatocarcinogenic risk in humans. First, we assessed AAI genotoxicity by evaluating AAI-DNA adducts and micronucleus frequency. In hiHep cells, AAI (0.7-2.5 µM) induced up to 105 adducts per 108 nucleotides, indicating high metabolic activation of AAI. A concentration-dependent increase in micronucleus frequency indicated a significant increase in chromosomal aberrations in hiHep cells. Considering the evidence of AAI inducing oxidative stress, we assessed 8-hydroxy-2'-deoxyguanosine and reactive oxygen species levels to evaluate DNA oxidative damage. For both indicators, significantly elevated levels were observed. A mechanism involving oxidative damage was further supported by observations of mitochondrial dysfunction, including changes in mitochondrial membrane potential and mitochondrial complex activity. Ascorbate treatment decreased AAI-induced oxidative DNA damage and DNA adduct formation, providing direct cellular evidence for free radical intermediates in AAI metabolic activation-a mechanism previously hypothesized but not experimentally validated in a human-relevant hepatocyte model. Our study findings revealed the genotoxic effects of AAI on hiHep cells and implicated oxidative stress as the key mechanism. These findings strengthen the association between AAI exposure and liver disease and highlight the potential role of antioxidant therapies in mitigating AAI-associated carcinogenesis.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143200","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":"A pooled analysis of host factors that affect nucleotide excision repair in humans.","authors":"Congying Zheng, Sergey Shaposhnikov, Andrew Collins, Gunnar Brunborg, Amaya Azqueta, Sabine A S Langie, Maria Dusinska, Jana Slyskova, Pavel Vodicka, Frederik-Jan van Schooten, Stefano Bonassi, Mirta Milic, Irene Orlow, Roger Godschalk","doi":"10.1093/mutage/geae028","DOIUrl":"10.1093/mutage/geae028","url":null,"abstract":"<p><p>Nucleotide excision repair (NER) is crucial for repairing bulky lesions and crosslinks in DNA caused by exogenous and endogenous genotoxins. The number of studies that have considered DNA repair as a biomarker is limited, and therefore one of the primary objectives of the European COST Action hCOMET (CA15132) was to assemble and analyse a pooled database of studies with data on NER activity. The database comprised 738 individuals, gathered from 5 laboratories that ran population studies using the comet-based in vitro DNA repair assay. NER activity data in peripheral blood mononuclear cells were normalized and correlated with various host-related factors, including sex, age, body mass index (BMI), and smoking habits. This multifaceted analysis uncovered significantly higher NER activity in female participants compared to males (1.08 ± 0.74 vs. 0.92 ± 0.71; P = .002). Higher NER activity was seen in older subjects (>30 years), and the effect of age was most pronounced in the oldest females, particularly those over 70 years (P = .001). Females with a normal BMI (<25 kg/m2) exhibited the highest levels of NER, whereas the lowest NER was observed in overweight males (BMI ≥ 25 kg/m2). No independent effect of smoking was found. After stratification by sex and BMI, higher NER was observed in smoking males (P = .017). The biological implication of higher or lower repair capacity remains unclear; the inclusion of DNA repair as a biomarker in molecular epidemiological trials should elucidate the link between health and disease status.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":"137-144"},"PeriodicalIF":2.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12022221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818626","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":"Slightly increased level of DNA migration in the comet assay: does statistical significance equal biological significance?","authors":"Peter Møller, Andrew Collins, Adriana Rodriguez-Garraus, Sabine A S Langie, Roger Godschalk, Amaya Azqueta","doi":"10.1093/mutage/geaf004","DOIUrl":"10.1093/mutage/geaf004","url":null,"abstract":"<p><p>In the comet assay, DNA damage is assessed by differences in DNA migration from gel-embedded nucleoids. Even a small difference in DNA migration between exposure groups can be statistically significant but may invite speculation about the biological significance of such slight increases in DNA migration. A small difference can be defined as a net difference of 1-2% Tail DNA, but background levels of DNA migration typically vary already more than 1-2% Tail DNA between studies. Here, we have used studies on ionizing radiation to assess the lowest detectable differences in DNA migration; variation in exposure-effect relationships; variation in central tendencies of DNA migration; unsystematic (residual) variation; and the actual number of lesions detectable with the comet assay. A total of 51 studies on ionizing radiation exposure in mammalian cells have been systematically reviewed, including results from ring-trial studies where the same batch of irradiated cells has been analysed in different laboratories. Ring-trial studies have shown that unsystematic variation is approximately 4% Tail DNA in studies on ionizing radiation. Studies on ionizing radiation in cell cultures have shown statistically significant effects when the net increase of DNA migration is 0.3-3.1% Tail DNA. Among those experiments, the ones with optimal assay conditions to detect low levels of DNA damage show statistically significant effects with doses of around 0.30 Gy, which corresponds to approximately 350 lesions per diploid cell. However, it has also been shown that the same dose of ionizing radiation can give rise to different levels of DNA migration (i.e. 0.7-7.8% Tail DNA per Gy) in different studies. In summary, the results show that even a small statistically significant difference in DNA migration has biological significance within the same experiment, but comparisons of DNA migration values between studies have limited biological implications.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":"99-110"},"PeriodicalIF":2.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12022222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441506","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}