Environmental and Molecular Mutagenesis最新文献_第8页

In vivo genotoxicity testing strategies: Report from the 8th International Workshop on Genotoxicity Testing (IWGT). 体内基因毒性测试策略：第八届国际基因毒性测试研讨会报告。

IF 2.8 4区医学

Environmental and Molecular Mutagenesis Pub Date : 2023-11-09 DOI: 10.1002/em.22578

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

{"title":"In vivo genotoxicity testing strategies: Report from the 8th International Workshop on Genotoxicity Testing (IWGT).","authors":"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","doi":"10.1002/em.22578","DOIUrl":"10.1002/em.22578","url":null,"abstract":"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 and Development (OECD) test guideline (TG) 474 recommendations and if sufficient bone marrow exposure is demonstrated; consensus on the evidence required to demonstrate \"sufficient\" exposure was not reached. The liver MN test using six-week-old rats is sufficiently validated to develop an OECD TG, but the impact of animal age warrants additional study. Ki-67 is a reliable marker for cellular proliferation in hepatocytes. The gastrointestinal tract MN test is useful for detecting poorly absorbed or rapidly degraded aneugens, and for genotoxic metabolites formed in the colon. Although current validation data are insufficient to support the development of an OECD TG, the methodologies are sufficient to consider as an appendix to OECD TG474. Comparison of comet assay results to laboratory historical control data (HCD) should not be used in data evaluation, unless the HCD distribution is demonstrated to be stable and the predominant source of HCD variation is due to animal, not study, factors. No universally acceptable negative control limit for any tissue was identified. Methodological differences in comet studies can result in variable data interpretations; more data are required before best practice recommendations can be made. Hedgehogs alone are unreliable indicators of cytotoxicity and additional investigations into cytotoxicity markers are required.","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2023-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71520850","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}

引用次数: 1

The PIG-A gene mutation assay in human biomonitoring and disease PIG-A基因突变检测在人类生物监测和疾病中的应用。

IF 2.8 4区医学

Environmental and Molecular Mutagenesis Pub Date : 2023-11-05 DOI: 10.1002/em.22577

Rachel Lawrence, Kathryn Munn, Hamsa Naser, Laura Thomas, Hasan Haboubi, Lisa Williams, Shareen Doak, Gareth Jenkins

{"title":"The PIG-A gene mutation assay in human biomonitoring and disease","authors":"Rachel Lawrence, Kathryn Munn, Hamsa Naser, Laura Thomas, Hasan Haboubi, Lisa Williams, Shareen Doak, Gareth Jenkins","doi":"10.1002/em.22577","DOIUrl":"10.1002/em.22577","url":null,"abstract":"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 GPI-anchored proteins (e.g., CD55) using flow cytometry. The studies published to date by different research groups demonstrate a remarkable consistency in PIG-A mutant frequencies. Moreover, with the low background level of mutant erythrocytes in healthy subjects (2.9–5.56 × 10−6 mutants), induction of mutation post genotoxic exposure can be detected. Cigarette smoking, radiotherapy, and occupational exposures, including lead, have been shown to increase mutant levels. Future applications of this test include identifying new harmful agents and establishing new exposure limits. This mutational monitoring approach may also identify individuals at higher risk of cancer development. In addition, identifying protective agents that could mitigate these effects may reduce baseline somatic mutation levels and such behaviors can be encouraged. Further technological progress is required including establishing underlying mechanisms of GPI anchor loss, protocol standardization, and the development of cryopreservation methods to improve GPI-anchor stability over time. If successful, this assay has the potential be widely employed, for example, in rural and low-income countries. Here, we review the current literature on PIG-A mutation in humans and discuss the potential role of this assay in human biomonitoring and disease detection.","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"64 8-9","pages":"480-493"},"PeriodicalIF":2.8,"publicationDate":"2023-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22577","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71479488","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}

引用次数: 0

Assessment of the in vivo genotoxic potential of three smoke flavoring primary product mixtures 三种烟味初级产品混合物的体内基因毒性潜力评估。

IF 2.8 4区医学

Environmental and Molecular Mutagenesis Pub Date : 2023-11-02 DOI: 10.1002/em.22576

Chad M. Thompson, Gregory Brorby, Zena Keig-Shevlin, Robert Smith, Allison Franzen, Kristina Ulrich, Alexander D. Blanchette, Candace Doepker

{"title":"Assessment of the in vivo genotoxic potential of three smoke flavoring primary product mixtures","authors":"Chad M. Thompson, Gregory Brorby, Zena Keig-Shevlin, Robert Smith, Allison Franzen, Kristina Ulrich, Alexander D. Blanchette, Candace Doepker","doi":"10.1002/em.22576","DOIUrl":"10.1002/em.22576","url":null,"abstract":"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 in rats and transgenic rodent (TGR) mutation assays in Muta™Mice were conducted on three SFPPs. For most studies, typical limit doses were exceeded to comply with regulatory requests. Exposure to SFPPs by oral gavage did not result in significant increases in bone marrow micronucleus formation. Except for one group, exposure to SFPPs via feed for 28 days did not result in significant increases in mutant frequency (MF) in the glandular stomach or liver. One group exposed to a maximal feasible dietary dose of 50,000 ppm (>10,000 mg/kg bodyweight per day) exhibited a statistically significant increase in liver MF; however, the MF in all mice in this group were within the historical vehicle control 95% quantile confidence intervals and therefore not considered biologically relevant. Based on estimates of human dietary exposure to each SFPP, the margin of exposure (MOE) values in the TGR assays exceed 10,000. The MOE for one unintentionally present constituent, 2,5(H)-furanone, also exceeds 10,000. Collectively, these data indicate that these SFPPs pose no genotoxic risk and are safe alternatives to conventional smoking.","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"64 8-9","pages":"420-431"},"PeriodicalIF":2.8,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22576","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71421801","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}

引用次数: 0

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 HepaRG的基因毒性评估™ 细胞作为一种新的方法——人类TK6细胞微核测定中阳性反应的后续研究：萘案例研究。

IF 2.8 4区医学

Environmental and Molecular Mutagenesis Pub Date : 2023-09-13 DOI: 10.1002/em.22575

Leslie Recio, Jasmine Fowler, Lincoln Martin, Carol Swartz

{"title":"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","authors":"Leslie Recio, Jasmine Fowler, Lincoln Martin, Carol Swartz","doi":"10.1002/em.22575","DOIUrl":"10.1002/em.22575","url":null,"abstract":"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 of rat liver S9. of naphthalene. In HepaRG™ cells, naphthalene genotoxicity was assessed using either 6 (CometChip™) or 12 concentrations of naphthalene (MN assay) with the top dose used for assessment of genotoxicity for the Comet and MN assay was 1.25 and 1.74 mM respectively, corresponding to approximately 45% cell survival. In contrast to human TK6 cell with S9, naphthalene was not genotoxic in either the HepaRG™ MN assay or the Comet assay using CometChip®. The lack of genotoxicity in both the MN and comet assays in HepaRG™ cells is likely due to Phase II enzymes removing phenols preventing further bioactivation to quinones and efficient detoxication of naphthalene quinones or epoxides by glutathione conjugation. In contrast to CYP450 mediated metabolism, these Phase II enzymes are inactive in rat liver S9 due to lack of appropriate cofactors causing a positive genotoxic response. Rat liver S9-derived BMD10 over-predicts naphthalene genotoxicity when compared to the negative genotoxic response observed in HepaRG™ cells. Metabolically competent hepatocyte models like HepaRG™ cells should be considered as human-relevant NAMs for use genotoxicity assessments to reduce reliance on rodents.","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"64 8-9","pages":"458-465"},"PeriodicalIF":2.8,"publicationDate":"2023-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10234934","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}

引用次数: 0

The association of epidermal growth factor variant with oral squamous cell carcinoma 表皮生长因子变异与口腔鳞状细胞癌的关系

IF 2.8 4区医学

Environmental and Molecular Mutagenesis Pub Date : 2023-09-02 DOI: 10.1002/em.22572

Baris Ertugrul, Amal Mohammed, Goksu Kasarci, Sinem Bireller, Murat Ulusan, Bedia Cakmakoglu

{"title":"The association of epidermal growth factor variant with oral squamous cell carcinoma","authors":"Baris Ertugrul, Amal Mohammed, Goksu Kasarci, Sinem Bireller, Murat Ulusan, Bedia Cakmakoglu","doi":"10.1002/em.22572","DOIUrl":"10.1002/em.22572","url":null,"abstract":"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 A > G (rs4444903) and EGFR R497K (rs2227983) were analyzed. According to the EGF + 61 A > G genotype distribution, individuals with the GG genotype were more prevalent in the OSCC group when compared to the healthy controls. But the AA genotype frequency was significantly higher in the healthy control group. The frequency of G allele carriers was 2.3 times higher than A allele carriers in OSCC patients (p < .001). For the EGFR R497K genotype, there was no significant difference between the OSCC and healthy control groups. Regarding the study results, the G allele of EGF + 61 A > G polymorphism was associated with OSCC. Larger populations and functional investigations should be used to explore the nature of the interaction between EGF and OSCC.","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"64 8-9","pages":"473-479"},"PeriodicalIF":2.8,"publicationDate":"2023-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10669319","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}

引用次数: 0

Abstracts From the 54th Annual Meeting of the Environmental Mutagenesis and Genomics Society, September 9 – 13, 2023 - Chicago, IL, USA, EMGS in the Windy City: Billowing the Sails of DNA Science 第54届环境诱变与基因组学学会年会，2023年9月9日至13日在美国伊利诺伊州芝加哥举行，EMGS在风城:吹动DNA科学的风帆

IF 2.8 4区医学

Environmental and Molecular Mutagenesis Pub Date : 2023-08-31 DOI: 10.1002/em.22571

引用次数: 0

Oxidative DNA damage on the VEGF G-quadruplex forming promoter is repaired via long-patch BER VEGF G-四链体形成启动子上的氧化性DNA损伤通过长片BER修复。

IF 2.8 4区医学

Environmental and Molecular Mutagenesis Pub Date : 2023-08-22 DOI: 10.1002/em.22570

Adil S. Hussen, Haley L. Kravitz, Bret D. Freudenthal, Amy M. Whitaker

{"title":"Oxidative DNA damage on the VEGF G-quadruplex forming promoter is repaired via long-patch BER","authors":"Adil S. Hussen, Haley L. Kravitz, Bret D. Freudenthal, Amy M. Whitaker","doi":"10.1002/em.22570","DOIUrl":"10.1002/em.22570","url":null,"abstract":"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 of each BER factor to conduct its repair activity on VEGF promoter G4 DNA substrates by employing pre-steady-state kinetics assays and in vitro coupled BER assays. OGG1 was able to initiate BER on double-stranded VEGF promoter G4 DNA substrates. Moreover, pre-steady-state kinetics revealed that compared to B-form DNA, APE1 repair activity on the G4 was decreased ~two-fold and is the result of slower product release as opposed to inefficient strand cleavage. Interestingly, Pol β performs multiple insertions on G4 substrates via strand displacement DNA synthesis in contrast to a single insertion on B-form DNA. The multiple insertions inhibit ligation of the Pol β products, and hence BER is not completed on the VEGF G4 promoter substrates through canonical short-patch BER. Instead, repair requires the long-patch BER flap-endonuclease activity of FEN1 in response to the multiple insertions by Pol β prior to ligation. Because the BER proteins and their repair activities are a key part of the VEGF transcriptional enhancement in response to oxidative DNA damage of the G4 VEGF promoter, the new insights reported here on BER activity in the context of this promoter are relevant toward understanding the mechanism of transcriptional regulation.","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 S1","pages":"25-39"},"PeriodicalIF":2.8,"publicationDate":"2023-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10984112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10182876","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}

引用次数: 0

Genome-wide impact of cytosine methylation and DNA sequence context on UV-induced CPD formation 胞嘧啶甲基化和DNA序列背景对紫外线诱导CPD形成的全基因组影响。

IF 2.8 4区医学

Environmental and Molecular Mutagenesis Pub Date : 2023-08-09 DOI: 10.1002/em.22569

Hannah E. Wilson, John J. Wyrick

{"title":"Genome-wide impact of cytosine methylation and DNA sequence context on UV-induced CPD formation","authors":"Hannah E. Wilson, John J. Wyrick","doi":"10.1002/em.22569","DOIUrl":"10.1002/em.22569","url":null,"abstract":"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 the TP53 tumor suppressor are often sites of mutation hotspots in skin cancers. It has been argued that this is because cytosine methylation promotes UV-induced CPD formation; however, the effects of cytosine methylation on CPD formation are controversial, with conflicting results from previous studies. Here, we use a genome-wide method known as CPD-seq to map UVB- and UVC-induced CPDs across the yeast genome in the presence or absence in vitro methylation by the CpG methyltransferase M.SssI. Our data indicate that cytosine methylation increases UVB-induced CPD formation nearly 2-fold relative to unmethylated DNA, but the magnitude of induction depends on the flanking sequence context. Sequence contexts with a 5′ guanine base (e.g., GCCG and GTCG) show the strongest induction due to cytosine methylation, potentially because these sequence contexts are less efficient at forming CPD lesions in the absence of methylation. We show that cytosine methylation also modulates UVC-induced CPD formation, albeit to a lesser extent than UVB. These findings can potentially reconcile previous studies, and define the impact of cytosine methylation on UV damage across a eukaryotic genome.","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 S1","pages":"14-24"},"PeriodicalIF":2.8,"publicationDate":"2023-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10853481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10121130","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}

引用次数: 0

The role of Transcription Factor IIH complex in nucleotide excision repair 转录因子 IIH 复合物在核苷酸切除修复中的作用

IF 2.8 4区医学

Environmental and Molecular Mutagenesis Pub Date : 2023-08-06 DOI: 10.1002/em.22568

Allyson Hoag, Mingrui Duan, Peng Mao

{"title":"The role of Transcription Factor IIH complex in nucleotide excision repair","authors":"Allyson Hoag, Mingrui Duan, Peng Mao","doi":"10.1002/em.22568","DOIUrl":"10.1002/em.22568","url":null,"abstract":"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 chemotherapeutics, such as cisplatin. A main component for the NER pathway is transcription factor IIH (TFIIH), a multifunctional, 10-subunit protein complex with crucial roles in both transcription and NER. In transcription, TFIIH is a component of the pre-initiation complex and is important for promoter opening and the phosphorylation of RNA Polymerase II (RNA Pol II). During repair, TFIIH is important for DNA unwinding, recruitment of downstream repair factors, and verification of the bulky lesion. Several different disease states can arise from mutations within subunits of the TFIIH complex. Most strikingly are xeroderma pigmentosum (XP), XP combined with Cockayne syndrome (CS), and trichothiodystrophy (TTD). Here, we summarize the recruitment and functions of TFIIH in the two NER subpathways, global genomic (GG-NER) and transcription-coupled NER (TC-NER). We will also discuss how TFIIH's roles in the two subpathways lead to different genetic disorders.","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 S1","pages":"72-81"},"PeriodicalIF":2.8,"publicationDate":"2023-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10903506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10102551","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}

引用次数: 0

Impact of individual factors on DNA methylation of drug metabolism genes: A systematic review 个体因素对药物代谢基因DNA甲基化的影响:系统综述

IF 2.8 4区医学

Environmental and Molecular Mutagenesis Pub Date : 2023-07-31 DOI: 10.1002/em.22567

Jialu Bian, Jinxia Zhao, Yinyu Zhao, Xu Hao, Shiyu He, Yuanyuan Li, Lin Huang

引用次数: 0