Environmental and Molecular Mutagenesis最新文献_第6页

Assessing the genotoxicity of N-nitrosodiethylamine with three in vivo endpoints in male Big Blue® transgenic and wild-type C57BL/6N mice 在雄性大蓝®转基因小鼠和野生型 C57BL/6N 小鼠体内通过三个体内终点评估 N-亚硝基二乙胺的遗传毒性。

IF 2.3 4区医学

Environmental and Molecular Mutagenesis Pub Date : 2024-07-16 DOI: 10.1002/em.22615

Shaofei Zhang, Stephanie L. Coffing, William C. Gunther, Michael L. Homiski, Richard A. Spellman, Phu Van, Maik Schuler

{"title":"Assessing the genotoxicity of N-nitrosodiethylamine with three in vivo endpoints in male Big Blue® transgenic and wild-type C57BL/6N mice","authors":"Shaofei Zhang, Stephanie L. Coffing, William C. Gunther, Michael L. Homiski, Richard A. Spellman, Phu Van, Maik Schuler","doi":"10.1002/em.22615","DOIUrl":"10.1002/em.22615","url":null,"abstract":"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 for novel nitrosamines without sufficient carcinogenicity data. In a previous study we compared the dose–response relationships of N-nitrosodiethylamine (NDEA) in three in vivo genotoxicity endpoints in rats. Here we report a comparison of NDEA's genotoxicity profile in mice. Big Blue® mice were administered NDEA at doses of 0.001, 0.01, 0.1, 1 and 3 mg/kg/day by oral gavage for 28 days followed by 3 days of expression. Statistically significant increases in the NDEA induced mutations were detected by both the transgenic rodent mutation assay (TGR) using the cII endpoint and by duplex sequencing in the liver but not bone marrow of mice. In addition, administration of NDEA for two consecutive days in male C57BL/6N mice caused elevated DNA damage levels in the liver as measured by % tail DNA in comet assay. The benchmark dose (BMD) analysis shows a BMDL50 of 0.03, 0.04 and 0.72 mg/kg/day for TGR, duplex sequencing and comet endpoints, respectively. Overall, this study demonstrated a similar genotoxicity profile of NDEA between mice and rats and provides a reference that can be used to compare the potential potency of other novel nitrosamines for the induction of gene mutations.","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 6-7","pages":"190-202"},"PeriodicalIF":2.3,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22615","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619665","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

Mutation spectra of the BRCA1/2 genes in human breast and ovarian cancer and germline 人类乳腺癌、卵巢癌和种系中 BRCA1/2 基因的突变谱。

IF 2.8 4区医学

Environmental and Molecular Mutagenesis Pub Date : 2024-06-11 DOI: 10.1002/em.22614

Yumiko Koi, Arisa Watanabe, Akari Kawasaki, Satomi Ideo, Nao Matsutani, Kaname Miyashita, Seijiro Shioi, Eriko Tokunaga, Mototsugu Shimokawa, Yoshimichi Nakatsu, Isao Kuraoka, Shinya Oda

{"title":"Mutation spectra of the BRCA1/2 genes in human breast and ovarian cancer and germline","authors":"Yumiko Koi, Arisa Watanabe, Akari Kawasaki, Satomi Ideo, Nao Matsutani, Kaname Miyashita, Seijiro Shioi, Eriko Tokunaga, Mototsugu Shimokawa, Yoshimichi Nakatsu, Isao Kuraoka, Shinya Oda","doi":"10.1002/em.22614","DOIUrl":"10.1002/em.22614","url":null,"abstract":"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 were obtained. We then compared their mutation spectra, i.e., the frequencies of two transition- and four transversion-type mutations, in each category. Intriguingly, in BRCA1 variants, A:T to C:G transversion, which was relatively frequent in the germline, was extremely rare in somatic, particularly breast cancer, cells (p = .03). Conversely, A:T to T:A transversion was most infrequent in the germline, but not rare in somatic cells. Thus, BRCA1 variants with A:T to T:A transversion may be suspected as somatic, and those with A:T to C:G as being in the germline. These tendencies of mutation spectrum may also suggest the biological and chemical origins of the base alterations. On the other hand, unfortunately, variants of uncertain significance (VUS) were not distinguishable by mutation spectrum. Our findings warrant further and more detailed studies.","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 5","pages":"179-186"},"PeriodicalIF":2.8,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22614","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141300385","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

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). 将突变作为风险评估毒理学终点的效应严重性考虑因素：第八届国际遗传毒性测试研讨会（IWGT）报告。

IF 2.8 4区医学

Environmental and Molecular Mutagenesis Pub Date : 2024-06-03 DOI: 10.1002/em.22599

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

{"title":"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).","authors":"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","doi":"10.1002/em.22599","DOIUrl":"https://doi.org/10.1002/em.22599","url":null,"abstract":"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 as teratogenicity, irreversible reproductive effects, neurotoxicity, or cancer was observed in the reference study. Although mutation data have been used historically for hazard identification, this endpoint is suitable for quantitative dose-response modeling and risk assessment. As part of the 8th International Workshops on Genotoxicity Testing, a sub-group of the Quantitative Analysis Work Group (WG) explored how the concept of effect severity could be applied to mutation. To approach this question, the WG reviewed the prevailing regulatory guidance on how an ESAF is incorporated into risk assessments, evaluated current knowledge of associations between germline or somatic mutation and severe disease risk, and mined available data on the fraction of human germline mutations expected to cause severe disease. Based on this review and given that mutations are irreversible and some cause severe human disease, in regulatory settings where an ESAF is used, a majority of the WG recommends applying an ESAF value between 2 and 10 when deriving a HBGV from mutation data. This recommendation may need to be revisited in the future if direct measurement of disease-causing mutations by error-corrected next generation sequencing clarifies selection of ESAF values.","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199876","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

Establishment of a nonradioactive DNA ligation assay and its applications in murine tissues 非放射性 DNA 连接试验的建立及其在鼠组织中的应用

IF 2.8 4区医学

Environmental and Molecular Mutagenesis Pub Date : 2024-05-20 DOI: 10.1002/em.22602

Sharleen Friese, Tom Heinze, Franziska Ebert, Tanja Schwerdtle

{"title":"Establishment of a nonradioactive DNA ligation assay and its applications in murine tissues","authors":"Sharleen Friese, Tom Heinze, Franziska Ebert, Tanja Schwerdtle","doi":"10.1002/em.22602","DOIUrl":"10.1002/em.22602","url":null,"abstract":"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. Briefly, tissue extracts were incubated with those complementary oligonucleotides so that in an ensuing gel electrophoresis ligated strands could be separated from unconnected molecules. Originally, the method was intended for use in cerebellum tissue to further elucidate possible mechanisms of neurodegenerative diseases. However, due to its inhomogeneous anatomy, DNA ligation efficiency varied strongly between different cerebellar areas, illuminating the established assay to be suitable only for homogenous organs. Thus, for murine liver tissue sufficient intra- and interday repeatability was shown during validation. In further experiments, the established assay was applied to an animal study comprising young and old (24 and 110 weeks) mice which showed that DNA ligation efficiency was affected by neither sex nor age. Finally, the impact of in vitro addition of the trace elements copper, iron, and zinc on DNA ligation in tissue extracts was investigated. While all three metals inhibited DNA ligation, variations in their potency became evident. In conclusion, the established method can be reliably used for investigation of DNA ligation efficiency in homogenous murine tissues.","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 3-4","pages":"106-115"},"PeriodicalIF":2.8,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22602","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141065149","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

Visualization strategies to aid interpretation of high-dimensional genotoxicity data 帮助解读高维遗传毒性数据的可视化策略。

IF 2.8 4区医学

Environmental and Molecular Mutagenesis Pub Date : 2024-05-17 DOI: 10.1002/em.22604

Stephen D. Dertinger, Erica Briggs, Yusuf Hussien, Steven M. Bryce, Svetlana L. Avlasevich, Adam Conrad, George E. Johnson, Andrew Williams, Jeffrey C. Bemis

{"title":"Visualization strategies to aid interpretation of high-dimensional genotoxicity data","authors":"Stephen D. Dertinger, Erica Briggs, Yusuf Hussien, Steven M. Bryce, Svetlana L. Avlasevich, Adam Conrad, George E. Johnson, Andrew Williams, Jeffrey C. Bemis","doi":"10.1002/em.22604","DOIUrl":"10.1002/em.22604","url":null,"abstract":"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 with visualizing seven biomarker responses were further complicated whenever there was a desire to represent the entire 126 chemical data set as opposed to results from a single chemical. Scatter plots, spider plots, parallel coordinate plots, hierarchical clustering, principal component analysis, toxicological prioritization index, multidimensional scaling, t-distributed stochastic neighbor embedding, and uniform manifold approximation and projection are each considered in turn. Our report provides a comparative analysis of these techniques. In an era where multiplexed assays and machine learning algorithms are becoming the norm, stakeholders should find some of these visualization strategies useful for efficiently and effectively interpreting their high-dimensional data.","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 5","pages":"156-178"},"PeriodicalIF":2.8,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22604","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140956794","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 genotoxicity of tert-butyl alcohol in an in vivo thyroid comet assay 在体内甲状腺彗星试验中评估叔丁醇的遗传毒性。

IF 2.8 4区医学

Environmental and Molecular Mutagenesis Pub Date : 2024-05-08 DOI: 10.1002/em.22601

Chad M. Thompson, Nicole Dewhurst, Dmitri Moundous, Susan J. Borghoff, Laurie C. Haws, Marie Z. Vasquez

{"title":"Assessment of the genotoxicity of tert-butyl alcohol in an in vivo thyroid comet assay","authors":"Chad M. Thompson, Nicole Dewhurst, Dmitri Moundous, Susan J. Borghoff, Laurie C. Haws, Marie Z. Vasquez","doi":"10.1002/em.22601","DOIUrl":"10.1002/em.22601","url":null,"abstract":"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 TBA was inconclusive, largely based on non-standard studies such as in vitro comet assays. As such, the potential role of genotoxicity in the mode of action of thyroid tumors and therefore human relevance was considered uncertain. To address the potential role of genotoxicity in TBA-associated thyroid tumor formation, CD-1 mice were exposed up to a maximum tolerated dose of 1500 mg/kg-day via oral gavage for two consecutive days and DNA damage was assessed with the comet assay in the thyroid. Blood TBA levels were analyzed by headspace GC–MS to confirm systemic tissue exposure. At study termination, no significant increases (DNA breakage) or decreases (DNA crosslinks) in %DNA tail were observed in TBA exposed mice. In contrast, oral gavage of the positive control ethyl methanesulfonate significantly increased %DNA tail in the thyroid. These findings are consistent with most genotoxicity studies on TBA and provide mechanistic support for non-linear, threshold toxicity criteria for TBA. While the mode of action for the thyroid tumors remains unclear, linear low dose extrapolation methods for TBA appear more a matter of policy than science.","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 3-4","pages":"129-136"},"PeriodicalIF":2.8,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140876164","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

Comparison between inhalational anesthetics in terms of DNA damage and immunological markers 不同吸入麻醉剂对 DNA 损伤和免疫标志物的影响比较

IF 2.8 4区医学

Environmental and Molecular Mutagenesis Pub Date : 2024-04-28 DOI: 10.1002/em.22600

Mariana G. Braz, Mariane A. P. Silva, Carlos E. Scorza, Juliana R. Lara, José Reinaldo C. Braz, Leandro G. Braz

{"title":"Comparison between inhalational anesthetics in terms of DNA damage and immunological markers","authors":"Mariana G. Braz, Mariane A. P. Silva, Carlos E. Scorza, Juliana R. Lara, José Reinaldo C. Braz, Leandro G. Braz","doi":"10.1002/em.22600","DOIUrl":"10.1002/em.22600","url":null,"abstract":"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 assay; proinflammatory interleukin (IL)-6 was detected by flow cytometry, and white blood cells were detected via an automatic hematology analyzer. The characteristics of both groups were similar, and neither of the two anesthetics induced DNA damage. Similarly, mild neutrophilia was observed after anesthesia in both groups. Increased IL-6 levels were observed 1 day after anesthesia regardless of the type of anesthetic, but this increase was greater in the isoflurane group. Our study suggested that isoflurane and sevoflurane administration may contribute to changes in the immune parameters measured, though no genotoxic hazard was identified, in healthy adult patients who undergo low-stress surgery.","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 3-4","pages":"137-142"},"PeriodicalIF":2.8,"publicationDate":"2024-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140837704","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

Within-laboratory reproducibility of Ames test results: Are repeat tests necessary? 艾姆斯试验结果在实验室内的重现性：是否有必要重复试验？

IF 2.8 4区医学

Environmental and Molecular Mutagenesis Pub Date : 2024-04-23 DOI: 10.1002/em.22597

Errol Zeiger, Constance A. Mitchell, Stefan Pfuhler, Yang Liao, Kristine L. Witt

{"title":"Within-laboratory reproducibility of Ames test results: Are repeat tests necessary?","authors":"Errol Zeiger, Constance A. Mitchell, Stefan Pfuhler, Yang Liao, Kristine L. Witt","doi":"10.1002/em.22597","DOIUrl":"10.1002/em.22597","url":null,"abstract":"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 such as botanical extracts, a cross-sector working group examined the within-laboratory reproducibility of the Ames test using the extensive, publicly available National Toxicology Program (NTP) Ames test database comprising more than 3000 distinct test articles, most of which are individual chemicals. This study focused primarily on NTP tests conducted using the standard Organization for Economic Co-operation and Development Test Guideline 471 preincubation test protocol with 10% rat liver S9 for metabolic activation, although 30% rat S9 and 10 and 30% hamster liver S9 were also evaluated. The reproducibility of initial negative responses in all strains with and without 10% S9, was quite high, ranging from 95% to 99% with few exceptions. The within-laboratory reproducibility of initial positive responses for strains TA98 and TA100 with and without 10% rat liver S9 was ≥90%. Similar results were seen with hamster S9. As expected, the reproducibility of initial equivocal responses was lower, <50%. These results will provide context for determining the optimal design of recommended test protocols for use in screening both individual chemicals and complex mixtures, including botanicals.","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 3-4","pages":"116-120"},"PeriodicalIF":2.8,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22597","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140670393","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

AOP report: Development of an adverse outcome pathway for deposition of energy leading to cataracts AOP 报告：制定能量沉积导致白内障的不良后果途径

IF 2.3 4区医学

Environmental and Molecular Mutagenesis Pub Date : 2024-04-21 DOI: 10.1002/em.22594

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

{"title":"AOP report: Development of an adverse outcome pathway for deposition of energy leading to cataracts","authors":"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","doi":"10.1002/em.22594","DOIUrl":"10.1002/em.22594","url":null,"abstract":"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 pathway (AOP) framework was used to structure and evaluate knowledge across biological levels of organization (e.g., macromolecular, cell, tissue, organ, organism and population). AOPs identify a sequence of key events (KEs) causally connected by key event relationships (KERs) beginning with a molecular initiating event to an adverse outcome (AO) of relevance to regulatory decision-making. To construct the cataract AO and retrieve evidence to support it, a scoping review methodology was used to filter, screen, and review studies based on the modified Bradford Hill criteria. Eight KEs were identified that were moderately supported by empirical evidence (e.g., dose-, time-, incidence-concordance) across the adjacent (directly linked) relationships using well-established endpoints. Over half of the evidence to justify the KER linkages was derived from the evidence stream of biological plausibility. Early KEs of oxidative stress and protein modifications had strong linkages to downstream KEs and could be the focus of countermeasure development. Several identified knowledge gaps and inconsistencies related to the quantitative understanding of KERs which could be the basis of future research, most notably directed to experiments in the range of low or moderate doses and dose-rates, relevant to radiation workers and other occupational exposures.","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 S3","pages":"31-56"},"PeriodicalIF":2.3,"publicationDate":"2024-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22594","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140636982","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

Inspiring basic and applied research in genome integrity mechanisms: Dedication to Samuel H. Wilson 激励基因组完整性机制方面的基础研究和应用研究：献给塞缪尔-H-威尔逊

IF 2.8 4区医学

Environmental and Molecular Mutagenesis Pub Date : 2024-04-15 DOI: 10.1002/em.22595

Shan Yan, Shobhan Gaddameedhi, Robert W. Sobol

{"title":"Inspiring basic and applied research in genome integrity mechanisms: Dedication to Samuel H. Wilson","authors":"Shan Yan, Shobhan Gaddameedhi, Robert W. Sobol","doi":"10.1002/em.22595","DOIUrl":"https://doi.org/10.1002/em.22595","url":null,"abstract":"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 four reviews that highlight cutting edge research findings and perspectives, from both established leaders and junior trainees, on DNA repair mechanisms. In particular, the authors provided an updated understanding on several distinct enzymes (e.g., DNA polymerase beta, DNA polymerase theta, DNA glycosylase NEIL2) and the associated molecular mechanisms in base excision repair, nucleotide excision repair, and microhomology-mediated end joining of double-strand breaks. In addition, genome-wide sequencing analysis or site-specific mutational signature analysis of DNA lesions from environmental mutagens (e.g., UV light and aflatoxin) provide further characterization and sequence context impact of DNA damage and mutations. This SI is dedicated to the legacy of Dr. Samuel H. Wilson from the U.S. National Institute of Environmental Health Sciences at the National Institutes of Health.","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 S1","pages":"4-8"},"PeriodicalIF":2.8,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22595","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140556278","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