Environmental and Molecular Mutagenesis最新文献

{"title":"Correction to “Mutation spectra of the BRCA1/2 genes in human breast and ovarian cancer and germline”","authors":"","doi":"10.1002/em.22617","DOIUrl":"https://doi.org/10.1002/em.22617","url":null,"abstract":"<p>\u0000 <span>Koi, Y.</span>, <span>Watanabe, A.</span>, <span>Kawasaki, A.</span>, <span>Ideo, S.</span>, <span>Matsutani, N.</span>, <span>Miyashita, K.</span>, <span>Shioi, S.</span>, <span>Tokunaga, E.</span>, <span>Shimokawa, M.</span>, <span>Nakatsu, Y.</span>, <span>Kuraoka, I.</span>, <span>Oda, S.</span> <span>Mutation spectra of the BRCA1/2 genes in human breast and ovarian cancer and germline</span>. <i>Environmental and Molecular Mutagenesis.</i> <span>2024</span>; <span>65</span>: <span>179</span>–<span>186</span>.</p><p>The gray shading in Table 1 that denotes analyses with an insufficient number of data (as noted in the table footnote) was missing in the original publication. It has been corrected and republished.</p><p>We apologize for these errors.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 6-7","pages":"230"},"PeriodicalIF":2.3,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22617","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160168","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 learning and memory impairment","authors":"Ahmad Sleiman,&nbsp;Kathleen B. Miller,&nbsp;Danicia Flores,&nbsp;Jaqueline Kuan,&nbsp;Kaitlyn Altwasser,&nbsp;Benjamin J. Smith,&nbsp;Tatiana Kozbenko,&nbsp;Robyn Hocking,&nbsp;Scott J. Wood,&nbsp;Janice Huff,&nbsp;Christelle Adam-Guillermin,&nbsp;Nobuyuki Hamada,&nbsp;Carole Yauk,&nbsp;Ruth Wilkins,&nbsp;Vinita Chauhan","doi":"10.1002/em.22622","DOIUrl":"10.1002/em.22622","url":null,"abstract":"<p>Understanding radiation-induced non-cancer effects on the central nervous system (CNS) is essential for the risk assessment of medical (e.g., radiotherapy) and occupational (e.g., nuclear workers and astronauts) exposures. Herein, the adverse outcome pathway (AOP) approach was used to consolidate relevant studies in the area of cognitive decline for identification of research gaps, countermeasure development, and for eventual use in risk assessments. AOPs are an analytical construct describing critical events to an adverse outcome (AO) in a simplified form beginning with a molecular initiating event (MIE). An AOP was constructed utilizing mechanistic information to build empirical support for the key event relationships (KERs) between the MIE of deposition of energy to the AO of learning and memory impairment through multiple key events (KEs). The evidence for the AOP was acquired through a documented scoping review of the literature. In this AOP, the MIE is connected to the AO via six KEs: increased oxidative stress, increased deoxyribonucleic acid (DNA) strand breaks, altered stress response signaling, tissue resident cell activation, increased pro-inflammatory mediators, and abnormal neural remodeling that encompasses atypical structural and functional alterations of neural cells and surrounding environment. Deposition of energy directly leads to oxidative stress, increased DNA strand breaks, an increase of pro-inflammatory mediators and tissue resident cell activation. These KEs, which are themselves interconnected, can lead to abnormal neural remodeling impacting learning and memory processes. Identified knowledge gaps include improving quantitative understanding of the AOP across several KERs and additional testing of proposed modulating factors through experimental work. Broadly, it is envisioned that the outcome of these efforts could be extended to other cognitive disorders and complement ongoing work by international radiation governing bodies in their review of the system of radiological protection.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 S3","pages":"57-84"},"PeriodicalIF":2.3,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22622","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125172","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":"Poly-ADP-ribosylation dynamics, signaling, and analysis","authors":"Rasha Q. Al-Rahahleh,&nbsp;Robert W. Sobol","doi":"10.1002/em.22623","DOIUrl":"10.1002/em.22623","url":null,"abstract":"<p>ADP-ribosylation is a reversible post-translational modification that plays a role as a signaling mechanism in various cellular processes. This modification is characterized by its structural diversity, highly dynamic nature, and short half-life. Hence, it is tightly regulated at many levels by cellular factors that fine-tune its formation, downstream signaling, and degradation that together impacts cellular outcomes. Poly-ADP-ribosylation is an essential signaling mechanism in the DNA damage response that mediates the recruitment of DNA repair factors to sites of DNA damage via their poly-ADP-ribose (PAR)-binding domains (PBDs). PAR readers, encoding PBDs, convey the PAR signal to mediate cellular outcomes that in some cases can be dictated by PAR structural diversity. Several PBD families have been identified, each with variable PAR-binding affinity and specificity, that also recognize and bind to distinct parts of the PAR chain. PARylation signaling has emerged as an attractive target for the treatment of specific cancer types, as the inhibition of PAR formation or degradation can selectively eliminate cancer cells with specific DNA repair defects and can enhance radiation or chemotherapy response. In this review, we summarize the key players of poly-ADP-ribosylation and its regulation and highlight PBDs as tools for studying PARylation dynamics and the expanding potential to target PARylation signaling in cancer treatment.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 9","pages":"315-337"},"PeriodicalIF":2.3,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105586","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":"Evaluation of the nitrosamine impurities of ACE inhibitors using computational, in vitro, and in vivo methods demonstrate no genotoxic potential","authors":"Jennifer Cheung,&nbsp;Krista Dobo,&nbsp;Shaofei Zhang,&nbsp;Raphael Nudelman,&nbsp;Friedemann Schmidt,&nbsp;Jan Wenzel,&nbsp;Andreas Czich,&nbsp;Maik Schuler","doi":"10.1002/em.22618","DOIUrl":"10.1002/em.22618","url":null,"abstract":"<p>Evaluation and mitigation of the potential carcinogenic risks associated with nitrosamines in marketed pharmaceutical products are areas of interest for pharmaceutical companies and health authorities alike. Significant progress has been made to establish acceptable intake (AI) levels for <i>N</i>-nitrosamine drug substance-related impurities (NDSRIs) using SAR, however some compounds require experimental data to support derivation of a recommended AI. Many angiotensin-converting enzyme inhibitors, identified by the suffix “pril,” have secondary amines that can potentially react to form nitrosamines. Here we consider a structural assessment and metabolism data, coupled with comprehensive in vitro and in vivo (mouse) genotoxicity testing to evaluate this particular class of nitrosamines. <i>N</i>-nitroso ramipril and <i>N</i>-nitroso quinapril, both of which are predicted to have inhibited nitrosamine bioactivation due to steric hinderance and branching at the α-position were non-genotoxic in the in vivo liver comet assay and non-mutagenic in the in vivo Big Blue® mutation and duplex sequencing assays. Predicted metabolism along with in vitro metabolism data and quantum chemical calculations related to DNA interactions offer a molecular basis for the negative results observed in both in vitro and in vivo testing. These nitrosamines are concluded to be non-mutagenic and non-carcinogenic; therefore, they should be controlled according to ICH Q3B guidance. Furthermore, these results for <i>N</i>-nitroso ramipril and <i>N</i>-nitroso quinapril should be considered when evaluating the appropriate AI and control strategy for other structurally similar “pril” NDSRIs.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 6-7","pages":"203-221"},"PeriodicalIF":2.3,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22618","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046498","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":"Abstracts From the 55th Annual Meeting of the Environmental Mutagenesis and Genomics Society, September 7 – 11, 2024 - Palm Springs, CA, USA, An Oasis of DNA Discoveries","authors":"","doi":"10.1002/em.22620","DOIUrl":"https://doi.org/10.1002/em.22620","url":null,"abstract":"","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 S2","pages":"6-135"},"PeriodicalIF":2.3,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142021811","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 evaluation of methyl tertiary- butyl ether in multiple tissues of transgenic rats following whole body inhalation exposure","authors":"B. Bhaskar Gollapudi,&nbsp;Erik K. Rushton","doi":"10.1002/em.22616","DOIUrl":"10.1002/em.22616","url":null,"abstract":"<p>Methyl <i>tertiary</i>-butyl ether (MTBE) is used as a component of motor vehicle fuel to enhance combustion efficiency and to reduce emissions of carbon monoxide and nitrogen oxides. Although MTBE was largely negative in the in vitro and in vivo genotoxicity studies, isolated reports of positive findings along with the observation of tumors in the rat cancer bioassays raised concern for its in vivo mutagenic potential. To investigate this, transgenic male Big Blue Fischer 344 rats were exposed to 0 (negative control), 400, 1000, and 3000 ppm MTBE via whole body inhalation for 28 consecutive days, 6 h/day. Mutant frequencies (MF) at the <i>cII</i> locus of the transgene in the nasal epithelium (portal of entry tissue), liver (site of primary metabolism), bone marrow (rapidly proliferating tissue), and kidney (tumor target) were analyzed (5 rats/exposure group) following a 3-day post-exposure manifestation period. MTBE did not induce a mutagenic response in any of the tissues investigated. The adequacy of the experimental conditions to detect induced mutations was confirmed by utilizing tissue samples from animals treated with the known mutagen ethyl nitrosourea. These data provide support to the conclusion that MTBE is not an in vivo mutagen and male rat kidney tumors are not likely the result of a mutagenic mode of action.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 6-7","pages":"222-229"},"PeriodicalIF":2.3,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22616","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619666","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":"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,&nbsp;Stephanie L. Coffing,&nbsp;William C. Gunther,&nbsp;Michael L. Homiski,&nbsp;Richard A. Spellman,&nbsp;Phu Van,&nbsp;Maik Schuler","doi":"10.1002/em.22615","DOIUrl":"10.1002/em.22615","url":null,"abstract":"<p>The detection of <i>N</i>-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 <i>N</i>-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 <i>cII</i> 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.</p>","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}

{"title":"Mutation spectra of the BRCA1/2 genes in human breast and ovarian cancer and germline","authors":"Yumiko Koi,&nbsp;Arisa Watanabe,&nbsp;Akari Kawasaki,&nbsp;Satomi Ideo,&nbsp;Nao Matsutani,&nbsp;Kaname Miyashita,&nbsp;Seijiro Shioi,&nbsp;Eriko Tokunaga,&nbsp;Mototsugu Shimokawa,&nbsp;Yoshimichi Nakatsu,&nbsp;Isao Kuraoka,&nbsp;Shinya Oda","doi":"10.1002/em.22614","DOIUrl":"10.1002/em.22614","url":null,"abstract":"<p>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 <i>BRCA1</i>/1861 <i>BRCA2</i> germline missense variants and 294 <i>BRCA1</i>/420 <i>BRCA2</i> 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 <i>BRCA1</i> variants, A:T to C:G transversion, which was relatively frequent in the germline, was extremely rare in somatic, particularly breast cancer, cells (<i>p</i> = .03). Conversely, A:T to T:A transversion was most infrequent in the germline, but not rare in somatic cells. Thus, <i>BRCA1</i> 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.</p>","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}

{"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":"<p><p>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.</p>","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}

{"title":"Establishment of a nonradioactive DNA ligation assay and its applications in murine tissues","authors":"Sharleen Friese,&nbsp;Tom Heinze,&nbsp;Franziska Ebert,&nbsp;Tanja Schwerdtle","doi":"10.1002/em.22602","DOIUrl":"10.1002/em.22602","url":null,"abstract":"<p>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.</p>","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}