Environmental and Molecular Mutagenesis最新文献

{"title":"Evaluation of the standard battery of in vitro genotoxicity tests to predict in vivo genotoxicity through mathematical modeling: A report from the 8th International Workshop on Genotoxicity Testing.","authors":"Mirjam Luijten, Jan van Benthem, Takeshi Morita, Raffaella Corvi, Patricia A Escobar, Yurika Fujita, Jennifer Hemmerich, Naveed Honarvar, David Kirkland, Naoki Koyama, David P Lovell, Miriam Mathea, Andrew Williams, Stephen Dertinger, Stefan Pfuhler, Jeroen L A Pennings","doi":"10.1002/em.22640","DOIUrl":"https://doi.org/10.1002/em.22640","url":null,"abstract":"<p><p>In human health risk assessment of chemicals and pharmaceuticals, identification of genotoxicity hazard usually starts with a standard battery of in vitro genotoxicity tests, which is needed to cover all genotoxicity endpoints. The individual tests included in the battery are not designed to pick up all endpoints. This explains why resulting data can appear contradictory, thereby complicating accurate interpretation of the findings. Such interpretation could be improved through application of mathematical modeling. One of the advantages of mathematical modeling is that the strengths and weaknesses of each test are taken into account. Furthermore, the generated predictions are objective and convey the associated uncertainties. This approach was explored by the working group \"Predictivity of In Vitro Genotoxicity Testing,\" convened in the context of the 8th International Workshop on Genotoxicity Testing (IWGT). Specifically, we applied mathematical modeling to a database with publicly available in vitro and in vivo data for genotoxicity. The results indicate that a mammalian in vitro clastogenicity test and a mammalian cell gene mutation test together provide strong predictive weight-of-evidence for evaluating genotoxic hazard of a substance, although they are better in predicting absence of genotoxic potential than in predicting presence of genotoxic potential. Remarkably, the bacterial reverse mutation (Ames) test did not significantly change these predictions when used in combination with in vitro mutagenicity and clastogenicity tests using cells of mammalian origin. However, in case only data from a bacterial reverse mutation test are available for the assessment of genotoxic potential, these do bear weight of evidence and thus can be used. Genotoxicity assays are generally executed in tiers, in which the bacterial reverse mutation test often is the starting point. Thus, it is reasonable to suspect that early in development test results from the bacterial reverse mutation test have influenced the composition of the database studied here. We performed several tests on the robustness of the database used for the analyses presented here, and the forthcoming results do not indicate a strong bias. Further research comparing in vitro genotoxicity data with in vivo data for additional compounds will provide more insights whether it is indeed time to reconsider the composition of the standard in vitro genotoxicity battery.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767318","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":"Hollaender award 2023: Adventures in applied genetic toxicology","authors":"Rosalie K. Elespuru","doi":"10.1002/em.22642","DOIUrl":"10.1002/em.22642","url":null,"abstract":"<p>This work describes career “adventures” into applied research in environmental mutagenesis. Surprising and interesting results, as well as publications in <i>Nature and Science</i>, may counter an assumption that applied research is not as exciting or impactful as basic research. The narrative is described in terms of “mentors,” whose advice had a lasting impact and resonated in many ways. Adventures included forays into nitrosamine mutagenicity, nanomaterial assessment, photoactivated DNA damaging agents, p53 gene mutagenicity, germ cell mutagenic risk, bacterial mutagenicity assays, genotoxicity of cell phone radiation, Covid diagnostic PCR assays, personalized cancer prevention, and &gt;25 years in regulatory safety assessment at FDA. FDA work included review of genotoxicity data, experiments in the lab, international standards generation, and collaboration with others to foster better analyses of DNA damaging agents, generally in relation to cancer risk. As demonstrated by accidental adventures that led to scientific as well as life-altering personal realizations, many of the most critical happenings in science and in life turn out to be “random,” unexpected, events. Finally, with this work and that of my lifelong tripmate William Lijinsky as models, it is suggested that a “non-hypothesis driven,” open-ended approach to research can be path-breaking and forefront.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 9","pages":"301-314"},"PeriodicalIF":2.3,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142727278","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":"Transcriptomic and epigenomic signatures distinguish high- and low-risk endotypes for liver tumor development","authors":"Sandra L. Grimm,&nbsp;Tia Talley,&nbsp;Rahul K. Jangid,&nbsp;Amrit Koirala,&nbsp;Micah B. Castillo,&nbsp;Preethi H. Gunaratne,&nbsp;Cristian Coarfa,&nbsp;Cheryl L. Walker","doi":"10.1002/em.22639","DOIUrl":"10.1002/em.22639","url":null,"abstract":"<p>The epigenome is a target for environmental exposures and a potential determinant of inter-individual differences in response. In genetically identical C57Bl/6 mice exposed from gestation to weaning to the endocrine-disrupting chemical (EDC) tributyltin (TBT), hepatic tumor development later in life varied across multiple cohorts over time and depending on sex and diet. In one cohort where approximately half of TBT-exposed male mice developed liver tumors at 10 months (Katz et al. Hepatic tumor formation in adult mice developmentally exposed to organotin, <i>Environmental Health Perspectives</i>, <b>128</b> (1), 17010, 2020), transcriptomic (RNA-seq) and epigenomic (ChIP-seq) profiling was performed on blood and liver tissue from mice that developed tumors (i.e., “high-risk”) and equivalently exposed mice did not (i.e., “low-risk”). Blood transcriptomic signatures separated TBT-exposed from vehicle controls but did not discriminate between animals that developed tumors versus those that did not. However, uninvolved liver tissue of mice with tumors exhibited transcriptomic and epigenomic signatures distinct from liver tissue of mice without tumors and had many features in common with tumors. These high-risk transcriptomic and epigenomic features were also found in 10/26 TBT-exposed mice at 5 months, indicating that this risk signature preceded tumor development. Thus, while early life exposure to TBT exhibits variable penetrance for hepatic tumor development, indicating TBT exposure is not sufficient for liver tumorigenesis, increased risk for hepatic tumor development is linked to epigenomic and transcriptomic reprogramming of the liver induced by this EDC.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 9","pages":"351-359"},"PeriodicalIF":2.3,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715689","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":"Bruce Nathan Ames, 1928–2024: A meaningful scientific life","authors":"Errol Zeiger","doi":"10.1002/em.22641","DOIUrl":"10.1002/em.22641","url":null,"abstract":"","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 9","pages":"298-300"},"PeriodicalIF":2.3,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22641","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of mutagenicity of styrene in tumor target and non-target tissues of transgenic Big Blue® mice","authors":"B. Bhaskar Gollapudi,&nbsp;Karen Philp,&nbsp;Jeffrey T. Weinberg","doi":"10.1002/em.22638","DOIUrl":"10.1002/em.22638","url":null,"abstract":"<p>Styrene has been shown to induce lung tumors in mice, but not in rats. The current study investigated the potential role of genotoxicity as an initial key event in the mode of action for styrene-induced lung tumors in mice. Transgenic male B6C3F1 Big Blue® mice were treated by oral gavage for 28 consecutive days with 0 (corn oil), 75, 150, or 300 mg/kg/day of styrene. The 300 mg/kg/day represented the tumorigenic dose in the oral gavage carcinogenicity study conducted in B6C3F1 mice. Following a 28-day expression period, mutant frequencies were assessed at the <i>cII</i> locus of the transgene in the tumor target (lung) and non-target tissues (liver, glandular stomach, and duodenum). Mice treated with <i>N</i>-ethyl-<i>N</i>-nitrosourea (40 mg/kg/day) by oral gavage on Days 1, 2, and 3 of the study and sacrificed on Day 56 served as the positive control group. Genomic DNA was extracted from the selected tissues, processed for the recovery of the transgene into infectious phage, plated onto <i>Escherichia coli</i> strain G1250, and incubated at 37°C for titer determination or at 24°C for the selection of mutant plaques. There were no treatment-related increases in mutant frequency in any of the tissues. The positive control group had a significant increase in the frequency of <i>cII</i> mutants assuring the adequacy of the experimental conditions to detect induced mutations. To conclude, mutagenicity is not considered a plausible initial key event in the mode of action for styrene-induced mouse lung tumors as these data support that styrene is not an in vivo mutagen.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"66 1-2","pages":"34-44"},"PeriodicalIF":2.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22638","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"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 abnormal vascular remodeling","authors":"Tatiana Kozbenko,&nbsp;Nadine Adam,&nbsp;Veronica S. Grybas,&nbsp;Benjamin J. Smith,&nbsp;Dalya Alomar,&nbsp;Robyn Hocking,&nbsp;Janna Abdelaziz,&nbsp;Amanda Pace,&nbsp;Marjan Boerma,&nbsp;Omid Azimzadeh,&nbsp;Steve Blattnig,&nbsp;Nobuyuki Hamada,&nbsp;Carole Yauk,&nbsp;Ruth Wilkins,&nbsp;Vinita Chauhan","doi":"10.1002/em.22636","DOIUrl":"10.1002/em.22636","url":null,"abstract":"<p>Cardiovascular diseases (CVDs) are complex, encompassing many types of heart pathophysiologies and associated etiologies. Radiotherapy studies have shown that fractionated radiation exposure at high doses (3–17 Gy) to the heart increases the incidence of CVD. However, the effects of low doses of radiation on the cardiovascular system or the effects from space travel, where radiation and microgravity are important contributors to damage, are not clearly understood. Herein, the adverse outcome pathway (AOP) framework was applied to develop an AOP to abnormal vascular remodeling from the deposition of energy. Following the creation of a preliminary pathway with the guidance of field experts and authoritative reviews, a scoping review was conducted that informed final key event (KE) selection and evaluation of the Bradford Hill criteria for the KE relationships (KERs). The AOP begins with a molecular initiating event of deposition of energy; ionization events increase oxidative stress, which when persistent concurrently causes the release of pro-inflammatory mediators, suppresses anti-inflammatory mechanisms and alters stress response signaling pathways. These KEs alter nitric oxide levels leading to endothelial dysfunction, and subsequent abnormal vascular remodeling (the adverse outcome). The work identifies evidence needed to strengthen understanding of the causal associations for the KERs, emphasizing where there are knowledge gaps and uncertainties in both qualitative and quantitative understanding. The AOP is anticipated to direct future research to better understand the effects of space on the human body and potentially develop countermeasures to better protect future space travelers.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 S3","pages":"4-30"},"PeriodicalIF":2.3,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22636","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

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

{"title":"Anatomy of a hotspot: Cisplatin hotspots in the tdk gene of Escherichia coli","authors":"Courtney Young,&nbsp;Mackenzie Lee,&nbsp;Zoe Ge,&nbsp;Jeana Shin,&nbsp;Bella Bursulaya,&nbsp;Dana Sorensen,&nbsp;Arnav Saud,&nbsp;Ananya Sridharan,&nbsp;Ava Gonick,&nbsp;Nhu Phi,&nbsp;Kelly Nguyen,&nbsp;Shawal Bhalli,&nbsp;Jyotsna Hiranandani,&nbsp;Jeffrey H. Miller","doi":"10.1002/em.22635","DOIUrl":"10.1002/em.22635","url":null,"abstract":"<p>We previously reported that certain sub-regions of the <i>thyA</i> gene of <i>Escherichia coli</i> are more mutable than others when many different mutagens and mutators are analyzed (Mashiach et al., <i>Mutation Research Fundamental Molecular Mechansims of Mutagenesis</i>, <b>821</b>: 111702, 2021). In this study, we focus on a single mutagen, cisplatin and verify that mutations occur preferentially at specific 3 bp sequences, but only when they appear in certain subregions of the gene. Moreover, we show that hotspots for some premutational lesions are camouflaged by the preferential repair effected by the <i>uvrA,B,C</i>-encoded excision repair system, even when they appear on the same strand. We do this by using a novel reporter gene in <i>E. coli</i>, the <i>tdk</i> gene that codes for thymidine deoxykinase, and we describe some of the advantages of utilizing this detection system.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 9","pages":"338-350"},"PeriodicalIF":2.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22635","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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