Mutation research. Genetic toxicology and environmental mutagenesis最新文献

{"title":"Assessing the multi-dimensional impact of lead-induced toxicity on collembola found in maize fields: From oxidative stress to genetic disruptions","authors":"Samar Mahmood ,&nbsp;Hina Parwez ,&nbsp;Yasir Hasan Siddique ,&nbsp;Mohd Amir ,&nbsp;Saleem Javed","doi":"10.1016/j.mrgentox.2024.503789","DOIUrl":"https://doi.org/10.1016/j.mrgentox.2024.503789","url":null,"abstract":"<div><p>The prolonged exposure of agricultural soils to heavy metals from wastewater, particularly in areas near industrial facilities, poses a significant threat to the well-being of living organisms. The World Health Organization (WHO) has established standard permissible limits for heavy metals in agricultural soils to mitigate potential health hazards. Nevertheless, some agricultural fields continue to be irrigated with wastewater containing industrial effluents. This study aimed to assess the concentration of lead in soil samples collected from agricultural fields near industrial areas. Subsequently, we determined the lethal concentration (LC50) of lead (Pb) and other heavy metals for two Collembola species, namely <em>Folsomia candida</em>, a standard organism for soil ecotoxicity tests, and comparing it with <em>Proisotoma minuta</em>. The research further examined the toxic effects of lead exposure on these two species, revealing depletion in the energy reservoirs and alterations in the tissue histology of both organisms. The study revealed that lead can induce genotoxic damage as it evidently has moderate binding affinity with the ct-DNA and hence can cause DNA fragmentation and the formation of micronuclei. Elevated lipid peroxidation (LPO) levels and protein carbonylation levels were observed, alongside a reduction in antioxidant enzymes (CAT, SOD &amp; GPx). These findings suggest that lead disrupts the balance between oxidants and the antioxidant enzyme system, impairing defense mechanisms and consequential derogatory damage within microarthropods. The investigation elucidates a complex network of various signaling pathways compromised as a result of lead toxicity. Hence, it presents a novel perspective that underscores the pressing necessity for implementing an integrated risk assessment framework at the investigated site.</p></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"898 ","pages":"Article 503789"},"PeriodicalIF":2.3,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141540592","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 oxidative damage and genotoxicity in populations exposed to arsenic in drinking water from Santa Fe province, Argentina","authors":"Ana María Quiroga ,&nbsp;Carlina L. Colussi ,&nbsp;Lucía M. Odetti ,&nbsp;Alicia E. Loteste ,&nbsp;Adriana M. Paonessa ,&nbsp;Carlos R. Mastandrea ,&nbsp;Raúl A. Grigolato ,&nbsp;Gisela L. Poletta ,&nbsp;Mirna Sigrist ,&nbsp;M. Fernanda Simoniello","doi":"10.1016/j.mrgentox.2024.503787","DOIUrl":"https://doi.org/10.1016/j.mrgentox.2024.503787","url":null,"abstract":"<div><p>The presence of arsenic in the environment is a public health problem. Groundwater of certain regions of Argentina contains arsenic of natural origin in concentrations that exceed the guide level recommended by World Health Organization (WHO, 10 µg/L). Pathologies derived from chronic arsenic consumption justify the planning of human biomonitoring. Hence, the aim of this study was to evaluate oxidative damage and genotoxicity and its relationship with nutritional variables in populations exposed to arsenic through drinking water in Santa Fe province, Argentina. A total of 322 participants were analyzed for arsenic in urine together with biomarkers of genotoxicity (Comet assay in blood and frequency of Micronuclei and other Nuclear Abnormalities in exfoliated buccal cells) and oxidative stress (modified Comet assay with Endonuclease III, Lipid peroxidation and antioxidant enzyme activity), as well as nutritional and biochemical variables. Results showed that 45 % of participants excreted arsenic in the urine. Consumption of water with arsenic, whether currently or previously, was associated with statistically significant increase of oxidative DNA damage and lipid peroxidation. MN in exfoliated buccal cells serve as an early biomarker of genotoxicity and showed significant differences in the current exposed group. Biochemical results indicate dyslipidemias potentially linked to dietary choices, and insufficient intake of fruits and vegetables rich in antioxidants, was also noted. This study advocates risk communication to the population, educators, and health authorities, emphasizing the need for preventive health strategies and improved food education.</p></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"897 ","pages":"Article 503787"},"PeriodicalIF":1.9,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141323232","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":"Influence of genetic polymorphisms of Hg metabolism and DNA repair on the frequencies of micronuclei, nucleoplasmic bridges, and nuclear buds in communities living in gold mining areas","authors":"Lyda Espitia-Pérez ,&nbsp;Hugo Brango ,&nbsp;Ana Peñata-Taborda ,&nbsp;Claudia Galeano-Páez ,&nbsp;Manolo Jaramillo-García ,&nbsp;Pedro Espitia-Pérez ,&nbsp;Karina Pastor–Sierra ,&nbsp;Osnamir Bru-Cordero ,&nbsp;Luz Stella Hoyos-Giraldo ,&nbsp;Ingrid Reyes-Carvajal ,&nbsp;Diana Saavedra-Trujillo ,&nbsp;Dina Ricardo-Caldera ,&nbsp;Andrés Coneo–Pretelt","doi":"10.1016/j.mrgentox.2024.503790","DOIUrl":"https://doi.org/10.1016/j.mrgentox.2024.503790","url":null,"abstract":"<div><p>Fishing communities living near gold mining areas are at increased risk of mercury (Hg) exposure via bioaccumulation of methylmercury (MeHg) in fish. This exposure has been linked to health effects that may be triggered by genotoxic events. Genetic polymorphisms play a role in the risk associated with Hg exposure. This study evaluated the effect of single nucleotide polymorphisms (SNPs) in metabolic and DNA repair genes on genetic instability and total hair Hg (T-Hg) levels in 78 individuals from \"La Mojana\" in northern Colombia and 34 individuals from a reference area. Genetic instability was assessed by the frequency of micronuclei (MNBN), nuclear buds (NBUDS), and nucleoplasmic bridges (NPB). We used a Poisson regression to assess the influence of SNPs on T-Hg levels and genetic instability, and a Bayesian regression to examine the interaction between Hg detoxification and DNA repair. Among exposed individuals, carriers of <em>XRCC1</em>_{<em>Arg399Gln</em>} had a significantly higher frequency of MNBN. Conversely, the <em>XRCC1</em>_{<em>Arg194Trp</em>} and <em>OGG1</em>_{<em>Ser326Cys</em>} polymorphisms were associated with lower frequencies of MNBN. <em>XRCC1</em>_{<em>Arg399Gln</em>}, <em>XRCC1</em>_{<em>Arg280His</em>}, and <em>GSTM1</em>_{<em>Null</em>} carriers showed lower NPB frequencies. Our results also indicated that individuals with the <em>GSTM1</em>_{<em>Null</em>} <em>and GSTT1</em>_{<em>null</em>} polymorphisms had a 1.6-fold risk for higher T-Hg levels. The Bayesian model showed increased MNBN frequencies in carriers of the <em>GSTM1</em>_{<em>Null</em>} polymorphism in combination with <em>XRCC1</em>_{<em>Arg399Gln</em>} and increased NBUDS frequencies in the <em>GSTM1</em>_{<em>Null</em>} carriers with the <em>XRCC3</em>_{<em>Thr241Met</em>} and <em>OGG1</em>_{<em>Ser326Cys</em>} alleles. The <em>GSTM1</em>_<em>+</em> variant was found to be a protective factor in individuals carrying <em>OGG1</em>_{<em>Ser326Cys</em>} (MNBN) and <em>XRCC1</em>_{<em>Arg280His</em>} (NPB); the <em>GSTT1</em>_<em>+</em> polymorphism combined with <em>XRCC</em>_{<em>Arg194Trp</em>} also modulated lower MNBN frequencies, while <em>GSTT1</em>_<em>+</em> carriers with the <em>XRCC1</em>_{<em>Arg399Gln</em>} allele showed lower NPB frequencies. Consistent with <em>GSTM1, GSTT1</em>_{<em>Null</em>} carriers with <em>XRCC3</em>_{<em>Thr241Met</em>} showed increased NBUDS frequency. With the rise of gold mining activities, these approaches are vital to identify and safeguard populations vulnerable to Hg's toxic effects.</p></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"897 ","pages":"Article 503790"},"PeriodicalIF":1.9,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141429693","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":"Applications of intelligent technology in the evaluation of mutagenicity","authors":"Jia Li ,&nbsp;Wenli Xu ,&nbsp;Wenchao Zhang ,&nbsp;Dingjin Liu ,&nbsp;Shuyang Jiang ,&nbsp;Guohua Liu ,&nbsp;Yong Wang ,&nbsp;Haoran Sun ,&nbsp;Wenping Xu ,&nbsp;Biao Jiang ,&nbsp;Jianhua Yao","doi":"10.1016/j.mrgentox.2024.503785","DOIUrl":"https://doi.org/10.1016/j.mrgentox.2024.503785","url":null,"abstract":"<div><p>Bioassays are widely used in assessment of mutagenicity. Alternative methods have also been developed, including “intelligent evaluation”, which depends on the quality of data, strategies, and techniques. CISOC-PSMT is an Ames test prediction system. The strategies and techniques for intelligent evaluation and four applications of CISOC-PSMT are presented; roles in pesticide management, environmental protection, drug discovery, and safety management of chemicals are introduced.</p></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"897 ","pages":"Article 503785"},"PeriodicalIF":1.9,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141307810","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":"Genotoxicity and cytotoxicity evaluation of a heat-not-burn product","authors":"Fudong Fu ,&nbsp;Xiaoyu Li ,&nbsp;Younan Chen ,&nbsp;Lan Li ,&nbsp;Jiexiong Dou ,&nbsp;Kun Liang ,&nbsp;Yexian Chen ,&nbsp;Yanrong Lu ,&nbsp;Yuchuan Huang","doi":"10.1016/j.mrgentox.2024.503784","DOIUrl":"https://doi.org/10.1016/j.mrgentox.2024.503784","url":null,"abstract":"<div><p>‘Heat-not-burn’ products (HnBP) contain lower levels of harmful substances than traditional cigarettes, but the use of these products warrants further toxicological evaluation. We have compared the cytotoxicity and genotoxicity of a heat-not burn product with conventional cigarettes, <em>in vivo</em> and <em>in vitro</em>. Male Sprague Dawley rats were exposed to mainstream smoke from conventional cigarettes or a HnBP, for 4 or 28 days, followed by isolation of bone marrow polychromatic erythrocytes (PCE) and histological examination of the testes. Chinese hamster lung fibroblast cells were exposed <em>in vitro</em> to total particulate matter from cigarette smoke obtained through Cambridge filters. The cytotoxicity and genotoxicity of total particulate matter were assessed by the neutral red uptake assay, chromosome aberration assay, <em>in vitro</em> micronucleus test, comet assay, and Ames assay. In the short-term exposure rat models, only the conventional-cigarettes group showed a significant increase in the ratio of micronuclei to total PCE. There was no significant difference in rat testis histology in the long-term exposure models. <em>In vitro</em>, in the neutral red uptake assay, the HnBP product showed lower cytotoxicity than conventional cigarettes. Conventional cigarettes showed greater genotoxicity in the chromosome aberration assay, high-dose Ames tests with exogenous metabolic activation, and micronucleus tests. In summary, our results suggest that HnBP have lower cytotoxicity and genotoxicity than conventional cigarettes.</p></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"897 ","pages":"Article 503784"},"PeriodicalIF":1.9,"publicationDate":"2024-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141250331","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":"Frequencies of micronuclei in buccal cells and their spatial distribution in a population living in proximity to coal mining areas in southern Brazil","authors":"Niely Galeão da Rosa Moraes ,&nbsp;Alicia da Silva Bonifácio ,&nbsp;Fernanda Oliveira Reis ,&nbsp;Thais dos Anjos Velho ,&nbsp;Paula Florencio Ramires ,&nbsp;Rodrigo de Lima Brum ,&nbsp;Julia Oliveira Penteado ,&nbsp;Flávio Manoel Rodrigues Da Silva Júnior","doi":"10.1016/j.mrgentox.2024.503783","DOIUrl":"https://doi.org/10.1016/j.mrgentox.2024.503783","url":null,"abstract":"<div><p>The extraction and burning of coal release genotoxic pollutants, and understanding the relationship between genetic damage and the spatial distribution of residences in coal-using regions is crucial. The study aimed to conduct a spatial analysis of genotoxic damage through the of micronuclei (MNs) number and their proximity to coal mining/burning in the largest coal exploration region in Brazil. In this study, the detection of genotoxic damage was performed using the MN assay in oral cells of residents exposed to coal mining activities. Spatial analysis was conducted using QGIS 3.28.10 based on information obtained from a questionnaire administered to the population. Multiple linear regression analysis was carried out to assess the influence of the distance from residential areas to polluting sources on the number of MNs found. Additionally, Spearman's correlation was performed to identify the strength and direction of the association between the frequency of MNs and each of the polluting sources. A total of 147 MNs were quantified among all participants in the coal mining region. Notably, residents living within 2 km and 10 km of pollution sources exhibited the highest prevalence of MNs. The analysis demonstrated a significant correlation between closer proximity to pollution sources and increased MN frequency, underscoring the spatial relationship between these sources and genotoxic damage. Environmental pollutants from anthropogenic sources present a major health risk, potentially leading to irreversible damage. The spatial analysis in this study highlights the importance of targeted public policies. These policies should aim for a sustainable balance between economic development and public health, promoting effective measures to mitigate environmental impacts and protect community health.</p></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"897 ","pages":"Article 503783"},"PeriodicalIF":1.9,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141424147","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":"Use of peptide nucleic acid probe to determine telomere dynamics in improving chromosome analysis in genetic toxicology studies","authors":"Gavin Yong Quan Ng,&nbsp;Manoor Prakash Hande","doi":"10.1016/j.mrgentox.2024.503773","DOIUrl":"https://doi.org/10.1016/j.mrgentox.2024.503773","url":null,"abstract":"<div><p>Genetic toxicology, strategically located at the intersection of genetics and toxicology, aims to demystify the complex interplay between exogenous agents and our genetic blueprint. Telomeres, the protective termini of chromosomes, play instrumental roles in cellular longevity and genetic stability. Traditionally karyotyping and fluorescence in situ hybridisation (FISH), have been indispensable tools for chromosomal analysis following exposure to genotoxic agents. However, their scope in discerning nuanced molecular dynamics is limited. Peptide Nucleic Acids (PNAs) are synthetic entities that embody characteristics of both proteins and nucleic acids and have emerged as potential game-changers. This perspective report comprehensively examines the vast potential of PNAs in genetic toxicology, with a specific emphasis on telomere research. PNAs' superior resolution and precision make them a favourable choice for genetic toxicological assessments. The integration of PNAs in contemporary analytical workflows heralds a promising evolution in genetic toxicology, potentially revolutionizing diagnostics, prognostics, and therapeutic avenues. In this timely review, we attempted to assess the limitations of current PNA-FISH methodology and recommend refinements.</p></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"897 ","pages":"Article 503773"},"PeriodicalIF":1.9,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141243610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effect of acute exposure of yellowtail tetra fish Astyanax lacustris (Lütken, 1875) to the glyphosate-based herbicide Templo®","authors":"Camila Oliveira de Andrade ,&nbsp;Josiane Rodrigues Rocha da Silva ,&nbsp;Pablo Americo Barbieri ,&nbsp;Luciana Andrea Borin-Carvalho ,&nbsp;Ana Luiza de Brito Portela-Castro ,&nbsp;Carlos Alexandre Fernandes","doi":"10.1016/j.mrgentox.2024.503771","DOIUrl":"https://doi.org/10.1016/j.mrgentox.2024.503771","url":null,"abstract":"<div><p>The herbicide glyphosate (N-(phosphonomethyl)glycine) efficiently eliminates weeds, is frequently present in surface waters, and may damage the health of various non-target organisms. The main objective of this study was to investigate cytotoxic and genotoxic effects in erythrocytes, DNA, and chromosomes of native South American fish <em>Astyanax lacustris</em> exposed to a glyphosate-based commercial herbicide Templo®. The presenty study evaluated the presence of micronuclei (MN), chromosomal aberrations (CA), DNA damage revealed by comet assay, and cellular morphological changes (CMC) as biomarkers. The <em>A. lacustris</em> specimens were exposed to Templo® for 96 h at concentrations below the permitted Brazilian legislation for freshwater environments. The glyphosate-based herbicide caused MN formation, an increased incidence of CA, DNA damage, and several types of CMC in all tested concentrations on <em>A. lacustris</em>. Notably, analyses were significant (p&lt;0.05) for all concentrations, except in the frequency mean of MN at 3.7 µg/L. Thus, considering the intensive use of commercial glyphosate formulations in crops, the herbicide Templo® represents a potential risk of genotoxicity and cytotoxicity for aquatic organisms. Therefore, environmental protection agencies must review regulations for glyphosate-based herbicides in freshwater environments.</p></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"897 ","pages":"Article 503771"},"PeriodicalIF":1.9,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141289165","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":"Micronucleus test in reptiles: Current and future perspectives","authors":"L.M. Odetti ,&nbsp;E.V. Paravani ,&nbsp;Ma.F. Simoniello ,&nbsp;G.L. Poletta","doi":"10.1016/j.mrgentox.2024.503772","DOIUrl":"https://doi.org/10.1016/j.mrgentox.2024.503772","url":null,"abstract":"<div><p>Micronucleus (MN) cell counting emerged in 1973–1975 as a valid alternative for characterizing chromosomal damage caused by different agents. It was first described in mammals, but its application was rapidly extended to other vertebrates, mainly fish. However, it was not until 28 years later that this test was implemented in studies on reptiles. Nowadays, reptiles are found to be excellent non-target species from environmental contamination exposure and MN test has become a fundamental tool for analyzing genotoxic effects induced by various xenobiotics. In this article we provide an updated review of the application of the MN test in reptile species, from an ecotoxicological perspective. Therefore, we present (I) a bibliometric analysis of the available research on genotoxic-induced MN formation in reptile species; (II) the use of reptiles as sentinel organisms in ecotoxicological studies; and (III) the strength and weakness of the application of the MN test in this group. With this review, we aim to provide a comprehensive view on the use of the MN test in ecotoxicology and to encourage further studies involving reptile species.</p></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"897 ","pages":"Article 503772"},"PeriodicalIF":1.9,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141243609","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":"Non-clinical safety assessment of novel drug modalities: Genome safety perspectives on viral-, nuclease- and nucleotide-based gene therapies","authors":"Myriam Lemmens ,&nbsp;Lena Dorsheimer ,&nbsp;Andreas Zeller ,&nbsp;Yasmin Dietz-Baum","doi":"10.1016/j.mrgentox.2024.503767","DOIUrl":"https://doi.org/10.1016/j.mrgentox.2024.503767","url":null,"abstract":"<div><p>Gene therapies have emerged as promising treatments for various conditions including inherited diseases as well as cancer. Ensuring their safe clinical application requires the development of appropriate safety testing strategies. Several guidelines have been provided by health authorities to address these concerns. These guidelines state that non-clinical testing should be carried out on a case-by-case basis depending on the modality. This review focuses on the genome safety assessment of frequently used gene therapy modalities, namely Adeno Associated Viruses (AAVs), Lentiviruses, designer nucleases and mRNAs. Important safety considerations for these modalities, amongst others, are vector integrations into the patient genome (insertional mutagenesis) and off-target editing. Taking into account the constraints of in vivo studies, health authorities endorse the development of novel approach methodologies (NAMs), which are innovative in vitro strategies for genotoxicity testing. This review provides an overview of NAMs applied to viral and CRISPR/Cas9 safety, including next generation sequencing-based methods for integration site analysis and off-target editing. Additionally, NAMs to evaluate the oncogenicity risk arising from unwanted genomic modifications are discussed. Thus, a range of promising techniques are available to support the safe development of gene therapies. Thorough validation, comparisons and correlations with clinical outcomes are essential to identify the most reliable safety testing strategies. By providing a comprehensive overview of these NAMs, this review aims to contribute to a better understanding of the genome safety perspectives of gene therapies.</p></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"896 ","pages":"Article 503767"},"PeriodicalIF":1.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141067723","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}