Mutation research. Genetic toxicology and environmental mutagenesis最新文献

{"title":"Biological dosimetry of chronic radiation exposure in interventional radiologists using dicentric assay and a Bayesian framework","authors":"Volodymyr Vinnikov,&nbsp;Dominika Kochanová,&nbsp;Pavol Košík,&nbsp;Sachin Gulati,&nbsp;Katarína Vigašová,&nbsp;Matúš Durdík,&nbsp;Lucián Zastko,&nbsp;Dušan Šalát,&nbsp;Andrej Klepanec,&nbsp;Eva Marková,&nbsp;Igor Belyaev","doi":"10.1016/j.mrgentox.2026.503947","DOIUrl":"10.1016/j.mrgentox.2026.503947","url":null,"abstract":"<div><div>Cytogenetic studies in populations chronically exposed to mutagens are challenging due to a number of methodological constraints. The aim of the study was to demonstrate the applicability of dicentric assay, combined with advanced data interpretation, for radiation biodosimetry in chronically exposed medical staff.</div><div>Dicentric frequencies were measured in cultured blood lymphocytes from 12 interventional radiologists with 5–42 years of professional exposure and 14 unexposed controls. The data processing methodology included a mathematical \"unfolding\" of observed aberration yields, a robust linear dose-response coefficient derived from in vitro low-dose calibration curve for dicentrics, and a Bayesian-type statistical framework for calculating posterior probability densities for \"true\" aberration yields and corresponding dose estimates.</div><div>The mean dicentric frequency in radiologists significantly exceeded the control level, but individual yields showed no dependence on the years of service (<em>r</em> = 0.268). After “unfolding”, a strong positive correlation emerged (<em>r</em> = 0.843). “Unfolded” dicentric yields were converted into cumulative dose estimates of 49 – 595 mGy. Bayesian posterior probability densities of “true” aberration yields corresponded to the most probable annual doses of 3.7 – 27.9 mGy. Confidence intervals of annual doses, which are “more probable to be true than non-true”, ranged from 0.8 to 39.3 mGy, and their upper limits exceeded 20 mGy in eleven cases out of twelve.</div><div>The proposed approach substantially enhances the accuracy and interpretative power of cytogenetic biodosimetry of chronic irradiation. The resulting dose estimates can be used for assessment of radiation-associated health risks and support individual radiation protection measures for occupationally exposed individuals.</div></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"913 ","pages":"Article 503947"},"PeriodicalIF":2.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148502769","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":"A historical perspective of radioprotection studies in India with a focus on plant-derived radioprotectors","authors":"Anupam Chatterjee,&nbsp;Mercy Jacob Raman","doi":"10.1016/j.mrgentox.2026.503950","DOIUrl":"10.1016/j.mrgentox.2026.503950","url":null,"abstract":"<div><div>This article reviews the evolution of radioprotection research in major Indian laboratories over the past seventy years, tracing a systematic progression in the exploration of various protective agents. The significant contribution of premier Indian institutions dedicated to ‘Radioprotection Development Programme’ is highlighted. Early investigations focused on synthetic radiopro-tectors, particularly sulphydryl compounds, which demonstrated strong radioprotective effects in laboratory settings. However, their clinical application was limited due to severe tissue toxicity. Subsequent research shifted toward natural thiols, novel synthetic compounds, and antioxidant nutrients. While these approaches produced encouraging experimental results, only a few showed real promise in clinical contexts. In recent decades, there has been a marked increase in studies on phytochemicals and herbal extracts, especially in Asian countries, driven by rich biodiversity and traditional medicinal systems such as Ayurveda in India. These phyto-products have shown high potential as effective radioprotectors with minimal toxicity. India has emerged as a key contributor in this domain, with extensive indigenous research efforts. Using databases such as PubMed and Google Scholar, this review identifies and compiles 46 Indian medicinal plants investigated for their radioprotective properties. Extract-based studies reveal promising efficacy through multiple mechanisms, including antioxidant activity and tissue protection. Preclinical findings demonstrate the ability of plant-derived bioactive compounds to mitigate radiation-induced damage. Notable examples include orientin and vicinin (<em>Ocimum sanctum)</em>, podophyllin (<em>Podophyllum hexandrum)</em>, curcumin (<em>Curcuma longa)</em>, phyllanthin and flavonoids (<em>Phyllanthus niruri)</em> and polyphenol rich <em>Rhodiola imbricata</em>. Despite promising efficacy, clinical translation remains limited due to issues like poor bioavailability, low solubility, and formulation instability. This review concludes addressing the various pharmacological limitations, advanced delivery strategies, and the need for validated biomarkers for radiation damage to improve therapeutic effectiveness.</div></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"913 ","pages":"Article 503950"},"PeriodicalIF":2.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148642951","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":"Tobacco use and commercial variants: Trends in biomarker-based research","authors":"Mackawly Kelvym Guedes Soares,&nbsp;José Vinícius Bernardy,&nbsp;Renata Maria Pereira de Freitas,&nbsp;Daiany Folador Sotero,&nbsp;Ana Julia Pereira Peixoto Virote,&nbsp;Daniela de Melo e Silva","doi":"10.1016/j.mrgentox.2026.503952","DOIUrl":"10.1016/j.mrgentox.2026.503952","url":null,"abstract":"<div><div>The health consequences of cigarette smoking and its commercial variants have been extensively investigated for more than three decades. However, despite substantial evidence demonstrating the detrimental effects of tobacco use, including respiratory and cardiovascular diseases and several types of cancer, the global number of users remains alarmingly high. This scientometric review mapped the scientific literature on the health impacts of cigarettes and commercial tobacco products, focusing on studies employing biomarkers of toxicological effects, including the comet assay, micronucleus test, redox status assessment, and telomere length analysis. Of 1990 retrieved records, 155 articles met the inclusion criteria and were analyzed. Redox status assessment and the comet assay were the most frequently applied biomarkers. In vivo studies primarily analyzed blood samples, whereas in vitro investigations exposed diverse cell types to cigarette smoke. Although the adverse effects of conventional cigarettes are well established, the health impacts of alternative products, including e-cigarettes, pods, and vapes, remain insufficiently investigated. This review provides a focused scientometric overview of biomarker-based research on tobacco-related toxicological effects and highlights the need for broader future studies incorporating additional biomarkers, health outcomes, and emerging tobacco and nicotine products.</div></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"913 ","pages":"Article 503952"},"PeriodicalIF":2.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148713075","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":"Evaluation of genetic instability in patients with amyotrophic lateral sclerosis","authors":"Hendrew J.B.C. Souza,&nbsp;Kátina M. Souza,&nbsp;Matheus B. dos Santos,&nbsp;Mariane A.P. Silva,&nbsp;Tony F. Grassi,&nbsp;Maria V. Destro,&nbsp;Mariana G. Braz","doi":"10.1016/j.mrgentox.2026.503953","DOIUrl":"10.1016/j.mrgentox.2026.503953","url":null,"abstract":"<div><div>Genetic instability has been reported in several neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, but only a few studies have addressed sclerosis. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Micronuclei (MNi) and nuclear buds (NBUDs) are established markers of chromosomal instability, yet no data are available regarding a possible link between genetic instability and ALS. The novelty of this case-control study lies in the assessment of genetic instability in oral exfoliated cells from ALS patients (n = 20) and matched controls (n = 20), contributing to the identification of potential novel markers related to the molecular pathogenesis of this severe disorder. Groups were matched for age, sex, and lifestyle (p &gt; 0.05). No significant differences were observed in MNi or NBUD frequencies between groups (p &gt; 0.05). These findings suggest no association between ALS and MN/NBUD frequencies in oral cells.</div></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"913 ","pages":"Article 503953"},"PeriodicalIF":2.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148713155","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":"Micronuclei and nuclear buds in buccal mucosa cells from patients with acromegaly","authors":"Juan Ernesto Gutiérrez-Sevilla,&nbsp;Eduardo Meléndez-Domínguez,&nbsp;Ma. Gabriela Rangel-Sánchez,&nbsp;Ma. Tereza Muñoz-Magallanes,&nbsp;Guillermo Moisés Zúñiga-González,&nbsp;Ana Lourdes Zamora-Perez,&nbsp;Martha Patricia Gallegos-Arreola,&nbsp;Angélica Barros-Hernández,&nbsp;Blanca Miriam Torres-Mendoza,&nbsp;Belinda Claudia Gómez-Meda","doi":"10.1016/j.mrgentox.2026.503948","DOIUrl":"10.1016/j.mrgentox.2026.503948","url":null,"abstract":"<div><div>Acromegaly is characterized by the hypersecretion of growth hormone (GH) and insulin-like growth factor (IGF-1). Individuals with acromegaly have a higher risk of developing certain cancers, and the mitogenic and anti-apoptotic effects of GH and IGF-1 may heighten their predisposition to tumorigenesis. The presence of micronuclei (MN) and nuclear buds (NBs) in buccal mucosa cells is a marker of DNA damage, and high levels have been linked to carcinogenesis. The aims of this study were i) to comparatively analyze the proportions of buccal mucosa cells with MN and NBs in patients with acromegaly and controls, and ii) to identify associations between increased levels of such cells and patient and clinical factors. MN- and NB-containing cells were quantified using fluorescence microscopy. Data on the following demographic and clinical characteristics were collected: age, sex, smoking, alcohol consumption, time since acromegaly, GH and IGF-1 levels, radiation exposure, diabetes, body mass index, blood pressure, and cancer history. The patients with acromegaly (n = 42; 17 male, 25 female) had higher proportions of MN- and NB-containing cells than the controls, although only the levels of the MN-containing cells significantly differed (<em>p</em> = 0.023). The levels of MN-containing cells significantly differed with age (&lt; 45 vs. ≥ 45 years). A significant inverse correlation was observed between the frequency of MN-containing cells and the IGF-1/upper limit of normal ratio. In conclusion, the patients with acromegaly exhibited relatively higher proportions of buccal mucosa cells with MN, a marker of genomic instability.</div></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"913 ","pages":"Article 503948"},"PeriodicalIF":2.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148502845","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":"Does the 2-test in vitro genotoxicity battery of Ames plus in vitro micronucleus tests detect relevant substances that induce gene mutations in vivo?","authors":"David Kirkland,&nbsp;Damian Bowen,&nbsp;Paul Fowler","doi":"10.1016/j.mrgentox.2026.503949","DOIUrl":"10.1016/j.mrgentox.2026.503949","url":null,"abstract":"<div><div>The <em>in vitro</em> genotoxicity testing battery comprising a bacterial gene mutation test (Ames test) and an <em>in vitro</em> micronucleus (MNvit) test is widely recommended by regulatory authorities since it detects the 3 key modes of genotoxic action (gene mutations, clastogenicity and aneuploidy). The recommendations that this battery is acceptable for regulatory use are based on its ability to effectively detect <em>in vivo</em> genotoxins and carcinogens. However, substances inducing gene mutations are a particular concern (representing stable genetic change and a key step in the carcinogenic process), and more <em>in vivo</em> gene mutation data have been published in recent years due to the wider use of transgenic rodent gene mutation (TGR) and <em>Pig-a</em> assays. It is appropriate to question whether the Ames + MNvit battery is efficient at detecting substances that induce gene mutations <em>in vivo</em>. A review of several compilations of genotoxicity studies revealed 26 substances that were reported positive in TGR and/or <em>Pig-a</em> but negative in the Ames test. A detailed analysis showed that 25 of these results were questionable for various reasons, and not robust examples of the failure of the 2-test <em>in vitro</em> battery. Only procarbazine was convincingly positive <em>in vivo</em> but predominantly negative <em>in vitro</em>, and this is mainly due to its complex metabolism which is probably not optimal with standard <em>in vitro</em> metabolic activation systems. The analysis shows no evidence that adding a mammalian cell gene mutation test to the <em>in vitro</em> battery would improve the detection of <em>in vivo</em> gene mutagens.</div></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"913 ","pages":"Article 503949"},"PeriodicalIF":2.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148713095","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":"Alkaline comet assay in human biomonitoring studies by the Latin America / LA-COMET group","authors":"Juliana Da Silva ,&nbsp;Deidamia Franco ,&nbsp;Ana Leticia García ,&nbsp;Elda Leonor Pacheco-Pantoja ,&nbsp;María Fernanda Simoniello ,&nbsp;Noemi Tirado ,&nbsp;Leticia Yáñez- Estrada ,&nbsp;Guillermo Espinosa-Reyes ,&nbsp;Ana Rosa Flores-Márquez ,&nbsp;Sandra Gómez-Arroyo ,&nbsp;César Ilizaliturri-Hernández ,&nbsp;Laura Lafon-Hughes ,&nbsp;Grethel León-Mejía ,&nbsp;Patricia Mussali-Galante ,&nbsp;Diana M. Narváez ,&nbsp;Gisela L. Poletta ,&nbsp;Celeste Ruiz de Arcaute ,&nbsp;Sonia Soloneski ,&nbsp;Efrain Tovar-Sánchez ,&nbsp;Mahara Valverde ,&nbsp;Emilio Rojas","doi":"10.1016/j.mrgentox.2026.503940","DOIUrl":"10.1016/j.mrgentox.2026.503940","url":null,"abstract":"<div><div>Technological and chemical advancements have heightened human exposure to synthetic and natural substances, necessitating precise toxicological assessments through sensitive biomarkers. The comet assay has emerged as a robust, minimally invasive tool for biomonitoring. This study reviews 64 articles published between 1997 and 2022 by the LA-COMET group—a collaborative network of 17 research teams across seven Latin American countries (Argentina, Bolivia, Brazil, Colombia, Mexico, Paraguay, and Uruguay). The analysis reveals that research primarily focuses on occupational and environmental exposures, specifically evaluating the impact of pesticides, heavy metals, organic solvents, and particulate matter. The assay proved highly effective in identifying genotoxic effects in exposed populations compared to reference groups, including vulnerable cohorts such as children, women, and patients with clinical conditions like breast cancer and malaria. To enhance future research rigor, this work utilizes and proposes standardized scoring systems, namely QSca (assay quality score) and hmQS (human monitoring quality score). Ultimately, this review underscores the comet assay’s pivotal role in characterizing regional health risks and seeks to establish evidence-based practices to inform public health policies in Latin America.</div></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"912 ","pages":"Article 503940"},"PeriodicalIF":2.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147992045","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":"Biomarkers and bioindicators of genotoxicity assessment of solid waste emissions from India: Insights into mechanisms of its genome instability","authors":"Chibuisi Gideon Alimba ,&nbsp;Samuel Oluwasegun Adesida ,&nbsp;Deepa Gandhi ,&nbsp;Saravanadevi Sivanesan ,&nbsp;Kannan Krishnamurthi","doi":"10.1016/j.mrgentox.2026.503941","DOIUrl":"10.1016/j.mrgentox.2026.503941","url":null,"abstract":"<div><div>India’s rapid population growth positively correlates with solid waste generation. Indiscriminate disposal in unsanitary landfills is dominant, and releases hazardous contaminants, that pose genotoxic risks to humans and biota. This study evaluated DNA damage and genome instability induced by solid waste emissions of Indian origin. Following PRISMA guidelines, 36 peer-reviewed studies published until 2025 were selected. These studies reported 40 bioindicators and 56 genotoxic biomarkers, with cell lines and comet assay most frequently reported. Significant DNA strand breaks, micronucleus formation, chromosomal aberrations, nuclear abnormalities, and sperm defects in exposed models were consistently reported, often in dose- and time-dependent patterns. Random-effects meta-analysis using pooled standardized mean differences showed significant positive effect sizes for micronucleus and comet endpoints (p ≤ 0.0001), confirming increased genetic damage in exposed groups. Although substantial heterogeneity was observed (I² = 95.73% for micronucleus; 87.66% for comet), the direction of effect remained consistently positive. Risk-of-bias assessment indicated overall moderate to high methodological quality, with common reporting gaps in exposure characterization and blinding procedures. Oxidative stress and ROS generation are dominant drivers of genome instability. Signaling pathways causing DNA adduct, DNA repair impairment, epigenetic dysregulation, and mitochondrial-mediated apoptosis were other mechanisms. Despite strong evidence of somatic and germline genotoxicity, epidemiological data and quantitative exposure assessments remain inadequate. Integrated exposure monitoring, advanced molecular and epigenetic biomarkers, dose–response characterization and long-term population-level biomonitoring are needed to strengthen causal inference and human health risk assessment. Emissions from solid waste facilities in India represent a credible genotoxic hazard warranting improved waste management, and regulatory enforcement.</div></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"912 ","pages":"Article 503941"},"PeriodicalIF":2.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147992043","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":"Oxide-nanoparticles induce in vitro DNA damage and genomic instability in human peripheral blood cells","authors":"P V Vidya Balakrishnan ,&nbsp;Goran Gajski ,&nbsp;Alex George","doi":"10.1016/j.mrgentox.2026.503944","DOIUrl":"10.1016/j.mrgentox.2026.503944","url":null,"abstract":"<div><div>The increasing application of nanotechnology has raised concerns regarding the genotoxic potential of engineered nanoparticles due to their unique physicochemical properties and biological interactions. The present study evaluated the genotoxic effects of four oxide nanoparticles—aluminium oxide (Al₂O₃NPs), iron oxide (Fe₃O₄NPs), silicon dioxide (SiO₂NPs), and titanium dioxide (TiO₂NPs)—in human peripheral blood cells using the alkaline comet and cytokinesis-block micronucleus (CBMN) assays. Sublethal concentrations were selected based on IC₅₀ values determined by a resazurin-based cell viability assay. The comet assay revealed a significant dose-dependent increase in DNA strand breaks for all nanoparticles, with TiO₂NPs inducing the highest levels of primary DNA damage, as reflected by the percentage of tail DNA. In contrast, SiO₂NPs produced the highest frequency of micronuclei in the CBMN assay, indicating pronounced chromosomal instability. Fe₃O₄NPs showed a significant increase in nucleoplasmic bridge formation at higher concentrations, while Al₂O₃NPs exhibited comparatively lower genotoxic effects. Overall, these findings demonstrate differential genotoxic responses among oxide nanoparticles, influenced by particle size and composition, and highlight their potential to induce genome instability even at sublethal exposure levels.</div></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"912 ","pages":"Article 503944"},"PeriodicalIF":2.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148167937","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 applicability of the repeated-dose liver micronucleus assay in rats initiated at８weeks of age as in vivo genotoxicity assessment for 2,6-dninitrotoluene (2,6-DNT), a compound with reported cytostatic potential","authors":"Tsuyoshi Yokobata ,&nbsp;Rena Ishikawa ,&nbsp;Kota Nakajima ,&nbsp;Dai Kakiuchi ,&nbsp;Atsushi Hakura ,&nbsp;Masaki Kurakami ,&nbsp;Shuichi Hamada ,&nbsp;Shoji Asakura","doi":"10.1016/j.mrgentox.2026.503942","DOIUrl":"10.1016/j.mrgentox.2026.503942","url":null,"abstract":"<div><div>The repeated-dose liver micronucleus (RDLMN) assay is an in vivo genotoxicity test that is useful for detecting hepatocarcinogens and is anticipated to be incorporated into general toxicity studies. Although many RDLMN studies have been reported, further investigation is necessary to demonstrate age-related sensitivity and to evaluate compounds with cytostatic properties. In this study, a repeated oral dose study of 2,6-dinitrotoluene (2,6-DNT), a substance known to have cytostatic properties, was conducted in Crl:CD(SD) rats starting at 6 or 8 weeks of age for 28 days. Liver micronucleus (LMN) frequency, mitotic index (MI), and cell proliferation markers, Ki-67 and PCNA, were subsequently evaluated. As a result, LMN frequency increased significantly at all dose levels, showing a reverse dose-response relationship, and there were little differences between age groups. The number of Ki-67-positive cells increased in both age groups, and it was considered compensatory cell proliferation following toxicity at higher doses. Histopathological evaluation revealed prominent anisokaryosis, particularly at 8 weeks of age at start of dosing, and DNA content analysis confirmed that these cells were polyploid, suggesting endoreduplication. This study confirmed that LMN detection sensitivity in the RDLMN assay did not differ between rats aged 6 or 8 weeks at the start of dosing, and that micronucleus-inducing ability was detected even in compounds with cytostatic properties. For appropriate interpretation of the results, histopathological assessment, the analysis of cell proliferation markers and DNA content analysis are useful.</div></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"912 ","pages":"Article 503942"},"PeriodicalIF":2.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147992044","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}