Mutagenesis[JOURNAL]
Sun
200 papers
How genotoxic is the indoor air environment?
Meldrum K, Burgum MJ, Doak SH … +1 more , Clift MJD
Mutagenesis · 2026 Jun · PMID 42335033 · Publisher ↗
The indoor environment changes based on a variety of different factors, therefore changing the genotoxic potential of that environment. Despite the associations of exposure to outdoor air pollution and links to health im...
The indoor environment changes based on a variety of different factors, therefore changing the genotoxic potential of that environment. Despite the associations of exposure to outdoor air pollution and links to health impacts, enough is not currently known about the impacts to human health indoor air may have. Due to the variable nature of the indoor environment (multiple things can change this environment, including but not limited to, the use, occupants, materials within the environment, animals, the outside environment and ventilation) this can prove difficult. Indoor particulate matter (PM) of various sizes (PM2.5-PM10 for example) has been shown to induce reactive oxygen species, increase markers in oxidative stress, double strand DNA breaks, and cause 8-oxoguanine lesions in both in vitro and in vivo models (including humans). The particle type and source influence these responses, highlighting heating and cooking fuel sources that may be more genotoxic than others. A similar pattern has also been observed with volatile organic compounds (VOCs) with various mixtures of VOCs and different VOC compositions inducing DNA damage differently, with diet also being a contributing factor to genotoxic potential. A significant knowledge gap in the potential genotoxicity of indoor air pollution is the exposure of various biologicals found indoors. Moulds, other fungi, and allergens are an emerging health risk and are of significant public interest. Little is known about the inhalation toxicology and mechanisms of action of these components, and this is becoming increasing important to understand due to public deaths linked to them. There is overlap with the health effects of outdoor air pollution where there has been much more research focus. Therefore, the aim of this review is to establish what is already known, the potential limitations of the current work and where we should focus research in the future.
Unveiling the Genotoxic Safety and Antioxidant-Mediated DNA Protective Mechanisms of Triammonium Citrate: An Integrated In Vitro and In Silico Approach.
Öztürk E, İla HB
Mutagenesis · 2026 Jun · PMID 42319063 · Publisher ↗
Triammonium citrate (TAC) is a citrate salt widely utilized in diverse industrial and dietary applications, leading to widespread human exposure. While related citrate salts have established safety profiles, the specific...
Triammonium citrate (TAC) is a citrate salt widely utilized in diverse industrial and dietary applications, leading to widespread human exposure. While related citrate salts have established safety profiles, the specific genotoxic potential and molecular interactions of TAC remain largely unexplored. This study provides the first integrated in vitro and in silico mechanistic safety assessment of TAC. Cell viability, evaluated in NIH/3T3 and MCF-7 cells via the CCK-8 assay, remained above 90% at all tested concentrations (0.25-2 mg/mL). Furthermore, a comprehensive genotoxicity battery-including the Ames test, chromosomal aberration, micronucleus, and sister chromatid exchange assays in human lymphocytes-revealed no mutagenic, clastogenic, or aneugenic activity. Beyond its safety profile, TAC exhibited marked chemoprotective activity, preserving supercoiled plasmid DNA with up to 96% protection against H₂O₂-induced oxidative damage. Molecular docking studies substantiated these findings by predicting moderate binding affinities for DNA replication enzymes (DNA polymerase δ: ΔG = -5.7 kcal/mol; topoisomerase I: ΔG = -5.9 kcal/mol) while showing a preferential affinity for the metabolic enzyme glutamine synthetase (ΔG = -6.1 kcal/mol). These in silico results suggest that TAC does not interfere with critical DNA maintenance machinery. Collectively, these findings establish a robust safety profile for TAC and unveil a previously unrecognized, antioxidant-mediated DNA-protective function, highlighting its potential as a bioactive functional ingredient capable of mitigating oxidative DNA stress.
Nutritional maternal factors affect the frequency of DNA damage in newborns.
Araújo AC, de Medeiros Morais F, de Souza Araújo DF … +3 more , Bezerra DS, Navoni JA, Marques JCMT
Mutagenesis · 2026 Jun · PMID 42308399 · Publisher ↗
Maternal nutrition can influence genetic health during pregnancy, increasing the risk of DNA damage in both the mother and fetus. This study investigated the effect of maternal nutritional factors on DNA damage biomarker...
Maternal nutrition can influence genetic health during pregnancy, increasing the risk of DNA damage in both the mother and fetus. This study investigated the effect of maternal nutritional factors on DNA damage biomarkers in the mother-infant dyad. A cross-sectional study was conducted with pregnant women residing in Northeast Brazil. Participants included women aged ≥18 years in the third trimester, excluding those with non-communicable chronic diseases and smokers. Data collection included sociodemographic, lifestyle, anthropometric information, and a 76-item Food Frequency Questionnaire. The micronucleus cytome assay was performed on oral mucosa cells, with DNA damage biomarkers expressed per thousand cells (‰). Statistical analysis involved hierarchical clustering and Generalized Linear Models using Jamovi 2.5.6. The median age of the pregnant women (n = 209) was 26 years. Only 44.5% had adequate pre-pregnancy nutritional status, with a 9.5% increase in low birth weight. Total energy intake was 1842 (588-5709) kcal, with 72% consuming less than 90% of their caloric needs. The diet was predominantly hyperproteic and hyperlipidic, with over 60% showing inadequate intake of magnesium and folic acid. Among 209 participants, 80 consented to oral mucosa cell collection, and 59 mother-infant pairs were analyzed. Three maternal nutritional profiles were identified: Cluster 1 ('Multiple Burdens of Malnutrition'), Cluster 2 ('Low Burdens of Malnutrition'), and Cluster 3 ('High Nutritional Intake'). While maternal nutritional profiles did not affect nuclear abnormalities in mothers, they influenced newborns. Infants of mothers in Clusters 1 and 2 exhibited more nuclear abnormalities than those in Cluster 3. Maternal nutritional inadequacy was associated with increased nuclear abnormalities in newborns, suggesting an impact on fetal genomic stability.
Potassium bromate as a probable human Carcinogen: multi-organ toxicity and chemopreventive potential of dietary antioxidants-a comprehensive review.
Nazir S, Ahmad MK
Mutagenesis · 2026 May · PMID 42172136 · Publisher ↗
Potassium bromate (KBrO₃), classified as a probable human carcinogen, has long been used as a flour-improving and oxidizing agent in baking and food processing industries. It is also generated as a by-product during ozon...
Potassium bromate (KBrO₃), classified as a probable human carcinogen, has long been used as a flour-improving and oxidizing agent in baking and food processing industries. It is also generated as a by-product during ozonation of drinking water, raising concerns about widespread, low-dose exposure. Experimental studies consistently demonstrate that KBrO₃ induces multiple-organ toxicity primarily through oxidative stress-mediated mechanisms. Exposure to KBrO₃ leads to excessive generation of reactive oxygen species, resulting in depletion of glutathione reserves, enhanced lipid peroxidation, and oxidative DNA damage. Such genotoxic effects include DNA strand breaks, micronuclei formation, and chromosomal aberrations, which collectively contribute to its well-documented carcinogenic and mutagenic potential. Consequently, these molecular alterations promote renal, hepatic, and thyroid tumor formation reported in experimental animal models, while emerging epidemiological evidence suggests possible associations between chronic dietary exposure to KBrO₃ and gastrointestinal malignancies in humans. However, recent research has thoroughly investigated the chemopreventive potential of dietary antioxidants in mitigating KBrO₃-induced toxicity, highlighting their ability to attenuate oxidative damage through enhancement of endogenous antioxidant defenses, modulation of the key cytoprotective signaling pathways and restoration of cellular redox homeostasis. With continued usage of KBrO₃ and the inconsistency of regulatory enforcement worldwide, strengthening risk assessment, surveillance and preventive strategies-particularly the substitution of KBrO₃ with safer alternatives and the promotion of antioxidant-rich diets is crucial to reduce long term carcinogenic risk and safeguard global public health.
DNA damage in the leukocytes of nanocomposite-exposed workers.
Rossner P, Novotna B, Pelclova D … +10 more , Zdimal V, Lischkova L, Klusackova P, Ondracek J, Schwarz J, Maskova L, Dvorackova S, Milcova A, Ambroz A, Rossnerova A
Mutagenesis · 2026 May · PMID 42171640 · Publisher ↗
Human exposure to nanoparticles (NPs) poses potential health risks that are modulated, for example, by the physico-chemical characteristics of NPs, the exposure route and the dose of NPs. Among 21 workers involved for ma...
Human exposure to nanoparticles (NPs) poses potential health risks that are modulated, for example, by the physico-chemical characteristics of NPs, the exposure route and the dose of NPs. Among 21 workers involved for many years in welding on metal surfaces and the machining of nanocomposites, we investigated the role of NPs in the induction of DNA damage. Blood samples of the exposed subjects were collected before and after their working shifts. The controls (21 individuals without occupational exposer to NPs) were sampled in parallel with the exposed ones. NP exposure concentrations were assessed using stationary and personal monitors. DNA damage, including oxidized bases and strand breaks (DNA-SB), in leukocytes was analyzed using Comet assay. The particles monitoring showed that machining was the dominant source of NPs. When compared with the controls, nanocomposite-exposed workers had significantly increased levels of both DNA damage types. In subjects performing machining, post-shift DNA-SB levels were significantly higher than those pre-shift. In welders, such an effect was not observed. Importantly, in both groups, levels of oxidatively damaged DNA were comparable in the post-shift vs. pre-shift samples. The lack of increased DNA oxidation in the post-shift samples suggests the induction of adaptive processes, probably related to long-term occupational exposure to NPs, that protect the organism against this type of DNA damage. However, despite this observation, the potential negative health impacts associated with NP inhalation cannot be ruled out.
Ultra-Processed Foods and Diet Quality in Long COVID: Associations with Symptom Burden, DNA Damage, and Inflammation.
Freitas RDS, Garcia ALH, Martins BAA … +7 more , Dalberto D, Da Silva FR, Borges MS, Peralta GEP, Bobermin LD, Quincozes-Santos A, Da Silva J
Mutagenesis · 2026 May · PMID 42153547 · Publisher ↗
Diet quality can be a potential modifier of post-acute COVID-19 syndrome (PACS), yet the relationship between dietary patterns, symptom burden, and biological markers remains poorly understood. We hypothesized that a low...
Diet quality can be a potential modifier of post-acute COVID-19 syndrome (PACS), yet the relationship between dietary patterns, symptom burden, and biological markers remains poorly understood. We hypothesized that a low-quality diet would positively associate with PACS symptom burden, DNA damage, inflammatory and neurotrophic markers, and with overall health quality. 186 individuals were classified into three groups: control (n = 64), acute PACS (n = 66), and chronic PACS (n = 55). Dietary intake was assessed by a food frequency questionnaire (FFQ), and diet quality was quantified via the Protective and Risk Eating Score (PRES). Blood samples were analyzed for inflammatory (TNF-α, TGF-β, IL-6, IL-1β) and neurotrophic (BDNF, GDNF, S100B) markers. DNA damage was assessed by micronuclei frequency, telomere length, and comet assay parameters. Health index (HI) was assessed by daily habits (alcohol consumption, sleeping patterns, hydration, exercise frequency, smoking habits, anthropometric parameters, and PRES). No significant differences were found among groups in ultra-processed foods (UPF) or sugary products intake, PRES scores, inflammatory or neurotrophic biomarkers, DNA damage indicators, and HI. Of note, poorer diet quality was associated with higher symptom burden in PACS women, mainly in fatigue, memory, mental health, circulatory, and skin symptom domains. Few associations among diet quality, HI, and biomarkers emerged. Of note, principal component analysis shows that PACS relies on the convergence of genomic instability, systemic inflammation, and low diet quality. These findings suggest that diet may represent a modifiable factor in PACS management, warranting longitudinal and interventional studies to determine causality and therapeutic potential.
In Vitro Cytogenotoxicity of Novel Tetrazole-Based Schiff Bases and Their Platinum (II) Complexes: A Detailed Analysis Using Chromosomal Aberration, Micronucleus, and Comet Assays.
Okuş F, Yüzbaşıoğlu D, Çakmak G … +3 more , Demirel HB, Türker RÇ, Ünal F
Mutagenesis · 2026 May · PMID 42153540 · Publisher ↗
Previously, Tetrazole-based Schiff base ligands (TBSL) and their Pt(II) complexes were synthesized and evaluated for cytotoxic activity. The results revealed that low cytotoxicity for the ligands and moderate effects for...
Previously, Tetrazole-based Schiff base ligands (TBSL) and their Pt(II) complexes were synthesized and evaluated for cytotoxic activity. The results revealed that low cytotoxicity for the ligands and moderate effects for the Pt(II) complexes compared to cisplatin. Given these promising findings, the genotoxic potential of the Pt(II) complexes was further investigated. Genotoxicity was assessed using in vitro chromosomal aberration, micronucleus, and comet assays. The TBSL exhibited low genotoxicity, whereas the Pt(II) complexes induced higher genotoxic effects; however, these effects were lower than those observed for cisplatin. The low cytotoxic and genotoxic profiles of TBSL support their consideration for further pharmaceutical evaluation. In addition, the genotoxicity findings suggest that the Pt(II) complexes merit further investigation in the context of antitumor drug development.
Differential Roles of BRCA1 and BRCA2 in the DNA Damage Response Revealed by isogenic V79 Mutant Cell lines.
Chailapakul P, Maeda J, Miura T … +1 more , Kato TA
Mutagenesis · 2026 Apr · PMID 42028973 · Publisher ↗
This study aimed to establish a novel BRCA1 mutant cell line from Chinese hamster V79 cells and clarify the role of BRCA1 in the DNA damage response (DDR) by comparison with a BRCA2 mutant line, V-C8. Using CRISPR/Cas9 e...
This study aimed to establish a novel BRCA1 mutant cell line from Chinese hamster V79 cells and clarify the role of BRCA1 in the DNA damage response (DDR) by comparison with a BRCA2 mutant line, V-C8. Using CRISPR/Cas9 editing, we generated a hypomorphic BRCA1 mutant, designated B1-21, carrying a 27-bp in-frame deletion in exon 4. This mutation deletes nine amino acids within the RING domain. B1-21, V79, and V-C8 cells were analyzed for DDR phenotypes. Both mutants showed impaired RAD51 foci formation, defective homologous recombination repair, and increased sensitivity to DNA-damaging agents. B1-21 cells were particularly sensitive to camptothecin and the PARP inhibitor NU1025, whereas V-C8 cells showed higher sensitivity to etoposide, cisplatin, mitomycin C, and bleomycin. Although γH2AX and FANCD2 focus responses were similar between V79 and B1-21, RAD51 recruitment was only partially reduced in B1-21 and completely absent in V-C8. B1-21 also displayed chromosomal instability (19-20 chromosomes), while V79 and V-C8 maintained a stable karyotype. After gamma irradiation, V-C8 cells accumulated substantially more chromatid-type aberrations and retained unrepaired chromatin longer than B1-21. Neither mutant showed normal RAD51 foci formation, radiation-induced sister chromatid exchange or an effective G2/M checkpoint arrest, unlike wild-type cells. Mitotic index measurements further confirmed checkpoint failure: V79 cells suppressed mitotic entry after irradiation, while B1-21 and V-C8 continued to enter mitosis, with V-C8 showing the most complete checkpoint breakdown. These findings indicate that partial disruption of the BRCA1 RING domain results in a hypomorphic phenotype with impaired homologous recombination, defective checkpoint control, and enhanced genotoxic sensitivity. The isogenic BRCA1 and BRCA2 mutant V79 lines offer a valuable model for dissecting DDR pathway differences and developing mutation-specific therapeutic strategies targeting BRCA-mutant cancers.
Phytochemical compositions and chemoprotective effect of Lenzites betulinus mushroom in mononuclear cells of patients with acute coronary syndrome and heart failure in vitro.
Vukajlović JT, Simić I, Tosti T … +4 more , Djordjević K, Poskurica M, Murić M, Milošević-Djordjević O
Mutagenesis · 2026 Apr · PMID 42007559 · Publisher ↗
Cardiovascular diseases (CVD) are the leading cause of death globally, posing a major public health challenge due to their increasing prevalence and complex etiology. Natural products from medicinal mushrooms have gained...
Cardiovascular diseases (CVD) are the leading cause of death globally, posing a major public health challenge due to their increasing prevalence and complex etiology. Natural products from medicinal mushrooms have gained attention for their cardioprotective properties. To evaluate whether the aqueous extract of Lenzites betulinus can protect mononuclear cells of acute coronary syndrome (ACS) and heart failure (HF) patients from therapy-induced DNA damage and to determine its polyphenolic composition. The study included 30 healthy controls, 30 ACS and 30 HF patients. The genoprotective potential of aqueous mushroom extract at concentrations of 50, 100, 150, and 200 mg/mL was examined in vitro using the comet assay on human blood mononuclear cells. Total phenolic and flavonoid contents were determined spectrophotometrically, while polyphenolic profiling was performed using UHPLC-DAD-MS/MS. The mean level of DNA damage in treated cell cultures from healthy donors increased in a concentration-dependent manner compared with the negative control, but without statistical significance. The extract significantly reduced therapy-induced level of DNA damage in mononuclear cells of ACS and HF patients (p < 0.0005). DNA damage level was significantly higher in HF patients. In ACS patients, %DNA damage was significantly reduced at the three highest concentrations, while genetic damage index (GDI) decreased at all concentrations. In HF patients, %DNA damage decreased at the two highest concentrations, and GDI at all except the lowest. Phytochemical analysis revealed high levels of phenolics and flavonoids, with chlorogenic acid and quercetin as dominant compounds. L. betulinus possesses significant nutritional and functional value. Its rich phytochemical profile likely underlies its chemoprotective effects against therapy-induced DNA damage, suggesting potential as a natural agent for genome stability support in CVD patients.
Multi-herbal ergogenic supplement induces in vitro mutagenicity and cytogenetic damages in HepG2 and HEK293 cells.
Carrão Dantas EK, Thomé JPFT, Pontes Filho MO … +3 more , Coelho MGP, Felzenszwalb I, Araujo-Lima CF
Mutagenesis · 2026 Jun · PMID 41925244 · Publisher ↗
Popular ergogenic supplements for weight loss raise safety concerns due to potential cardiovascular, liver, and kidney toxicity. Their genotoxicity remains insufficiently studied, highlighting the need for more research...
Popular ergogenic supplements for weight loss raise safety concerns due to potential cardiovascular, liver, and kidney toxicity. Their genotoxicity remains insufficiently studied, highlighting the need for more research on their long-term effects. The Brazilian health surveillance and regulatory system does not include dietary supplements under OECD genotoxicity regulatory guidelines. This study evaluates the mutagenic, cytotoxic, and genotoxic effects of a multi-herbal ergogenic supplement using the Ames test, WST-1 cell viability assay, and cytokinesis-block micronucleus tests in HepG2 and HEK293 cell lines. The Ames test revealed dose-dependent mutagenicity, particularly with metabolic activation, while the WST-1 assay showed hepatocytotoxic and nephrocytotoxic potential with dose- and time-dependent response. The cytokinesis-block micronucleus assay further confirmed genotoxicity, with significant formation of micronuclei and other cellular damage indicators. Our study emphasizes the need for careful safety monitoring of ergogenic supplements, highlighting the toxicity risks associated with their mutagenic, cytotoxic, and genotoxic potential.
Sachi Prasad Ray-Chaudhuri: Drosophila genetics and mutagenesis in Indian science.
Raman R, Jha AN
Mutagenesis · 2026 Jun · PMID 41920973 · Full text
This article summarizes the scientific contributions of Professor Sachi Prasad Ray-Chaudhuri and his unwavering commitment to advancing research and teaching in mutagenesis and genetics in post-independence India, follow...
This article summarizes the scientific contributions of Professor Sachi Prasad Ray-Chaudhuri and his unwavering commitment to advancing research and teaching in mutagenesis and genetics in post-independence India, following his postgraduate training in the United Kingdom under the mentorship of Professor H. J. Muller. His contributions in basic mutagenesis, radiation protection, animal cytogenetics, and population genetics using a range of model and native species laid the foundation of scientific research in India in these contemporary fields. This played a pivotal role in advancing genetics and biological sciences in India at a time when scientific infrastructure and resources were limited. He also took the initiative to modernize the curriculum of biology teaching in India in line with the developments in the subject globally. He expanded these efforts by teaching as a visiting professor in different, often remote parts of the country, where he inspired the students. The seeds of his relentless effort to connect the advances in Indian science with those in the rest of the world have blossomed, and Indian science today contributes significantly to the global knowledge base. His pioneering scientific contributions and inspiring legacy continue unabated.
Induction of genotoxic damage and ROS production in HCT116 TP53+/+ and HCT116TP53-/- colorectal cancer cell lines by anticancer drugs.
Naldoni C, Guidotti I, Matteoli M … +5 more , Di Bello D, Scatolini V, Esposti V, Falaschi A, Scarpato R
Mutagenesis · 2026 Jun · PMID 41870588 · Publisher ↗
Reactive oxygen species (ROS) play a dual role in cancer biology, contributing to both tumor progression and therapeutic responses. Many chemotherapeutic agents exert their cytotoxic effects through ROS generation, altho...
Reactive oxygen species (ROS) play a dual role in cancer biology, contributing to both tumor progression and therapeutic responses. Many chemotherapeutic agents exert their cytotoxic effects through ROS generation, although the extent and biological relevance of this process remain influenced by cellular context, including the functional status of tumor suppressor genes such as TP53. In this study, we investigated the induction of genomic damage and oxidative stress in two isogenic human colorectal cancer cell lines-HCT116TP53+/+ and HCT116TP53-/--after exposure to four commonly used anticancer agents: oxaliplatin (OXA), irinotecan (IRI), paclitaxel (PAC), and 5-fluorouracil (5-FU). Drug concentrations were selected to ensure cell viability while inducing genotoxicity. Genome damage was assessed by micronucleus (MN) assay. ROS production was measured using the BODIPY581/591 C11 lipid peroxidation fluorescent probe. Our results showed that OXA and IRI induced both significant MN formation and robust ROS production in a dose-dependent manner, while PAC predominantly triggered genomic damage with limited ROS generation. Conversely, 5-FU exhibited marginal (or no) effect on both endpoints. Notably, with regard to the extent of ROS accumulation and MN induction, no significant differences were detected under the tested conditions between the two HCT116 cell lines. This suggests that under non-cytotoxic conditions, p53 is not a critical modulator of oxidative responses to these agents. Overall, our data reveal a drug-specific pattern of genome and oxidative damage in HCT116 colorectal cancer cells, emphasizing the importance of considering drug mechanism of action in evaluating redox responses. These insights may contribute to the development of targeted combinatorial therapies aimed at modulating oxidative stress, especially in TP53-mutated tumors.
Inclusion of a recovery period after pulse treatment in the primary human lymphocyte micronucleus assay covers potential cell cycle delays without loss of sensitivity.
Goepfert A, Spies M, Partosa N … +17 more , Spang S, Whitwell J, Smith R, Lamb A, Marchand C, Zeller A, Lott J, Trenz K, Elhajouji A, Martus HJ, Brichet M, Schneider M, Naumann S, Schulz M, Dieckhoff J, Honarvar N, Landsiedel R
Mutagenesis · 2026 Jun · PMID 41796012 · Publisher ↗
According to Organisation for Economic Co-operation and Development test guideline no. (TG) 487 for the in vitro mammalian cell micronucleus test (MNT), short (pulse) treatment of primary human lymphocytes should be foll...
According to Organisation for Economic Co-operation and Development test guideline no. (TG) 487 for the in vitro mammalian cell micronucleus test (MNT), short (pulse) treatment of primary human lymphocytes should be followed immediately by a sampling period of 1.5-2.0 cell cycle lengths in the presence of cytochalasin B. However, TG 487 allows extending the sampling period "if it is known or suspected that the test chemical affects the cell cycling time." It is often unknown in advance whether a test substance induces cell cycle delays, and therefore whether an extension of the sampling period is warranted. Here, we investigate whether extending the sampling time after pulse treatment-by including a recovery period prior to cytochalasin B treatment-affects the sensitivity of the in vitro MNT. Primary human lymphocytes were exposed to 11 mutagens and assessed using two protocols ("recovery" and "no recovery") in parallel from the same treatment culture. Including a recovery period after pulse treatment generally allowed testing of higher concentrations without excessive cytotoxicity. In addition, cultures subjected to a recovery period showed generally higher micronucleus rates at concentrations with acceptable levels of cytotoxicity, compared to cultures not having undergone a recovery period. To compare the sensitivity of both protocols at non-cytotoxic concentrations, benchmark concentration analysis was performed. Here, the "recovery method" proved to be at least as sensitive as the "no recovery method." The reproducibility of these findings was demonstrated in an interlaboratory ring trial using a subset of up to five mutagens. In conclusion, the inclusion of a recovery period after pulse treatment per se covers potential substance-induced cell cycle delays without any loss in sensitivity toward the induced mutagenic effect. The "recovery" protocol can be used for assessing the mutagenic potential of test substances affecting and not affecting the cell cycle.
Mutagenicity of N-nitroso-fluoxetine and N-nitroso-varenicline in human HepaRG cell models.
Seo JE, Xu HS, Revollo JR … +7 more , Miranda-Colon JA, Atrakchi AH, McGovern TJ, Davis Bruno KL, Keire DA, Heflich RH, Guo X
Mutagenesis · 2026 Jun · PMID 41725400 · Publisher ↗
Nitrosamine drug substance-related impurities (NDSRIs) have raised significant concern among the pharmaceutical industry and regulatory agencies, prompting a need to establish methods to determine the mutagenic risks ass...
Nitrosamine drug substance-related impurities (NDSRIs) have raised significant concern among the pharmaceutical industry and regulatory agencies, prompting a need to establish methods to determine the mutagenic risks associated with these substances. As human, metabolically competent HepaRG cells previously showed promise in evaluating the mutagenicity of a small-molecule nitrosamine impurity, N-nitroso-dimethylamine (NDMA), this study evaluated the suitability of HepaRG cells for mutagenesis assessment of NDSRIs. HepaRG cells, cultured in both two-dimensional (2D) and three-dimensional (3D) spheroid formats, were exposed to N-nitroso-fluoxetine and N-nitroso-varenicline for either 3 days or 14 days. DNA damage was evaluated using the comet assay, clastogenicity/aneugenicity was measured with the micronucleus (MN) assay, and mutagenesis was assessed using high-fidelity sequencing (HiFi-seq). N-Nitroso-fluoxetine and N-nitroso-varenicline were cytotoxic, produced DNA damage, and increased mutation frequency in both 2D and 3D HepaRG models. Both compounds increased MN formation only at the highest concentration in 3D spheroids after the 14-day exposure. Benchmark concentration (BMC) analysis indicated that, despite overlapping confidence intervals between 2D and 3D HepaRG cultures, in most instances BMC values tended to be lower in 3D than in 2D cultures after both 3-day and 14-day treatments. In addition, the 14-day treatments of both 2D and 3D HepaRG cultures with N-nitroso-fluoxetine resulted in higher levels of mutagenesis than the 3-day treatments, while 3-day and 14-day treatments with N-nitroso-varenicline produced similar mutagenesis responses. These findings demonstrate the feasibility of employing HepaRG cells with HiFi-seq as a mammalian cell assay for assessing NDSRI mutagenesis.
The micronucleus assay in exfoliated buccal cells induced by lifestyle factors: an overview.
Knasmüller S, Nersesyan A, Mišík M … +5 more , Ferk F, Grusch M, Matić IZ, Kundi M, Wultsch G
Mutagenesis · 2026 Mar · PMID 41700784 · Publisher ↗
We describe the impact of lifestyle related factors on the formation of micronuclei (MN) in buccal cells. It is known that consumption of alcohol and of other drugs including tobacco and other plants cause damage of the...
We describe the impact of lifestyle related factors on the formation of micronuclei (MN) in buccal cells. It is known that consumption of alcohol and of other drugs including tobacco and other plants cause damage of the genetic material and leads to adverse health effects. Overall, 235 articles were evaluated in total. Tobacco smoking, i.e., consumption of cigarettes (75 publications), water pipes (11 publications) and crack smoking (5 publications) caused mainly positive effects, while negative results were obtained with pure marijuana (2 publications). Chewing habits (smokeless tobacco (27 publications) and betel with and without tobacco (23 publications) caused induction of MN in cells from the oral cavity (numbers indicate the number of publications). A study concerning khat chewing yielded a positive finding while reduction of MN was seen in consumers of coca leaves. Investigations concerning the effects of alcohol (11 publications), meat consumption (3 publications) and studies concerning the impact of the body mass index and body fat (4 publications) led to inconsistent results. No evidence of MN induction was observed in studies on continuous physical exercise (2 publications). Furthermore, exhaustive sporting activities also showed no indications of chromosomal damage (2 publications). A number of studies (in total 22 publications) were realized to investigate the effects of mobile phone specific radiation. The exposure was not adequately assessed in these investigations with questionnaires, furthermore, frequently inadequate stains (11 publications). The findings are controversial, and a clear negative result was obtained in a recent controlled intervention study. Overall the results indicate that the MN assay with buccal cells can be used to monitor chromosomal damage caused by smoking and chewing habits and to predict adverse health effects in the respiratory system and on the upper gastrointestinal tract. To draw firm conclusions about the effects of nutrition, mobile phone use, physical exercise, and body weight, further well-controlled trials are needed.
Nitrosamine Ames Data Review and Method Development: proceedings of a US FDA/HESI workshop.
Atrakchi A, Puglisi R, Bercu J … +14 more , Cheung J, Czich A, Froestchl R, Davis-Bruno K, Heflich RH, Kobets T, McGovern TJ, Lynch A, Selby M, Schuler M, Silveira GO, Vespa A, Whomsley R, Chen CL
Mutagenesis · 2026 Jun · PMID 41689482 · Full text
Detection of N-nitrosamines (NA) in pharmaceuticals became a point of interest due to the mutagenic and carcinogenic potential of some compounds of this class, and their identification as nitrosated forms of marketed dru...
Detection of N-nitrosamines (NA) in pharmaceuticals became a point of interest due to the mutagenic and carcinogenic potential of some compounds of this class, and their identification as nitrosated forms of marketed drugs, otherwise known as NA Drug Substance-Related Impurities (NDSRIs). The Ames test is used to assess the mutagenic potential of drug impurities, including NAs. Concerns over the sensitivity of the Ames test, as recommended in Organization for Economic Co-operation and Development Test Guideline 471, in predicting the rodent carcinogenic potential of NAs has prompted optimization of several test parameters used for detecting the mutagenicity of NAs (e.g. methods used for metabolic activation and the selection of tester strains). In order to discuss optimal Ames test conditions for the evaluation of NAs, including NDSRIs, the Office of New Drugs in the US Food and Drug Administration's Center for Drug Evaluation and Research and the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee co-organized and co-sponsored a workshop entitled "Nitrosamines: Ames Data Review and Method Development Workshop". The workshop featured five sessions addressing charge questions pertinent to the Ames test conditions and performance through the presentation of data and panel discussions. This report outlines the key takeaway points from the workshop.
Patterns of chromosomal instability and epigenetic alterations in colorectal cancer progression: from high-grade dysplasia to liver metastases.
Saskova K, Landfors M, Hlavac V … +14 more , Seborova K, Bruha J, Honkova K, Tomasova K, Selvi S, Drabova J, Hackenhaar FS, Nilsson TK, Vodicka P, Valickova A, Liska V, Farkas SA, Degerman S, Kroupa M
Mutagenesis · 2026 Apr · PMID 41685784 · Publisher ↗
Chromosomal instability (CIN), impaired telomere biology, and aberrant DNA methylation are implicated in colorectal cancer (CRC) development. Tracking these alterations from precancerous lesions through tumors to metasta...
Chromosomal instability (CIN), impaired telomere biology, and aberrant DNA methylation are implicated in colorectal cancer (CRC) development. Tracking these alterations from precancerous lesions through tumors to metastases may reveal biomarkers of CRC initiation and progression. Tissue samples from 44 patients with either high-grade colorectal dysplasia (HGA; n = 13) or advanced metastatic CRC (n = 31) were analyzed. CIN was assessed in all patients using either low-coverage whole-exome sequencing or microarray-based comparative genomic hybridization. In a subset of patients, genome-wide CpG methylation profiling (n = 19) and telomere length measurements (n = 15) were performed. CIN was detected in 85% of HGA patients, spanning focal CNVs in MALAT1 (46%) to recurrent alterations on chromosomes 11, 13, and 20, with PTK6 being the most frequently amplified (61%). CIN was comparable between primary tumors and synchronous metastases but was significantly elevated in metachronous cases. DEK was amplified in all metastases but the aberration was absent in primaries, irrespective of tissue chronicity. Methylation profiling distinguished HGA from adjacent non-dysplastic mucosa (9859 differentially methylated CpGs) and unrelated tumor tissues (17 638 CpGs), whereas primary tumors and metastases differed at only five CpG sites. Both primary tumors and metastases appeared epigenetically younger than colonic mucosa. Metastases exhibited significantly shorter telomeres than both primary tumors (P = .019) and colonic mucosa (P = .001). The amplification of PTK6 may serve as an early biomarker detectable at the HGA stage, while DEK amplification appears crucial for metastatic progression and may represent a therapeutic target. Further validation is needed.
Changes in telomere length and mitochondrial DNA copy number in the colorectal adenoma-carcinoma sequence.
Valickova A, Tomasova K, Balounova K … +14 more , Horak J, Kroupa M, Hanak P, Danesova N, Jungwirth J, Kral J, Hucl T, Kohout P, Summerova S, Schneiderova M, Vodickova L, Vodicka P, Vymetalkova V, Vodenkova S
Mutagenesis · 2026 Apr · PMID 41685770 · Publisher ↗
Colorectal adenomas are anomalous growths of the intestinal epithelium and are considered precursors to colorectal cancer (CRC). Identifying early-stage CRC biomarkers is essential for reducing its high mortality rate. T...
Colorectal adenomas are anomalous growths of the intestinal epithelium and are considered precursors to colorectal cancer (CRC). Identifying early-stage CRC biomarkers is essential for reducing its high mortality rate. This study hypothesizes that the association of telomere length (TL) and mitochondrial DNA copy number (mtDNA-CN) could serve as a biomarker for the adenoma or CRC formation. TL, mtDNA-CN, telomerase reverse transcriptase (TERT), and mitochondrial transcription factor A (TFAM) expressions were studied in 132 adenoma and 95 early-stage CRC patients. TL and mtDNA-CN were measured by multiplex quantitative polymerase chain reaction (qPCR). Expression of TERT and TFAM was measured by reverse transcription-qPCR. Significant TL shortening was observed in adenomas (P = 8.96e-14), tumor-node-metastasis (TNM) I (P = 3.49e-05), and TNM II (P = 2.29e-04) stages compared to the adjacent mucosa. This tendency was also contingent on TERT expression. Differential TFAM expression was observed in all groups, but an elevated relative mtDNA-CN was, compared to the adjacent mucosa, detected only in adenomas (P = 1.50e-08), where it correlated with TL (P = 4.10e-03). Notably, mtDNA-CN levels were significantly higher in adenomas than in early-stage tumors (TNM I, P = 2.00e-02; TNM II, P = 2.40e-02), suggesting a progressive decline during tumorigenesis. We have provided fresh insights into the crosstalk between telomere and mitochondrial biology in CRC precursors. These findings hold promise in understanding adenoma formation and CRC progression, as mtDNA-CN elevation and its association with TL were specific to precancerous lesions and were lost with progression to tumor.
Antioxidant effects of melatonin on obese mice.
Longaretti LM, Magenis ML, Damiani AP … +8 more , da Luz Beretta ÂC, de Oliveira Monteiro I, Possamai OL, Dorneles GP, Peres A, de Bem Silveira G, Silveira PCL, de Andrade VM
Mutagenesis · 2026 Apr · PMID 41665256 · Publisher ↗
Overweight and obesity have been increasing drastically in recent years due to the growing consumption of fast food. Obese individuals exhibit reduced antioxidant defenses, which can lead to DNA damage. Thus, studies hav...
Overweight and obesity have been increasing drastically in recent years due to the growing consumption of fast food. Obese individuals exhibit reduced antioxidant defenses, which can lead to DNA damage. Thus, studies have been conducted to mitigate obesity-related complications. Animal research has used the cafeteria diet (CAF) as an obesity induction model, as it mimics human consumption of ultra-processed foods. Currently, complementary dietary strategies are being explored to prevent and/or alleviate obesity-related complications, particularly through natural compounds with anti-obesity effects. Among these, melatonin (MEL) has gained attention due to its antioxidant and anti-inflammatory properties. This study aimed to evaluate the effects of MEL supplementation on biochemical, genotoxic, and inflammatory parameters in mice fed a CAF diet. A total of 60 male Swiss mice were divided into six experimental groups (n = 10): (i) Standard Diet-fed standard chow for 21 weeks; (ii) SD + MEL-fed standard chow and supplemented with MEL for 24 weeks; (iii) CAF-fed CAF for 21 weeks; (iv) CAF + MEL-fed CAF and supplemented with MEL; (v) CAF/CAF + MEL-fed CAF for the first 17 weeks, then continued CAF while starting MEL supplementation for the last 4 weeks, totaling 17 weeks of CAF; (vi) CAF + MEL/CAF-fed CAF and supplemented with MEL for the first 17 weeks, then stopped MEL supplementation for the last 4 weeks, totaling 21 weeks. Blood samples were collected at 17 and 21 weeks to assess DNA damage, lipid profile (triglycerides, total cholesterol, and HDL), liver function (ALT and AST), inflammatory markers (TNF-α and IL-10), fasting glucose, and insulin tolerance in all six groups. At the end of the experiment, animals were euthanized, and liver, kidney, adipose tissue, and bone marrow were collected for further analyses, including the Comet Assay, Micronucleus Test, oxidative stress evaluation, and Western blot. Results showed that CAF induced an inflammatory state, characterized by increased TNF-α and decreased IL-10, along with alterations in lipid and liver profiles. Additionally, CAF led to DNA damage in multiple tissues and insulin resistance. MEL supplementation for 17 weeks reversed these changes. In the last 4 weeks of the experiment, CAF was associated with oxidative stress and damage in the liver, kidney, and bone marrow. MEL effectively attenuated these obesity-related alterations, primarily by modulating proteins involved in homologous and non-homologous DNA repair pathways. In conclusion, the findings demonstrate that MEL is a potent antioxidant and may be a promising candidate for reducing biochemical and genetic alterations associated with obesity.
The Evolution and Application of Animal-Free Models in Drug Discovery and Disease Mechanism Research.
Jarman E, Tufarelli C, Brown K
Mutagenesis · 2026 Feb · PMID 41660879 · Publisher ↗
Animal models have been key for disease mechanism research for years, but ethical concerns partly fuelled by the realisation that not all diseases can be recapitulated in animal systems have led to regulatory changes tha...
Animal models have been key for disease mechanism research for years, but ethical concerns partly fuelled by the realisation that not all diseases can be recapitulated in animal systems have led to regulatory changes that are driving a shift towards animal-free alternatives. As regulations continue to evolve, the transition to animal-free models is becoming increasingly crucial for laboratories aiming to comply with new standards without compromising on scientific progress. The past decade has seen a boost in the development of animal-free three-dimensional models including explants, co-cultures, spheroids, organoids, and organ-on-chip systems, creating a varied landscape that has significantly transformed disease research. These models incorporate advancements in stem cell technology, bioengineering, and microfluidics to provide more physiologically relevant systems that bridge the gap between traditional two-dimensional cell culture and in-vivo studies. Whilst traditional two-dimensional cultures offer a cost-effective method with replicable results, they fail to accurately represent the natural structure of tissues and cell-cell interactions. By contrast, animal-free culture systems provide a more appropriate representation of human physiology and tissue architecture with relevance to in-vivo conditions. Therefore, these models enable more translatable research outcomes and have the potential to provide data for the reduction of the high failure rates currently marring clinical trials. This review explores the evolution, advantages, and applications of animal-free models in advancing human disease research and refining preclinical studies with an emphasis on cancer research.
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