Mutagenesis[JOURNAL]
Sun
200 papers
DNA damage in oral mucosal epithelial cells cultured in complex and xenobiotic-free media: a comparison study.
Cabral JV, Vodenkova S, Tomasova K … +6 more , Vodickova L, El Yamani N, Rundén Pran E, Dusinska M, Safanda A, Jirsova K
Mutagenesis · 2025 Aug · PMID 40580048 · Full text
In this study, we evaluated the genomic stability of oral mucosal epithelial cells (OMECs) cultured in complex media (COM) and xenobiotic-free media (XF) to assess their potential clinical application for limbal stem cel...
In this study, we evaluated the genomic stability of oral mucosal epithelial cells (OMECs) cultured in complex media (COM) and xenobiotic-free media (XF) to assess their potential clinical application for limbal stem cell deficiency (LSCD) treatments. OMECs serve as a promising autologous cell source for bilateral LSCD treatment, offering an alternative to limbal epithelial cells (LECs). However, genomic integrity is crucial to ensure the long-term success of transplanted cells. We performed micronucleus (MNi) tests and comet assays to compare DNA damage in OMECs cultured in both media types. The results indicated no significant differences in cell morphology, viability, or size between the two conditions. The MNi frequency was similar, with 5.67 and 6.17 MNi per 1,000 cells in COM and XF conditions, respectively. Comet assay results showed low levels of strand breaks (SBs) and oxidized DNA lesions in both media, with XF showing a slightly lower, albeit statistically insignificant, percentage of tail DNA for net Fpg-sensitive sites. Our findings suggest that OMECs can be effectively cultivated in either COM or XF media without inducing significant DNA damage, supporting the potential use of XF media in clinical settings to reduce contamination risks. This study underscores the importance of genomic stability in cultured cells for ocular surface transplantation, contributing valuable insights into optimizing culture conditions for safer and more effective clinical applications.
Polystyrene microplastics induces the injury of human corneal epithelial cells through ROS-mediated p53 pathway.
Long J, Deng L, Liu J … +2 more , Zhou K, He S
Mutagenesis · 2025 Jun · PMID 40503930 · Publisher ↗
OBJECTIVE: To investigate the effects of polystyrene microplastics (PS-MPs) on human corneal epithelial cells (HCEP). METHODS: The cytotoxicity of PS-MPs on HCEP cells was evaluated using a CCK-8 assay to measure cell vi...
OBJECTIVE: To investigate the effects of polystyrene microplastics (PS-MPs) on human corneal epithelial cells (HCEP). METHODS: The cytotoxicity of PS-MPs on HCEP cells was evaluated using a CCK-8 assay to measure cell viability, flow cytometry to analyze cell cycle and status, immunofluorescence to detect reactive oxygen species (ROS) and γ-H2AX levels, and western blotting to assess protein expression. RESULTS: The effects of PS-MPs on HCEP cell morphology and viability were particle size- and concentration-dependent. Smaller particle sizes and higher concentrations of PS-MPs were associated with greater cytotoxicity. PS-MP exposure induced cell cycle arrest, necrosis, and apoptosis in HCEP cells, along with excessive ROS production and DNA damage. Furthermore, ROS scavengers significantly reduced PS-MP-induced ROS overproduction and DNA damage, thereby alleviating PS-MP-induced cell cycle arrest, necrosis, and apoptosis. At the molecular level, ROS scavengers reversed the PS-MP-induced changes in the expression of γ-H2AX, P53, cell cycle-related proteins (cyclin D1, CDK2, and CDK4), necrosis-related proteins (CypD, PARP-1, and SRX), and apoptosis-related proteins (Cyt C, AIF, and cleaved-caspase 3). CONCLUSION: PS-MP exposure leads to cell cycle arrest, necrosis, and apoptosis in HCEP cells, which is associated with ROS overproduction and activation of the P53 pathway.
Genotoxic effects of aristolochic acid I on functional human-induced hepatocyte-like cells.
Hu Y, Lei Y, Gao Z … +7 more , Cao Y, Xi J, Ma Y, Gao Q, Fu J, Zhang X, Luan Y
Mutagenesis · 2025 Oct · PMID 40417995 · Publisher ↗
Aristolochic acid I (AAI) is a carcinogen associated with various human cancers. However, its causal relationship with hepatocellular carcinoma remains controversial, and inconsistent results from rodent studies have sug...
Aristolochic acid I (AAI) is a carcinogen associated with various human cancers. However, its causal relationship with hepatocellular carcinoma remains controversial, and inconsistent results from rodent studies have suggested species-specific differences. Here we evaluated AAI genotoxicity using functional human-induced hepatocyte-like cells (hiHep cells), a model that closely mimics primary human hepatocytes in gene expression and function, thereby shedding light on its potential hepatocarcinogenic risk in humans. First, we assessed AAI genotoxicity by evaluating AAI-DNA adducts and micronucleus frequency. In hiHep cells, AAI (0.7-2.5 µM) induced up to 105 adducts per 108 nucleotides, indicating high metabolic activation of AAI. A concentration-dependent increase in micronucleus frequency indicated a significant increase in chromosomal aberrations in hiHep cells. Considering the evidence of AAI inducing oxidative stress, we assessed 8-hydroxy-2'-deoxyguanosine and reactive oxygen species levels to evaluate DNA oxidative damage. For both indicators, significantly elevated levels were observed. A mechanism involving oxidative damage was further supported by observations of mitochondrial dysfunction, including changes in mitochondrial membrane potential and mitochondrial complex activity. Ascorbate treatment decreased AAI-induced oxidative DNA damage and DNA adduct formation, providing direct cellular evidence for free radical intermediates in AAI metabolic activation-a mechanism previously hypothesized but not experimentally validated in a human-relevant hepatocyte model. Our study findings revealed the genotoxic effects of AAI on hiHep cells and implicated oxidative stress as the key mechanism. These findings strengthen the association between AAI exposure and liver disease and highlight the potential role of antioxidant therapies in mitigating AAI-associated carcinogenesis.
Global DNA methylation and its association with genetic instability and exposure to inorganic elements and polycyclic aromatic hydrocarbons in coal mining dust.
León-Mejía G, Cappetta M, Garcia ALH … +8 more , Fiorillo-Moreno O, Rohr P, Muñoz-Acevedo A, Miranda-Guevara A, Quintana-Sosa M, Martinez-Lopez W, Henriques JAP, da Silva J
Mutagenesis · 2025 Aug · PMID 40241266 · Publisher ↗
Coal mining has significant economic and environmental implications. The extraction and combustion of coal release harmful chemicals and dust, impacting air, soil, and water quality, as well as natural habitats and human...
Coal mining has significant economic and environmental implications. The extraction and combustion of coal release harmful chemicals and dust, impacting air, soil, and water quality, as well as natural habitats and human health. This study aimed to investigate the association between global DNA methylation, DNA damage biomarkers (including telomere length), and inorganic element concentrations in the blood of individuals exposed to coal mining dust. Additionally, polycyclic aromatic hydrocarbons were analyzed. The study included 150 individuals exposed to coal mining and 120 unexposed controls. Results showed significantly higher global DNA hypermethylation in the exposed group compared to controls. Moreover, in the exposed group, micronucleus frequency and age showed a significant correlation with global DNA hypermethylation. Blood levels of inorganic elements, including titanium, phosphorus, sodium, aluminum, iron, sulfur, copper, chromium, zinc, chlorine, calcium, and potassium, were potentially associated with DNA methylation and oxidative damage, as indicated by comet assay results. Furthermore, exposure to polycyclic aromatic hydrocarbons such as fluoranthene, naphthalene, and anthracene, emitted in mining particulate matter, may contribute to these effects. These findings highlight the complex interplay between genetic instability, global DNA hypermethylation, and environmental exposure in coal mining areas, emphasizing the urgent need for effective mitigation strategies.
High correlation between micronuclei in lymphocytes and buccal cells in humans provides further validation of their use as biomarkers of DNA damage and cancer risks in vivo.
Nersesyan A, Proietti S, Knasmueller S … +2 more , Bonassi S, Fenech M
Mutagenesis · 2026 Mar · PMID 40138706 · Publisher ↗
Micronuclei (MN) are cellular structures containing chromosome fragments or whole chromosomes that fail to be incorporated into the main nuclei during mitosis. MN measured in lymphocytes using the cytokinesis-block metho...
Micronuclei (MN) are cellular structures containing chromosome fragments or whole chromosomes that fail to be incorporated into the main nuclei during mitosis. MN measured in lymphocytes using the cytokinesis-block method and MN in buccal cells are among the most widely used methods for measuring DNA damage in humans. However, it remains unclear whether they correlate well with each other. This has important implications regarding whether existing evidence linking MN in lymphocytes to prospective cancer risk can also be extended to MN in buccal cells, a much less invasive approach. We therefore systematically reviewed results from published studies that reported MN frequencies simultaneously in buccal cells and lymphocytes. Data were extracted from a set of 81 study groups reported in 62 publications. The overall frequency of MN in groups exposed to increased risk of DNA damage was 2.54 times higher compared to controls (95% CI: 2.06-3.01) in buccal cells and 2.43 times higher (95% CI: 1.92-2.93) in lymphocytes. Frequencies of MN in populations investigated for occupational or environmental exposure to genotoxins, various diseases, and poor nutrition/lifestyle were also compared in each study and for each tissue (lymphocytes and buccal mucosa) with frequencies in control subjects using the mean ratio (MR). Concordance between the two MN assays was evaluated by comparing MRs for primary exposure in all studies using a correlation analysis. The overall Pearson correlation index was 0.768 (0.877 for case-control studies and 0.998 for intervention studies), showing that MR estimates from the two assays were highly and significantly correlated (P < .001). The results from this investigation indicate that data obtained using the buccal MN assay reflect results obtained using the lymphocyte cytokinesis-block MN assay. This suggests that the buccal MN assay may also identify those at increased risk of tumorigenesis. Prospective studies will ultimately be required to completely verify this hypothesis.
Carcinogenic parasites: insights into the epidemiology and possible mechanisms of cancer.
Rather SA, Wani ZA, Mustafa RA … +6 more , Bharti P, Kousar R, Ashraf MV, Ahmad S, Shah AA, Khan MAH
Mutagenesis · 2025 Aug · PMID 40067333 · Publisher ↗
Naturally, a wide range of genetic and environmental variables predominate, such as bacterial, viral, and parasite infective entities that have been identified as carcinogenic bioagents. Many helminth and protozoan paras...
Naturally, a wide range of genetic and environmental variables predominate, such as bacterial, viral, and parasite infective entities that have been identified as carcinogenic bioagents. Many helminth and protozoan parasitic diseases are liable to cause human cancer. Conveniently, three trematode parasites viz. Schistosoma haematobium, Opisthorchis viverrini, and Clonorchis sinensis have been reported to be intrinsically linked with human cancer. Similar studies for other parasitic infections are still imprecise and need further validation. Plasmodium falciparum is known to cause holoendemic Burkitt lymphoma despite the non-carcinogenic role of malaria. This review is endowed with a coupled correlation and underlying mechanisms by which parasitic infections lead to carcinogenicity. An empirical documentation covering the prevalence and incidence of viral, bacterial, and parasitic carcinogenicity is illustrated in this article. Moreover, some probable diagnostic and treatment procedures for parasitic carcinogenicity are also summarized. A detailed account of various mutational and genetic changes that lead to carcinogenesis via different pathways is appended in this article.
DNA damage, apoptosis, and serum inflammatory marker levels, but not white blood cell counts, are related to occupational exposure to waste anesthetic gases during medical residency: a longitudinal study.
Scorza CE, Aun AG, Guedes JL … +4 more , Destro MV, Golim MA, Braz LG, Braz MG
Mutagenesis · 2025 Aug · PMID 39985789 · Publisher ↗
The objective of this longitudinal study was to jointly assess DNA damage, apoptosis, inflammatory marker levels, and white blood cell (WBC) counts in physicians occupationally exposed to inhalation anesthetics during sp...
The objective of this longitudinal study was to jointly assess DNA damage, apoptosis, inflammatory marker levels, and white blood cell (WBC) counts in physicians occupationally exposed to inhalation anesthetics during specializations. Thus, we aimed to identify a possible cause-effect relationship between occupational exposure to waste anesthetic gases (WAGs), which were measured, and genotoxic, cytotoxic, and immunotoxic effects. Nineteen medical residents were evaluated at four time points: before entering medical residency (baseline) and at the beginning, middle, and end of medical residency. Peripheral blood mononuclear cells (PBMCs) were investigated for DNA damage, which was detected via the comet assay, and for apoptosis, which was detected via an annexin marker (flow cytometry). High-sensitivity C-reactive protein and serum inflammatory cytokines were evaluated via flow cytometry, and total and differential WBCs were counted. In addition, the concentrations of the WAGs measured in the workplace during the study were evaluated via an infrared spectrophotometer. The WAG concentrations were far higher than the internationally recommended values. Compared with those at previous time points, we observed increased DNA damage (P = .008) and apoptosis (P = .001) in PBMCs from the middle to the end of medical residency. Significant increases (P < .05) in the IL-8, IL-10, IL-12p70, IL-17A, IL-18, and IL-23 levels throughout medical residency were detected. There was no effect on the WBC count (P < .05), and all the means were within the reference range values. Occupational exposure to high levels of WAGs induces DNA damage, apoptosis, and changes in serum inflammatory marker levels, but not in leukocyte counts, in physicians who work in surgical theaters lacking an adequate scavenging system during medical residency.
Slightly increased level of DNA migration in the comet assay: does statistical significance equal biological significance?
Møller P, Collins A, Rodriguez-Garraus A … +3 more , Langie SAS, Godschalk R, Azqueta A
Mutagenesis · 2025 Apr · PMID 39963750 · Full text
In the comet assay, DNA damage is assessed by differences in DNA migration from gel-embedded nucleoids. Even a small difference in DNA migration between exposure groups can be statistically significant but may invite spe...
In the comet assay, DNA damage is assessed by differences in DNA migration from gel-embedded nucleoids. Even a small difference in DNA migration between exposure groups can be statistically significant but may invite speculation about the biological significance of such slight increases in DNA migration. A small difference can be defined as a net difference of 1-2% Tail DNA, but background levels of DNA migration typically vary already more than 1-2% Tail DNA between studies. Here, we have used studies on ionizing radiation to assess the lowest detectable differences in DNA migration; variation in exposure-effect relationships; variation in central tendencies of DNA migration; unsystematic (residual) variation; and the actual number of lesions detectable with the comet assay. A total of 51 studies on ionizing radiation exposure in mammalian cells have been systematically reviewed, including results from ring-trial studies where the same batch of irradiated cells has been analysed in different laboratories. Ring-trial studies have shown that unsystematic variation is approximately 4% Tail DNA in studies on ionizing radiation. Studies on ionizing radiation in cell cultures have shown statistically significant effects when the net increase of DNA migration is 0.3-3.1% Tail DNA. Among those experiments, the ones with optimal assay conditions to detect low levels of DNA damage show statistically significant effects with doses of around 0.30 Gy, which corresponds to approximately 350 lesions per diploid cell. However, it has also been shown that the same dose of ionizing radiation can give rise to different levels of DNA migration (i.e. 0.7-7.8% Tail DNA per Gy) in different studies. In summary, the results show that even a small statistically significant difference in DNA migration has biological significance within the same experiment, but comparisons of DNA migration values between studies have limited biological implications.
Defective DNA repair: a putative nexus linking immunological diseases, neurodegenerative disorders, and cancer.
Andarawi S, Vodickova L, Uttarilli A … +2 more , Hanak P, Vodicka P
Mutagenesis · 2025 Mar · PMID 39937585 · Publisher ↗
DNA damage is a common event in cells, resulting from both internal and external factors. The maintenance of genomic integrity is vital for cellular function and physiological processes. The inadequate repair of DNA dama...
DNA damage is a common event in cells, resulting from both internal and external factors. The maintenance of genomic integrity is vital for cellular function and physiological processes. The inadequate repair of DNA damage results in the genomic instability, which has been associated with the development and progression of various human diseases. Accumulation of DNA damage can lead to multiple diseases, such as neurodegenerative disorders, cancers, immune deficiencies, infertility, and ageing. This comprehensive review delves the impact of alterations in DNA damage response genes (DDR) and tries to elucidate how and to what extent the same traits modulate diverse major human diseases, such as cancer, neurodegenerative diseases, and immunological disorders. DDR is apparently the trait connecting important complex disorders in humans. However, the pathogenesis of the above disorders and diseases are different and lead to divergent consequences. It is important to discover the switch(es) that direct further the pathogenic process either to proliferative, or degenerative diseases. Our understanding of the influence of DNA damage on diverse human disorders may enable the development of the strategies to prevent, diagnose, and treat these diseases. In our article, we analysed publicly available GWAS summary statistics from the NHGRI-EBI GWAS Catalog and identified 12 009 single-nucleotide polymorphisms (SNPs) associated with cancer. Among these, 119 SNPs were found in DDR pathways, exhibiting significant P-values. Additionally, we identified 44 SNPs linked to various cancer types and neurodegenerative diseases (NDDs), including four located in DDR-related genes: ATM, CUX2, and WNT3. Furthermore, 402 SNPs were associated with both cancer and immunological disorders, with two found in the DDR gene RAD51B. This highlights the versatility of the DDR pathway in multifactorial diseases. However, the specific mechanisms that regulate DDR to initiate distinct pathogenic processes remain to be elucidated.
Impact of cigarette smoking on genetic stability, cell division, and cytotoxicity in buccal cells of old and young women.
Nersesyan A, Kundi M, Muradyan R … +4 more , Wultsch G, Mišík M, Ferk F, Knasmueller S
Mutagenesis · 2026 Mar · PMID 39903664 · Full text
We investigated the impact of cigarette smoking, daily exposure to tar and nicotine, and the duration of smoking on genetic instability (chromosomal damage-micronuclei, MN, nuclear buds-gene amplification) as well as on...
We investigated the impact of cigarette smoking, daily exposure to tar and nicotine, and the duration of smoking on genetic instability (chromosomal damage-micronuclei, MN, nuclear buds-gene amplification) as well as on disturbances in mitosis (resulting in binucleated cells). Furthermore, we analyzed markers of cytotoxic effects (such as the formation of condensed chromatin, pyknotic, karyolytic, and karyorrhectic cells) and the mitotic activity of the oral mucosa. These parameters were monitored in groups of old (postmenopausal) and young (premenopausal) smoking and nonsmoking women (n = 25/group). We found no differences in the MN frequencies in the non-smoking groups and only a moderate (not significant) increase of MN in both groups of smokers. However, we observed a clear increase in markers of genomic instability in both smoking groups. Furthermore, the mitotic activity of cells in the mucosa and of anomalies caused by acute cytotoxicity was higher in both smoking groups. Nicotine uptake was associated with pronounced acute toxic effects and increased cell division rate. Chromosomal damage (MN) was higher in individuals who consumed high amounts of tar (this effect was not significant) and caused moderate acute toxicity. Our findings indicate (i) that age and hormonal status have no strong impact on the genotoxic and cytotoxic effects in smoking women, (ii) consumption of up to 30 cigarettes/day does not cause chromosomal damage in buccal cells, however, positive results were found in earlier studies in heavy smokers, (iii) smoking increased markers which reflect genetic instability and the division rate of oral mucosa cells. These effects may play a role in the neoplastic transformation of cells in the upper respiratory tract in smokers. The duration of smoking was associated with a slight (not significant) increase in the mitotic activity and of chromosomal damage and with moderate acute cytotoxicity.
Maternal exercise before and during pregnancy protects against genotoxicity and promotes offspring hippocampal health in mice prenatally exposed to high fructose.
Magenis ML, de Oliveira Monteiro I, Damiani AP … +13 more , Dagostin LS, Possamai OL, Medeiros EB, Budni J, Bittencourt JVS, Mendes C, Silveira PCL, Garcia ALH, da Silva J, de Feveri W, Langie SAS, Godschalk R, de Andrade VM
Mutagenesis · 2025 Apr · PMID 39803898 · Publisher ↗
The fetal brain is susceptible to programming effects during pregnancy, potentially leading to long-term consequences for offspring's cognitive health. Fructose (FRU) intake is thought to adversely affect fetal brain dev...
The fetal brain is susceptible to programming effects during pregnancy, potentially leading to long-term consequences for offspring's cognitive health. Fructose (FRU) intake is thought to adversely affect fetal brain development, whereas physical exercise before and during pregnancy may be protective. Therefore, this study aimed to assess biochemical and genotoxic changes in maternal hippocampi and behavioral, genotoxic, and biochemical alterations in offspring hippocampi. Seventy female mice were exposed to FRU (20%/L) and/or voluntary physical exercise (VPE) pre-pregnancy for eight weeks, and then mated and exposure was continued until weaning. Offspring were evaluated at 60 days old using behavioral test, genotoxic, and biochemical markers. FRU-induced long-term memory impairment in male offspring, which was alleviated by VPE. VPE mitigated DNA damage from maternal FRU consumption in both maternal and offspring hippocampi in female offspring, VPE increased levels of apurine/apyrimidinic endonuclease 1, erythroid nuclear factor 2, and cAMP response element binding proteins, whereas in males, 8-oxoguanine DNA glycosylase-1 levels upregulate. FRU consumption led to oxidative stress and antioxidant defense alterations in offspring, while VPE mitigated these effects. Telomere shortening was observed in male offspring from mothers who consumed FRU during pregnancy. Our findings suggest that exposure to FRU during (pre)pregnancy and lactation has adverse effects on offspring's hippocampi later in life, and VPE has a protective effect. Overall, the study underscores the significance of maternal dietary and physical habits on long-term offspring health, with an emphasis on implications for adult cognitive function.
A pooled analysis of host factors that affect nucleotide excision repair in humans.
Zheng C, Shaposhnikov S, Collins A … +11 more , Brunborg G, Azqueta A, Langie SAS, Dusinska M, Slyskova J, Vodicka P, van Schooten FJ, Bonassi S, Milic M, Orlow I, Godschalk R
Mutagenesis · 2025 Apr · PMID 39670868 · Full text
Nucleotide excision repair (NER) is crucial for repairing bulky lesions and crosslinks in DNA caused by exogenous and endogenous genotoxins. The number of studies that have considered DNA repair as a biomarker is limited...
Nucleotide excision repair (NER) is crucial for repairing bulky lesions and crosslinks in DNA caused by exogenous and endogenous genotoxins. The number of studies that have considered DNA repair as a biomarker is limited, and therefore one of the primary objectives of the European COST Action hCOMET (CA15132) was to assemble and analyse a pooled database of studies with data on NER activity. The database comprised 738 individuals, gathered from 5 laboratories that ran population studies using the comet-based in vitro DNA repair assay. NER activity data in peripheral blood mononuclear cells were normalized and correlated with various host-related factors, including sex, age, body mass index (BMI), and smoking habits. This multifaceted analysis uncovered significantly higher NER activity in female participants compared to males (1.08 ± 0.74 vs. 0.92 ± 0.71; P = .002). Higher NER activity was seen in older subjects (>30 years), and the effect of age was most pronounced in the oldest females, particularly those over 70 years (P = .001). Females with a normal BMI (<25 kg/m2) exhibited the highest levels of NER, whereas the lowest NER was observed in overweight males (BMI ≥ 25 kg/m2). No independent effect of smoking was found. After stratification by sex and BMI, higher NER was observed in smoking males (P = .017). The biological implication of higher or lower repair capacity remains unclear; the inclusion of DNA repair as a biomarker in molecular epidemiological trials should elucidate the link between health and disease status.
Resolution of historically discordant Ames test negative/rodent carcinogenicity positive N-nitrosamines using a sensitive, OECD-aligned design.
Thomas DN, Wills JW, Burman M … +10 more , Williams AN, Harte DSG, Buckley RA, Urquhart MW, Bretonnet AS, Jeffries B, White AT, Harvey JS, Howe JR, Lynch AM
Mutagenesis · 2025 Apr · PMID 39485309 · Full text
The in vitro bacterial reverse mutation (Ames) test is crucial for evaluating the mutagenicity of pharmaceutical impurities. For N-nitrosamines (NAs) historical data indicated that for certain members of this chemical cl...
The in vitro bacterial reverse mutation (Ames) test is crucial for evaluating the mutagenicity of pharmaceutical impurities. For N-nitrosamines (NAs) historical data indicated that for certain members of this chemical class, the outcomes of the Ames test did not correlate with their associated rodent carcinogenicity outcomes. This has resulted in negative outcomes in an OECD (Organization for Economic Cooperation and Development)-aligned Ames test alone (standard or enhanced) no longer being considered sufficient by regulatory authorities to assess potential carcinogenic risk of NAs if present as impurities in drug products. Consequently, extensive follow-up in vivo testing can be required to characterize the potential mutagenicity and genotoxic carcinogenicity of NA impurities (i.e. beyond that defined in the ICH M7 guideline for non-NA impurities). We previously demonstrated that the mutagenicity of alkyl-nitrosamines can be detected by the appropriately designed, OECD-aligned Ames test and identified those conditions that contributed most to assay sensitivity. This OECD-aligned Ames test design was used to assess seven NAs, i.e. (methyl(neopentyl)nitrosamine, N-methyl-N-nitroso-2-propanamine, N-nitrosodiisopropylamine, bis(2-methoxyethyl)nitrosoamine, N-nitroso-N-methyl-4-fluoroaniline, dinitrosoethambutol, (R,R)- and mononitrosocaffeidine) that were reported to be negative in historical Ames tests but positive in rodent carcinogenicity studies. All seven of the NAs were demonstrated to be mutagenic in the OECD-aligned Ames test and therefore these compounds should no longer be considered as discordant (false negatives) with respect to the correlation of the Ames test and rodent carcinogenicity. These results confirm the sensitivity of the OECD-aligned Ames test for the detection of NA mutagenicity and provides further support of its pivotal placement within the ICH M7 framework for the assessment of mutagenic impurities in pharmaceuticals to limit potential carcinogenic risk. In addition, we present data for 1-cyclopentyl-4-nitrosopiperazine, that indicates it could serve as a suitable positive control to provide further confidence in the sensitivity of the Ames test for the NA chemical class.
Industrial Genotoxicology Group: 36th Annual Meeting Report.
Kidd D, Crooks I, Saccardo A … +9 more , Ponting DJ, Kocks G, Gandhi R, Thomas D, Pass E, Lynch A, Johnson G, Fowler P, Wilson A
Mutagenesis · 2025 Apr · PMID 39447060 · Publisher ↗
The proceedings of the 36th annual meeting of the Industrial Genotoxicology Group (IGG) are shared here. The meeting held at Lhasa Limited, Leeds, UK on 28 November 2023, focussed on two aspects; new approach methodologi...
The proceedings of the 36th annual meeting of the Industrial Genotoxicology Group (IGG) are shared here. The meeting held at Lhasa Limited, Leeds, UK on 28 November 2023, focussed on two aspects; new approach methodologies (NAMs), including those for the assessment of non-standard modalities such as gas-vapour assessments and nanomaterials, and addressing the regulatory challenges associated with understanding the genotoxic and carcinogenic potential of N-nitrosamines and N-nitrosamine impurities. New approach methodologies, such as error-corrected sequencing and enhanced Ames tests that may help address these challenges were also discussed.
Terminalia ivorensis demonstrates antioxidant properties and alters proliferation, genomic instability, and migration of human colon cancer cells in vitro.
Moomin A, Knott RM, Russell WR … +2 more , Moyer MP, Duthie SJ
Mutagenesis · 2025 Aug · PMID 39441622 · Full text
Colorectal cancer is a global killer that causes approximately 940 thousand deaths annually. Terminalia ivorensis (TI) is a tropical tree, the bark of which is used in African traditional medicine for the treatment of di...
Colorectal cancer is a global killer that causes approximately 940 thousand deaths annually. Terminalia ivorensis (TI) is a tropical tree, the bark of which is used in African traditional medicine for the treatment of diabetes, malaria, and ulcer. This study investigated TI as a potential anticancer agent in human colon cells in vitro. TI was extracted sequentially with petroleum ether, chloroform, ethyl acetate, and ethanol. Antioxidant activity was assessed by DPPH and FRAP, and differential effects on cell viability, growth, DNA damage, DNA repair, and migration were measured in human colon cancer cells (CaCo-2) and/or non-cancerous human colonocytes (NCM460). The TI phytochemicals most strongly associated with these effects were identified by partial least-squares discriminant analysis. DPPH and FRAP activity was highest in TI ethyl acetate and ethanol extracts (P = .001). All TI extracts significantly inhibited cell viability and growth and induced DNA damage and inhibited DNA repair in both cell models. The majority of TI extracts were significantly (P = .01) more toxic to cancer cells than non-cancerous colonocytes. DNA repair was significantly (P = .001) inhibited in CaCo-2 cells by ethyl acetate extract compared with NCM460 cells. Migration was also significantly inhibited (P < .001) in CaCo-2 by ethyl acetate (80%) and ethanol extracts (75%). Specific benzoic acids, flavonoids, and phenols were identified to be strongly associated with these effects. TI displayed strong antioxidant activity and specific anticancer effects by inducing cell death and DNA damage, and by inhibiting DNA repair, cell proliferation, and migration.
An added value of azithromycin: mitigation of doxorubicin-associated oxidative damage and genotoxicity in normal human bronchial epithelium cells.
Shokrzadeh S, Moghim S, Shokrzadeh M … +1 more , Aghajanshakeri S
Mutagenesis · 2025 Apr · PMID 39373202 · Publisher ↗
Doxorubicin, a well-known and widely used antineoplastic agent with direct ROS-accumulating activity, has proven effective in treating various cancer types. However, its non-specific cytotoxicity towards non-cancerous ce...
Doxorubicin, a well-known and widely used antineoplastic agent with direct ROS-accumulating activity, has proven effective in treating various cancer types. However, its non-specific cytotoxicity towards non-cancerous cells prompts concerns regarding potential adverse effects. Azithromycin is an antibiotic for treating bacterial infections and an anti-inflammatory agent, particularly beneficial in managing respiratory conditions like bronchitis and sinusitis. Despite azithromycin's well-documented antibacterial properties, its potential cellular/genomic protective effects remain unexplored. As an in vitro model, BEAS-2B cells (normal human bronchial epithelium cells) were employed in this study to assess whether azithromycin possesses any protective properties against doxorubicin-induced cellular toxicity. Cells in pretreatment culture were treated to various amounts of azithromycin (3.125, 6.25, 12.5, 25, and 50 μg/ml) in combination with doxorubicin at IC50 (0.08 μg/ml). Doxorubicin at 0.08 μg/ml highlighted cytotoxicity, oxidative stress, and genotoxicity. Azithromycin at 25 and 50 μg/ml markedly modulated oxidative stress and genomic damage by decreasing the ROS and LPO amounts and suppressing DNA fragmentation in the comet assay parameters. Consequently, azithromycin may be regarded as a cytomodulating, antigenotoxic, and antioxidant agent.
Plasma miR-122-5p and miR-142-5p and their role in chemoresistance of patients with colon cancer.
Vokacova K, Landecka A, Selvi S … +5 more , Horak J, Novosadova V, Manakova K, Levy M, Vymetalkova V
Mutagenesis · 2025 Mar · PMID 39275807 · Publisher ↗
Chemoresistance represents a major issue affecting cancer therapy efficacy. Because microRNAs (miRNAs) regulate gene expression on multiple levels, their role in chemoresistance development is reasonably certain. In our...
Chemoresistance represents a major issue affecting cancer therapy efficacy. Because microRNAs (miRNAs) regulate gene expression on multiple levels, their role in chemoresistance development is reasonably certain. In our previous study, miR-122-5p and miR-142-5p were identified as diagnostic, prognostic, and predictive biomarkers for primary and metastatic rectal cancer. The aim of the present study was to investigate whether these miRNAs can also reflect the disease course of patients with colon cancer (CC). Further, we focused on a deeper understanding of their involvement in 5-fluorouracil (5-FU) chemoresistance development.
Exploring the relationship between genetic instability and health outcomes in acute and chronic post-COVID syndrome.
Martins BAA, Garcia ALH, Borges MS … +10 more , Picinini J, Serpa ET, Nobles DDR, Silva LL, Dalberto D, Hansen AW, Spilki FR, Schuler-Faccini L, Rampelotto PH, Da Silva J
Mutagenesis · 2024 Nov · PMID 39215662 · Publisher ↗
The COVID-19 pandemic has led to the emergence of acute and chronic post-COVID syndromes, which present diverse clinical manifestations. The underlying pathophysiology of these conditions is not yet fully understood, but...
The COVID-19 pandemic has led to the emergence of acute and chronic post-COVID syndromes, which present diverse clinical manifestations. The underlying pathophysiology of these conditions is not yet fully understood, but genetic instability has been proposed as a potential contributing factor. This study aimed to explore the differential impact of physical and psychological health factors on genetic instability in individuals with acute and chronic post-COVID syndromes. In this study, three groups of subjects were analyzed: a control group, an acute post-COVID group, and a chronic post-COVID group, with a total of 231 participants. The participants were assessed using a questionnaire for long-COVID-19COVID, and female participants reported more symptoms than male participants in areas related to fatigue, memory, mental health, and well-being during the chronic phase. Genetic instability was assessed using the comet assay, and participants' physical and psychological profiles were evaluated. The overall results showed no significant differences in DNA damage, as measured by the comet assay, among the three groups, suggesting that genetic instability, as assessed by this method, may not be a primary driver of the distinct clinical presentations observed in post-COVID syndromes. However, when gender was considered, male participants in the acute long COVID group exhibited higher levels of genetic instability compared to females. Multiple linear regression analysis revealed that gender, age, and waist circumference were significant predictors of DNA damage. Among females in the acute group, sexual health, and eye-related symptoms significantly influenced the increase in DNA damage. These findings indicate the need for further investigation on the gender-specific differences in genetic instability and their potential implications for the pathophysiology of post-COVID syndromes. Exploring alternative markers of genetic instability and the interplay between genetic, inflammatory, and cellular processes could provide valuable insights for the management of these debilitating post-viral sequelae.
The Allium cepa comet assay for environmental sample assessment: a scoping review.
Alias C, Zerbini I, Zani C … +1 more , Feretti D
Mutagenesis · 2024 Sep · PMID 39178319 · Publisher ↗
The purposes of this review were to investigate the application of the comet assay in Allium cepa root cells to assess the genotoxicity of environmental samples and to analyse the experimental procedures employed. A lite...
The purposes of this review were to investigate the application of the comet assay in Allium cepa root cells to assess the genotoxicity of environmental samples and to analyse the experimental procedures employed. A literature search was performed selecting articles published between January 2000 and October 2023 from online databases using the combined search terms 'comet assay' and 'A. cepa'. Only 18 papers met the inclusion criteria. None of these were published in the first eight years (2000-2007), highlighting the increasing interest in using the comet assay on A. cepa to analyse environmental samples over the last decade. The majority of the selected studies (15/18, 83%) were performed on samples belonging to the water compartment on onion bulbs. Half of the selected studies (9/18) were conducted to demonstrate the DNA damaging effect of the sample, while the other half of the studies not only recognized the presence of genotoxic agents but also addressed possible remediation measures. Detailed analysis of the experimental procedures revealed heterogeneity in many key steps, such as exposure time, test controls, nuclei isolation solutions, duration of electrophoresis, and number of nuclei scored. This literature review has shown that the comet assay on A. cepa, although recognized as an appropriate tool, is underutilized in environmental toxicology. Greater standardization could lead to its more widespread use, providing valuable information on the genotoxicity of environmental samples and the ability of different processes to mitigate their negative effects on plants.
Determination of global DNA methylation level by methylation-sensitive comet assay in patients with urinary bladder cancer.
Kocak O, Kankaya S, Kalender G … +3 more , Citgez S, Onal B, Dincer Y
Mutagenesis · 2024 Nov · PMID 39126352 · Publisher ↗
DNA methylation is an important mechanism in the regulation of gene expression and maintenance of genomic integrity. Aberrant DNA methylation is an early event in carcinogenesis. DNA methyltransferase inhibitors are used...
DNA methylation is an important mechanism in the regulation of gene expression and maintenance of genomic integrity. Aberrant DNA methylation is an early event in carcinogenesis. DNA methyltransferase inhibitors are used to restore aberrant DNA methylation and inhibit tumor growth. Evaluation of DNA methylation level is important for an effective anti-cancer therapy. In the present study, the determination of global DNA methylation levels in patients with urinary bladder cancer was proposed. The methylation-sensitive comet assay determined the global DNA methylation level at the level of single cells. McrBC enzyme, a methylation-sensitive restriction endonuclease, was used for enzymatic digestion to generate additional breaks at methylated sites. % DNA methylation level was significantly higher in patients with bladder cancer compared to the control group. The clinical performance of % DNA methylation analysis by methylation-sensitive comet assay was evaluated by ROC curve. Using the cutoff value of 6.5% DNA methylation, 92% sensitivity, and 42% specificity were obtained. In conclusion, global DNA methylation measured by methylation-sensitive comet assay may be a promising noninvasive biomarker that reduces interventional tests required in the diagnosis and follow-up of urinary bladder cancer.
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