Mutation research. Genetic toxicology and environmental mutagenesis最新文献_第3页

Protective role of Cockayne Syndrome B (CSB) protein in maintaining genome integrity in human cells under oxidative stress Cockayne综合征B （CSB）蛋白在氧化应激下维持人类细胞基因组完整性中的保护作用

IF 2.5 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation research. Genetic toxicology and environmental mutagenesis

Pub Date : 2025-09-09 DOI: 10.1016/j.mrgentox.2025.503887

Grace Kah Mun Low, Gavin Yong-Quan Ng, Dimphy Zeegers, Aloysius Ting, Kalpana Gopalakrishnan, Aik Kia Khaw, Manikandan Jayapal, Manoor Prakash Hande

Cockayne Syndrome (CS), a progeroid disorder characterised by premature ageing and neurodevelopmental abnormalities, is primarily caused by mutations in the CSB protein, a key component of the transcription-coupled nucleotide excision repair pathway. This study investigates the role of CSB in managing oxidative DNA damage and preserving telomere integrity under oxidative stress. Using CSB-deficient human fibroblasts (CS-B) and matched controls, we exposed cells to acute and chronic oxidative stress via hydrogen peroxide (H₂O₂) and elevated oxygen (40 %) levels. CS-B fibroblasts showed relative resistance to acute oxidative stress in terms of cell death, maintaining viability and displaying limited cell cycle arrest. In contrast, chronic oxidative exposure induced accelerated senescence in CS-B cells, evidenced by increased telomere attrition, senescent morphology, and early activation of senescence-associated β-galactosidase associated with increased DNA damage and aberrant DNA repair. Gene expression profiling revealed downregulation of key DNA repair and cell cycle genes in CS-B fibroblasts following H₂O₂ treatment, indicating impaired damage response pathways. These findings highlight the essential role of CSB in genome maintenance and suggest that its loss contributes to CS pathology through heightened sensitivity to chronic oxidative stress and telomere dysfunction. This work enhances our understanding of CS-related cellular mechanisms and may inform future therapeutic strategies targeting oxidative stress and DNA repair.

柯凯因综合征（CS）是一种以早衰和神经发育异常为特征的类早衰疾病，主要由CSB蛋白突变引起，CSB蛋白是转录偶联核苷酸切除修复途径的关键成分。本研究探讨了CSB在氧化应激下管理氧化DNA损伤和保持端粒完整性中的作用。使用csb缺陷的人成纤维细胞（CS-B）和匹配的对照，我们通过过氧化氢（H₂O₂）和高氧（40 %）水平将细胞暴露于急性和慢性氧化应激中。CS-B成纤维细胞在细胞死亡、维持活力和有限的细胞周期阻滞方面显示出对急性氧化应激的相对抗性。相反，慢性氧化暴露诱导CS-B细胞加速衰老，这可以通过端粒磨损增加、衰老形态和衰老相关β-半乳糖苷酶的早期激活来证明，该酶与DNA损伤增加和异常DNA修复有关。基因表达谱显示，在h2o2处理后，CS-B成纤维细胞中关键的DNA修复和细胞周期基因下调，表明损伤反应途径受损。这些发现强调了CSB在基因组维持中的重要作用，并表明CSB的缺失通过对慢性氧化应激和端粒功能障碍的敏感性增加而导致CS病理。这项工作增强了我们对cs相关细胞机制的理解，并可能为未来针对氧化应激和DNA修复的治疗策略提供信息。

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引用次数: 0

Genotoxicity mode of action exploration of polyethylene glycol terephthalate (PET) acetic acid migration solution under repeated-dose exposure in rats 聚对苯二甲酸乙二醇酯（PET）醋酸迁移液对大鼠重复剂量暴露的遗传毒性作用模式探讨

IF 2.5 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation research. Genetic toxicology and environmental mutagenesis

Pub Date : 2025-09-09 DOI: 10.1016/j.mrgentox.2025.503886

Liang Wang , Li Cao , Xiaoya Wang , Yufei Liu , Weiwei Zhang , Yurui Gou , Jun He , Jiao Huo , Xiaomeng Li , Jinyao Chen

As a commonly used material that contacts food, polyethylene glycol terephthalate (PET) may interact with food, and since certain components can migrate, this has become a food safety concern. This study aims to investigate the genotoxicity of PET acetic acid migration solution and its toxic mode of action using an in vivo multi-endpoint genotoxicity evaluation system and quantitative liver proteomics analysis. Forty-eight male Sprague–Dawley rats were randomly divided into eight groups: the PET acetic acid migration solution group, the acetic acid group, the phosphate-buffered saline (PBS) control group, the N-ethyl-N-nitrosourea (ENU) positive control group, and their corresponding satellite groups. PBS and ENU were administered by gavage, while the PET acetic acid migration solution and acetic acid were administered orally in the drinking water. The exposure duration was 35 days, followed by a recovery period of 15 days. The PET acetic acid migration solution can cause heart, liver, and kidney injury in rats. On the 15th day, mutations were seen in the Pig-a gene test. On the 35th day, DNA damage was observed in peripheral blood and liver cells. Gene ontology (GO) analysis of the liver proteomics revealed enrichment in DNA metabolism and binding processes, while Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis highlighted the DNA replication pathway. Immunohistochemical analysis demonstrated a significant increase in 8-hydroxydeoxyguanosine (8-OHdG) and a decrease in single-stranded-binding (SSB) protein in the PET acetic acid migration solution group. In summary, the PET acetic acid migration solution has the potential to induce DNA damage, possibly by inhibiting DNA replication and DNA repair pathways. However, the likelihood of genetic toxicity is low.

聚乙二醇对苯二甲酸乙二醇酯（PET）作为一种常用的与食品接触的材料，可能与食品发生相互作用，并且由于某些成分可以迁移，这已经成为食品安全问题。本研究旨在通过体内多终点遗传毒性评价系统和定量肝脏蛋白质组学分析，探讨PET乙酸迁移液的遗传毒性及其毒性作用方式。48只雄性Sprague-Dawley大鼠随机分为8组：PET乙酸迁移液组、乙酸组、磷酸盐缓冲盐水（PBS）对照组、n -乙基-n -亚硝基脲（ENU）阳性对照组及相应的卫星组。PBS和ENU灌胃，PET醋酸迁移液和醋酸灌胃。暴露时间为35天，恢复期为15天。PET醋酸迁移液可引起大鼠心、肝、肾损伤。第15天，在猪-a基因测试中发现了突变。第35天，外周血和肝细胞均出现DNA损伤。肝脏蛋白质组学的基因本体（GO）分析揭示了DNA代谢和结合过程的富集，而京都基因与基因组百科全书（KEGG）分析则强调了DNA复制途径。免疫组织化学分析显示，PET醋酸迁移液组8-羟基脱氧鸟苷（8-OHdG）显著增加，单链结合（SSB）蛋白显著减少。综上所述，PET乙酸迁移液可能通过抑制DNA复制和DNA修复途径诱导DNA损伤。然而，遗传毒性的可能性很低。

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引用次数: 0

Protective effects of nicotinamide mononucleotide on DNA damage and cell death in A549 cells and aging in C. elegans caused by hydrogen peroxide 烟酰胺单核苷酸对过氧化氢致秀丽隐杆线虫A549细胞DNA损伤、细胞死亡及衰老的保护作用

IF 2.5 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation research. Genetic toxicology and environmental mutagenesis

Pub Date : 2025-08-30 DOI: 10.1016/j.mrgentox.2025.503885

Chuncao He , Xueying Sun , Ting Xu , Xiaoqiang Hu , Jinyi Han , Kexin Xu , Qin Song , Ting Duan , Jun Yang

Oxidative stress is a major factor for aging. Nicotinamide mononucleotide (NMN) is a naturally occurring bioactive nucleotide and a precursor for nicotinamide adenine dinucleotide (NAD⁺), and accumulating evidences have shown that NMN is a promising anti-aging agent, however, the underlying molecular mechanisms remain to be elucidated. Therefore, in the current study, the protective effects of NMN on oxidative stress-induced damage to cells, in particular, the various types of cell death induced by oxidative stress, were evaluated. It was found that NMN inhibited hydrogen peroxide (H₂O₂)-induced decrease in A549 cell viability·H₂O₂-triggered reactive oxygen species (ROS) production was also diminished by NMN. Furthermore, results from 8-hydoxy 2 deoxyguanosine (8-OHdG) level, alkaline comet assay, and γ-H2AX foci formation indicated that NMN protected cells from H₂O₂-induced DNA damage. Detailed cell death analysis revealed that H₂O₂ caused A549 cell death mainly through apoptosis and ferroptosis, but not necroptosis or parthanatos, and NMN could effectively inhibit the apoptosis and ferroptosis pathways, thus protected cells from H₂O₂-induced cell death. Finally, we validated NMN protected against H₂O₂-induced organismal senescence in C. elegans. Taken together, these results suggests that NMN is a potent agent against oxidative stress, which could contribute to its anti-aging effects.

氧化应激是衰老的主要因素。烟酰胺单核苷酸（NMN）是一种天然存在的生物活性核苷酸，是烟酰胺腺嘌呤二核苷酸（NAD+）的前体，越来越多的证据表明NMN是一种很有前景的抗衰老剂，但其潜在的分子机制仍有待阐明。因此，在本研究中，我们评估了NMN对氧化应激诱导的细胞损伤，特别是氧化应激诱导的各种类型的细胞死亡的保护作用。研究发现，NMN抑制过氧化氢（H2O2）诱导的A549细胞活力下降，NMN也减少H2O2引发的活性氧（ROS）的产生。此外，8-羟基2脱氧鸟苷（8-OHdG）水平、碱性彗星试验和γ-H2AX灶形成的结果表明，NMN可以保护细胞免受h2o2诱导的DNA损伤。详细的细胞死亡分析表明，H2O2主要通过凋亡和ferroptosis导致A549细胞死亡，而不是通过坏死性死亡或旁咽下，NMN可以有效抑制凋亡和ferroptosis途径，从而保护细胞免受H2O2诱导的细胞死亡。最后，我们验证了NMN对h2o2诱导的秀丽隐杆线虫的机体衰老具有保护作用。综上所述，这些结果表明NMN是一种有效的抗氧化应激剂，这可能有助于其抗衰老作用。

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引用次数: 0

Perchloroethylene: Genotoxicity and cytotoxicity in human peripheral blood lymphocytes in vitro 过氯乙烯：体外对人外周血淋巴细胞的遗传毒性和细胞毒性

IF 2.5 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation research. Genetic toxicology and environmental mutagenesis

Pub Date : 2025-08-26 DOI: 10.1016/j.mrgentox.2025.503884

Tülay Aşkın Çelik , Ümit Ünsal

Perchloroethylene (PCE), a widely used solvent, is classified as a probable human carcinogen. We have studied its genotoxicity, clastogenicity, and cytotoxicity in cultured human peripheral lymphocytes (HPLs). Cytogenetic tests used were the chromosomal aberration (CA), sister chromatid exchange (SCE), mitotic index (MI), replication index (RI), and micronucleus (MN) assays. Positive results were obtained with each of these assays: a dose-dependent increase in CA, a significant increase in SCE, a significant decrease in MI and RI, and an increase in MN frequency at the highest concentration of PCE. These results demonstrate that PCE induces significant genotoxic and clastogenic effects in human peripheral lymphocytes.

全氯乙烯（PCE）是一种广泛使用的溶剂，被列为可能的人类致癌物。我们研究了其在培养的人外周血淋巴细胞（HPLs）中的遗传毒性、致裂性和细胞毒性。使用的细胞遗传学检测包括染色体畸变（CA）、姐妹染色单体交换（SCE）、有丝分裂指数（MI）、复制指数（RI）和微核（MN）测定。这些实验均获得阳性结果：CA呈剂量依赖性增加，SCE显著增加，MI和RI显著降低，在PCE浓度最高时MN频率增加。这些结果表明，PCE对人外周血淋巴细胞具有显著的遗传毒性和致裂作用。

引用次数: 0

The PPAR-β/δ agonist GW0742 alleviates DNA damage and lupus nephritis in an animal model of systemic lupus erythematosus via restoring DNA repair gene expression PPAR-β/δ激动剂GW0742通过恢复DNA修复基因表达，减轻系统性红斑狼疮动物模型的DNA损伤和狼疮肾炎

IF 2.5 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation research. Genetic toxicology and environmental mutagenesis

Pub Date : 2025-08-01 DOI: 10.1016/j.mrgentox.2025.503881

Mohamed S.M. Attia , Mohammed A. Al-Hamamah , Sheikh F. Ahmad , Ahmed Nadeem , Saleh A. Bakheet , Mushtaq A. Ansari , Gamaleldin I. Harisa , Talha Bin Emran , Sabry M. Attia

Systemic lupus erythematosus (SLE) is a persistent autoimmune inflammatory disease associated with an elevated risk of kidney damage. The etiology of SLE remains unclear; nevertheless, current investigations increasingly indicate that increased DNA damage and deficiencies in the mechanisms of its repair might contribute to its pathogenesis, necessitating the identification and management of the disease. Therapies for SLE have improved considerably over recent decades. However, drugs that specifically address the underlying pathogenic pathways, such as potential DNA repair deficiencies, are unavailable. In this situation, drugs that ameliorate the altered DNA damage/repair might be a possible option for treating SLE. We investigated whether GW0742, an agonist of the peroxisome proliferator activator receptor β/δ, improves kidney function and ameliorates DNA damage/repair alteration in female lupus-prone mice. The results demonstrate that the repeated administration of GW0742 significantly ameliorates DNA damage/repair alteration in the bone marrow cells of lupus-prone animals, as assessed by the comet test. Furthermore, the administration of GW0742 restored the impaired DNA damage/repair pathway in lupus-prone mice by decreasing Gadd45a and p53 expression while elevating Ogg1 and Parp1 in the kidney tissues. The administration of GW0742 recovered the disturbed kidney redox balance in lupus-prone mice. It also ameliorated the altered biochemical markers related to lupus nephritis, as demonstrated by reduced levels of urinary protein and albumin, serum creatinine, and BUN. GW0742's protective outcome was verified by its ability to diminish the increased inflammatory marker MPO activity and ameliorated kidney histological characteristics of SLE. This suggests that GW0742 is a promising novel therapeutic agent for managing SLE and its associated complications.

系统性红斑狼疮（SLE）是一种持续性自身免疫性炎症性疾病，与肾损害风险升高相关。SLE的病因尚不清楚；然而，目前的研究越来越多地表明，DNA损伤的增加及其修复机制的缺陷可能导致其发病机制，因此有必要对该疾病进行识别和管理。近几十年来，SLE的治疗方法有了很大的改进。然而，专门针对潜在致病途径的药物，如潜在的DNA修复缺陷，是不可用的。在这种情况下，改善DNA损伤/修复改变的药物可能是治疗SLE的一种可能选择。我们研究了GW0742，一种过氧化物酶体增殖物激活物受体β/δ的激动剂，是否能改善雌性狼疮易感小鼠的肾功能和改善DNA损伤/修复改变。结果表明，重复给药GW0742显著改善狼疮易感动物骨髓细胞的DNA损伤/修复改变，如彗星试验所评估的那样。此外，GW0742通过降低Gadd45a和p53的表达，同时提高肾组织中Ogg1和Parp1的表达，恢复了狼疮易感小鼠受损的DNA损伤/修复途径。GW0742可恢复狼疮易感小鼠的肾脏氧化还原平衡。它还改善了与狼疮肾炎相关的生化标志物的改变，如尿蛋白和白蛋白、血清肌酐和BUN水平的降低。GW0742的保护效果通过其降低炎症标志物MPO活性和改善SLE肾脏组织学特征的能力得到证实。这表明GW0742是一种很有前景的治疗SLE及其相关并发症的新型药物。

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引用次数: 0

Effect of xthA deletion in the activation of the E. coli SOS response by gamma rays, UV-C light and other genotoxic agents xthA缺失对γ射线、UV-C光和其他基因毒性物质激活大肠杆菌SOS反应的影响

IF 2.5 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation research. Genetic toxicology and environmental mutagenesis

Pub Date : 2025-08-01 DOI: 10.1016/j.mrgentox.2025.503879

Jorge Serment-Guerrero , Viridiana Dominguez-Monroy , Martha Patricia Cruces-Martinez , Jorge Luis Fuentes-Lorenzo , Silvia Cristina Serment-Gonzalez

The SOS response contains a set of about 45 genes related to the repair or tolerance to DNA damage. These genes are normally blocked but when lesions upon the genetic material occur an SOS signal is generated allowing their expression. Most types of DNA lesions must be modified or processed to induce SOS. In a previous work, a model was proposed suggesting the possible paths that could be followed from the different types of lesions to the induction of the response. One of these possible routes is through the base excision repair mechanism (BER). Since in E. coli the AP endonuclease exonuclease III plays a key role in this repair pathway, in the present study we evaluate the participation of xthA product in the processing of DNA lesions made by gamma rays, UV-C light, ethyl methanesulphonate, methyl methanesulphonate, mitomycin C, hydrogen peroxide and tert-buthylhydroperoxide to trigger the SOS response. A strain defective in xthA and a wt strain were exposed to different genotoxic agents and survival and SOS induction were analyzed. The results show differences in the survival and SOS induction to each genotoxic agent between the wt strain and the xthA mutant; depending on the type of DNA damage inflicted, the SOS response level was either higher or lower compared to the wt strain. This suggests that while the AP endonuclease role of exonuclease III enzyme suppresses SOS induction when bulky and methylated lesions occur, it enhances SOS induction when the damage is generated by ROS, in agreement with a previously proposed model.

SOS反应包含一组约45个基因，这些基因与DNA损伤的修复或耐受有关。这些基因通常是被阻断的，但当遗传物质发生病变时，就会产生SOS信号，允许它们表达。大多数类型的DNA损伤必须经过修饰或处理才能诱发SOS。在之前的工作中，提出了一个模型，提出了从不同类型的病变到诱导反应的可能路径。其中一个可能的途径是通过碱基切除修复机制（BER）。由于在大肠杆菌中，AP核酸内切酶外切酶III在这一修复途径中起着关键作用，因此在本研究中，我们评估了xthA产物在伽马射线、UV-C光、甲磺酸乙酯、甲磺酸甲酯、丝裂霉素C、过氧化氢和过氧化叔丁基氢引起的DNA损伤的处理中参与SOS反应。将一株xthA缺陷菌株和一株wt菌株暴露于不同的基因毒性物质中，分析其存活和SOS诱导情况。结果表明，wt菌株和xthA突变体的存活率和对各基因毒性物质的SOS诱导存在差异；根据DNA损伤类型的不同，与wt菌株相比，SOS反应水平或高或低。这表明，虽然外切酶III酶的AP内切酶作用在大体积和甲基化病变发生时抑制SOS诱导，但当ROS产生损伤时，它会增强SOS诱导，这与先前提出的模型一致。

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引用次数: 0

Epistatic interactions in DNA repair genes as biomarkers of susceptibility for DNA damage in pesticide-exposed agricultural workers of Punjab, North-West India DNA修复基因的上位相互作用作为农药暴露农业工人DNA损伤易感性的生物标志物

IF 2.5 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation research. Genetic toxicology and environmental mutagenesis

Pub Date : 2025-08-01 DOI: 10.1016/j.mrgentox.2025.503880

Karashdeep Kaur , Rupinder Kaur

Some occupational exposures to pesticides have been associated with genotoxicity which arises from DNA single-strand breaks (SSBs), repair of DNA double-strand breaks (DSBs), DNA adduct formation, or DNA-DNA and DNA-protein cross-links. Polymorphisms in genes encoding enzymes of DNA repair pathways may modulate the individual’s susceptibility to pesticide-induced genotoxicity. A total of 450 subjects were included in this study, which comprises 225 agricultural workers exposed to complex mixtures of pesticides and 225 non-exposed controls from Punjab, North-West India. Susceptibility of OGG1 Ser326Cys (C1245G), XRCC1 Arg194Trp (C26304T), XRCC1 Arg399Gln (G28152A), XPC Lys939Gln (A2920C), XPC Ala499Val (C21151T), XPD Asp312Asn (G23591A), XPD Lys715Gln (A35931C), XPF Arg415Gln (G1244A), XPG Asp1104His (G3507C), ERCC1 3′-UTR (C8092A) and ERCC1 Asn118Asn (C354T) gene polymorphisms with pesticide-induced DNA damage was determined by Kruskal-Wallis test. The association of epistatic gene interactions with DNA damage was studied by ANOVA. The results indicated significant interactions of variant OGG1 326Ser/Cys genotype with XRCC1 194Arg/Trp and XRCC1 399Arg/Gln genotypes in increased susceptibility to DNA damage. XPC 939Gln/Gln genotype significantly interacts with XPC 499Ala/Val, XPD 312Asp/Asp and XPD 715Gln/Gln variant genotypes to increase DNA damage susceptibility. Among exposed XPF 415Gln/Gln individuals, DNA damage was significantly higher in those individuals who had variant XPG Asp/His and ERCC1 8092CA genotypes. We observed some statistically significant epistatic gene interactions in DNA repair pathways in modulating DNA damage, which may be used as biomarkers of susceptibility in pesticide-exposed agricultural workers of Punjab, North-West India.

一些职业性农药暴露与DNA单链断裂（SSBs）、DNA双链断裂（DSBs）修复、DNA加合物形成或DNA-DNA和DNA-蛋白质交联引起的遗传毒性有关。编码DNA修复途径酶的基因多态性可能调节个体对农药遗传毒性的易感性。本研究共纳入450名受试者，其中包括225名接触复杂农药混合物的农业工人和225名来自印度西北部旁遮普省的非接触对照者。采用Kruskal-Wallis试验检测OGG1 Ser326Cys （C1245G）、XRCC1 Arg194Trp （C26304T）、XRCC1 Arg399Gln （G28152A）、XPC Lys939Gln （A2920C）、XPC Ala499Val （C21151T）、XPD Asp312Asn （G23591A）、XPD Lys715Gln （A35931C）、XPF Arg415Gln （G1244A）、XPG Asp1104His （G3507C）、ERCC1 Asn118Asn （C354T）基因多态性与农药诱导DNA损伤的易感性。通过方差分析研究上位性基因相互作用与DNA损伤的关系。结果表明，变异OGG1 326Ser/Cys基因型与XRCC1 194Arg/Trp和XRCC1 399Arg/Gln基因型的交互作用显著增加了DNA损伤的易感性。XPC 939Gln/Gln基因型与XPC 499Ala/Val、XPD 312Asp/Asp和XPD 715Gln/Gln基因型显著相互作用，增加DNA损伤易感性。在暴露的XPF 415Gln/Gln个体中，变异XPG Asp/His和ERCC1 8092CA基因型个体的DNA损伤显著更高。我们观察到在DNA修复途径中调节DNA损伤的一些具有统计学意义的epistatic基因相互作用，这可能被用作印度西北部旁遮普省农药暴露农业工人的易感性生物标志物。

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引用次数: 0

Comparison of different techniques for γH2AX/pH3 biomarkers quantification for chemical genotoxicity assessment 化学遗传毒性评价中γ - h2ax /pH3生物标志物定量方法的比较

IF 2.3 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation research. Genetic toxicology and environmental mutagenesis

Pub Date : 2025-07-25 DOI: 10.1016/j.mrgentox.2025.503878

Cynthia Recoules , Chloé Huertas , Julien Vignard, Marc Audebert

Chemical risk assessment relies on in vitro genotoxicity tests. Histone modifications (γH2AX and pH3) have emerged as valuable biomarkers for genotoxicity detection. In this study, we compared three parameters (global intensity, nuclear intensity, and foci number) for the γH2AX biomarker and two parameters (global intensity and % cell in mitosis) for the pH3 biomarker. These analyzes were performed in three cell lines: human osteosarcoma U2OS cells, human hepatocellular carcinoma HepG2 cells and rat intestinal epithelial IEC-6 cells. Cells were exposed for 24 h to four well-characterized hazardous substances: nocodazole (aneugen), etoposide (topoisomerase inhibitor), benzo[a]pyrene (DNA adducts inducer), and tunicamycin (apoptosis inducer). The Benchmark Concentration (BMC) approach indicated that the sensitivity of the technics varied depending on both the chemical compounds and the tested cell line. The γH2AX foci analysis provided the higher sensitivity for clastogenic compounds. For the aneugenic compound, the global intensity and the proportion of mitotic cells showed similar sensitivity. Following tunicamycin treatment, we only detected increase in γH2AX nuclear intensity in U2OS cell model, indicating that apoptosis does not interfere with γH2AX global intensity or foci number, thereby minimizing the risk of false positive results. Finally, we observed that compared to the other methods, global intensity permitted to monitor weaker fold inductions of the biomarkers. By comparing the different quantification methods of histone modifications used as genotoxicity biomarkers, this study highlights the most suitable parameters to be used.

化学品风险评估依赖于体外遗传毒性试验。组蛋白修饰（γ - h2ax和pH3）已成为遗传毒性检测的有价值的生物标志物。在这项研究中，我们比较了γ - h2ax生物标志物的三个参数（全局强度、核强度和焦点数）和pH3生物标志物的两个参数（全局强度和有丝分裂中细胞百分比）。这些分析是在三种细胞系中进行的：人骨肉瘤U2OS细胞、人肝癌HepG2细胞和大鼠肠上皮IEC-6细胞。将细胞暴露于四种具有明确特征的有害物质中24 h：诺可达唑（aneugen）、依托泊苷（拓扑异构酶抑制剂）、苯并[a]芘（DNA加合物诱导剂）和tunicamycin（凋亡诱导剂）。基准浓度（BMC）方法表明，该技术的灵敏度取决于化学成分和被测细胞系。γ - h2ax聚焦分析对致裂化合物具有较高的灵敏度。对于非优生化合物，整体强度和有丝分裂细胞的比例表现出相似的敏感性。tunicamycin处理后，我们在U2OS细胞模型中仅检测到γ - h2ax核强度的增加，表明凋亡不干扰γ - h2ax的整体强度或灶数，从而最大限度地降低了假阳性结果的风险。最后，我们观察到，与其他方法相比，全局强度允许监测较弱的生物标志物诱导。通过比较不同的组蛋白修饰作为遗传毒性生物标志物的定量方法，本研究突出了最适合使用的参数。

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引用次数: 0

Investigation of chemicals with inconsistent Ames results using miniaturized Ames test systems 使用小型Ames测试系统对具有不一致Ames结果的化学品进行调查

IF 2.3 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation research. Genetic toxicology and environmental mutagenesis

Pub Date : 2025-07-10 DOI: 10.1016/j.mrgentox.2025.503874

Csaba Boglári, Cécile Koelbert, Nicole Weiland-Jaeggi

The Ames assay is a bacterial reverse gene mutation test that has been a cornerstone of mutagenicity assessment. The emphasis now is on developing miniaturized versions of the Ames test in Petri dish to require less chemicals, reagents, and liver microsomal S9 fraction, thus reducing the number of test animals needed and to better comply with 3R principles. Miniaturized Ames assay versions promote high throughput testing of multiple samples during compound screening and facilitate the early exclusion of genotoxic agents during the product development process. Existing experimental data shed light on a high concordance between results gained with miniaturized Ames tests and the Petri dish-based method, yet further testing is required to corroborate these findings. We selected compounds with previously reported inconsistent outcomes and assessed their mutagenic potential using two miniaturized Ames assay formats, an agar-based 6-well plate test, and a liquid microplate fluctuation format assay. Investigation of dose-response curves of known mutagens with varying bacterial cell density inputs revealed that the sensitivity of the 6-well agar plate format might be increased by applying the right bacterial cell density. Our analysis indicates an overall good correlation between the results acquired with the two miniaturized Ames assay formats despite the conceptual characteristic differences in the assay paradigms. Furthermore, the miniaturized Ames assay formats could detect several chemicals as positive at lower concentrations than the Petri dish-based assay. Our findings indicate that the miniaturized Ames assay variations show promise as a reliable method for assessing chemical mutagenicity, while also aligning with environmentally friendly testing strategies. Finally, our results show that the miniaturized assays may exhibit increased sensitivity to impurities, potentially contributing to the observed discrepancies in the obtained results.

Ames试验是一种细菌反向基因突变试验，已成为致突变性评估的基石。现在的重点是在培养皿中开发小型化的Ames试验，以减少所需的化学品、试剂和肝微粒体S9分数，从而减少所需的试验动物数量，并更好地遵守3R原则。小型化的Ames检测版本在化合物筛选过程中促进了多个样品的高通量测试，并有助于在产品开发过程中早期排除基因毒性试剂。现有的实验数据表明，小型化Ames测试和基于培养皿的方法获得的结果高度一致，但需要进一步的测试来证实这些发现。我们选择了先前报道结果不一致的化合物，并使用两种小型化的Ames试验格式（琼脂基6孔板试验和液体微孔板波动格式试验）评估了它们的致突变性潜力。对已知诱变剂在不同细菌细胞密度下的剂量响应曲线的研究表明，适当的细菌细胞密度可以提高6孔琼脂平板格式的灵敏度。我们的分析表明，尽管在分析范式中存在概念特征差异，但在两种小型化的Ames分析格式中获得的结果之间总体上具有良好的相关性。此外，小型化的Ames检测格式可以在比培养皿检测更低的浓度下检测到几种化学物质的阳性。我们的研究结果表明，小型化的Ames试验变体有望作为评估化学诱变性的可靠方法，同时也与环境友好型测试策略相一致。最后，我们的结果表明，小型化的分析可能会对杂质表现出更高的敏感性，这可能会导致观察到的结果差异。

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引用次数: 0

Photogenotoxicity of N-nitrosoproline plus simultaneous UVA irradiation in human-derived keratinocytes n-亚硝基脯氨酸加同时UVA照射对人源性角质形成细胞的光毒性

IF 2.3 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation research. Genetic toxicology and environmental mutagenesis

Pub Date : 2025-07-01 DOI: 10.1016/j.mrgentox.2025.503876

Naomi Tomozane , Noriko Tanaka , Sakae Arimoto-Kobayashi

In this study, we investigated the genotoxicity of N-nitrosoproline (NPRO) in human-derived keratinocytes (HaCaT and NCTC2544 cells) using simultaneous UVA irradiation without metabolic activation. NPRO plus UVA exhibited dose- and intensity-dependent micronuclei formation in the keratinocytes, as well as nitric oxide (NO) production. The action spectra of genotoxicity and NO formation from NPRO plus UVA followed the absorption curve of NPRO, indicating that photoenergy was absorbed by the NPRO-triggered photoreaction. A significant increase in cyclic guanosine monophosphate (cGMP) was observed in HaCaT cells treated with NPRO plus UVA. NO production from UVA-irradiated NPRO paralleled micronuclei formation, and the phototoxicity of NPRO may have simultaneously interfered with the cGMP-related signaling systems caused by NO from photoactivated NPRO.

在这项研究中，我们研究了n-亚硝基脯氨酸（NPRO）在无代谢激活的同时UVA照射下对人源性角质形成细胞（HaCaT和NCTC2544细胞）的遗传毒性。NPRO加UVA在角质形成细胞中表现出剂量和强度依赖的微核形成，以及一氧化氮（NO）的产生。NPRO + UVA的遗传毒性和生成NO的作用谱符合NPRO的吸收曲线，说明NPRO触发的光反应吸收了光能。在NPRO加UVA处理的HaCaT细胞中，cGMP显著增加。uva辐照NPRO产生的NO与微核形成平行，NPRO的光毒性可能同时干扰了NPRO光活化NO引起的cgmp相关信号系统。

引用次数: 0