Chemical Research in Toxicology最新文献

{"title":"High-Resolution Mass Spectrometric Analysis of Selected DNA Adducts in Smokeless Tobacco Users’ Oral Cells","authors":"Guang Cheng,&nbsp;Irina Stepanov,&nbsp;Dorothy K. Hatsukami,&nbsp;Matthew W. Luedtke,&nbsp;Xianghua Luo,&nbsp;Qing Cao,&nbsp;Yingchun Zhao,&nbsp;Stephen S. Hecht","doi":"10.1021/acs.chemrestox.6c00328","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00328","url":null,"abstract":"<p>Smokeless tobacco, used by more than360 million peopleworldwide,is an accepted cause of cancers of the oral cavity, esophagus, andpancreas. DNA adducts are considered as critical intermediates inthe carcinogenic process, but there are no published studies thathave used structure-specific methods to identify and quantify oralcell DNA adducts in people who use smokeless tobacco. In the studypresented here, we used liquid chromatography-nanoelectrospray ionization-highresolution tandem mass spectrometry to identify and quantify DNA adductsin oral cells of 24 individuals who use smokeless tobacco and 25 individualsnot using any tobacco or nicotine product. We quantified the followingDNA adducts: (8<em>R</em>/<em>S</em>)-3-(2′-deoxyribos-1′-yl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-<em>a</em>]purine-10(3<em>H</em>)-one (γ-OH-Acr-dGuo)from acrolein; (6<em>S</em>,8<em>S</em> and 6<em>R</em>,8<em>R</em>)-3-(2′-deoxyribos-1′-yl)-5,6,7,8-tetrahydro-8-hydroxy-6-methylpyrimido[1,2-<em>a</em>]purine-10(3<em>H</em>)-one [(<em>S</em>,<em>R</em>)γ-OH-Cro-dGuo] from crotonaldehyde and/oracetaldehyde; 3-methyladenine (3-Me-Ade); 7-ethylguanine (7-Et-Gua);and 8-oxo-deoxyguanosine (8-oxo-dGuo). Levels [median (min, max)]fmol/μmol dGuo or Gua, in samples in which analytes were detected,were: γ-OH-Acr-dGuo [350 (169, 2217) vs 114 (14, 278)], (6<em>S</em>,8<em>S</em> and 6<em>R</em>,8<em>R</em>)γ-OH-Cro-dGuo [1058 (222, 2569) vs not detected], and 7-Et-Gua[2445 (1052, 5389) vs 102 (13, 627)], which were significantly greaterin the oral cell DNA of individuals who use smokeless tobacco thanin those not using any tobacco or nicotine product (all adjusted <em>Ps</em> &lt; 0.01), while amounts of 3-Me-Ade [3739 (93, 11495)vs 1447 (318, 3596) fmol/μmol Gua, adjusted <em>P</em> = 0.052] and 8-oxo-dGuo [1520 (513, 5232) vs 2092 (433, 3325) pmol/μmoldGuo, adjusted <em>P</em> = 0.13] were not significantly differentbetween the two groups. The sizable and significant elevations of7-Et-Gua and (6<em>S</em>,8<em>S</em> and 6<em>R</em>,8<em>R</em>)γ-OH-Cro-dGuo in oral cell DNAwhen smokeless tobacco was used versus controls were particularlynotable and unexpected. The results of this study provide some potentiallyimportant new data regarding DNA adduct levels in oral cells of peoplewho use smokeless tobacco.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 8","pages":"1617–1624"},"PeriodicalIF":4.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Dual Role of DNA Cross-linking Agents: From Genotoxicity to cGAS-STING-Mediated Immune Activation","authors":"Jingao Li,&nbsp;Luo Wang,&nbsp;Xuqing Mao,&nbsp;Dongmei Hu,&nbsp;Qinyue Lu,&nbsp;Chengyi Shi,&nbsp;Yifeng Wang,&nbsp;Zhaowei Meng,&nbsp;Heli Fan,&nbsp;Huabing Sun","doi":"10.1021/acs.chemrestox.6c00132","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00132","url":null,"abstract":"<p>DNA cross-linking agents remain a cornerstone of cancerchemotherapy.While their efficacy was traditionally attributed to direct genotoxicity,blocking DNA replication and transcription to induce cell death, recentevidence suggests that their therapeutic activity also involves innateimmune activation. Aberrant repair of DNA lesions generates cytosolicDNA fragments, which are sensed by cyclic GMP-AMP synthase (cGAS).This activates the cGAS-STING (stimulator of interferon genes) pathway,driving the production of type I interferons and proinflammatory cytokines,thereby eliciting antitumor immunity. This review traces the moleculartrajectory from DNA lesions formation to immune stimulation. We summarizethe chemistry of classical and emerging DNA cross-linking agents,the replication stress they impose, and DNA damage response (DDR)generating cytosolic DNA as a trigger for innate immune activation.We then highlight key mechanistic insights into cGAS-STING signaling.Finally, we discuss therapeutic opportunities in their combinationswith STING agonists for more effective immune activation. Collectively,this framework reframes DNA cross-linking agents from simple cytotoxinsinto in situ vaccines that harness DNA damage-driven immunity.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 8","pages":"1468–1482"},"PeriodicalIF":4.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, Synthesis, and Evaluation of Alkoxyamine Anticancer Prodrugs Bearing Galactoside as an Enzyme-Activated Trigger","authors":"Yuliana A. Kolesnikova,&nbsp;Alexander A. Abramov,&nbsp;Daria D. Eskova,&nbsp;Darya E. Votkina,&nbsp;Evgenii V. Plotnikov,&nbsp;Evgeny V. Tretyakov,&nbsp;Sylvain R.A. Marque,&nbsp;Gérard Audran,&nbsp;Pavel S. Postnikov,&nbsp;Elena V. Stepanova,&nbsp;Pavel V. Petunin","doi":"10.1021/acs.chemrestox.6c00193","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00193","url":null,"abstract":"<p>Enzyme-inducedcytotoxicity can be considered the main challengein modern cancer therapy that provides unique opportunities for targetedapoptosis. To address this challenge, we implemented enzyme-triggeredactivation of alkoxyamine–galactose conjugates with the formationof active carbon-centered radical species for the apoptosis of cancercells. The comparative analysis of two alkoxyamine derivatives, bearingstable and self-immolative linkers between the radical precursor andgalactose moiety, revealed the crucial role of molecular structurein anticancer activity. The study of cytotoxicity and induced oxidativestress of free amine and two galactosides revealed the enzyme-dependentnature of the activity of alkoxyamines having a self-immolative linkeragainst distinct cancer cell lines such as PC-3 (prostate adenocarcinoma),SKOV-3 (ovarian adenocarcinoma), MCF-7 (breast adenocarcinoma), A-431(epidermoid carcinoma), and Jurkat cells (human T-lymphoblastic leukemia).The collected data prove the applicability of enzyme-triggered glycosylatedalkoxyamines as a new family of targeted prodrugs against cancer.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 8","pages":"1584–1594"},"PeriodicalIF":4.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting DNA Methylation: New Paradigms and the Advent of Gene-Selective Tools","authors":"Julie Gilbert,&nbsp;Francesco Calzaferri","doi":"10.1021/acs.chemrestox.6c00218","DOIUrl":"10.1021/acs.chemrestox.6c00218","url":null,"abstract":"<p>DNA methylation canfunction as a toxic alkylation reaction exploitedby chemotherapeutic agents to induce cancer cell death. However, finelytuned DNA methylation plays a fundamental role in cellular physiology,particularly in the epigenetic regulation of gene expression. Oncethought to act solely as a repressor of gene transcription, its functionalrole has since been elucidated as genomic locus-specific and deeplyconnected with other epigenetic factors. Following the clinical approvalof DNA methyltransferase inhibitors, such as Azacitidine and Decitabine,for the treatment of hematological malignancies, considerable effortshave been devoted to developing pharmacological tools that modulateepigenetic DNA methylation. However, the lack of gene selectivityin these agents limits their therapeutic efficacy and increases off-targettoxicity. Moreover, the non-gene-selective nature of current DNA methylation-targetingmolecules fails to meet the standards required to discern the nuancedroles of DNA methylation across diverse pathophysiological contextsand genomic loci, particularly in an era where next-generation sequencingand omics technologies enable high-resolution epigenetic analyses.In this review, we examine the mechanisms and roles of DNA methylationin epigenetic regulation, evaluate the current landscape of DNA methylationmodulators, from traditional DNMT inhibitors to cutting-edge CRISPR-dCas9fusion systems and protein–protein interaction disruptors,and discuss their clinical relevance. Finally, we emphasize the needfor precise, locus-specific tools to advance both cancer researchand therapeutic strategies.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 8","pages":"1483–1502"},"PeriodicalIF":4.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148416997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3D Printing Filament Composition, Emissions, and Induced Proinflammatory Responses","authors":"Jonathan M. Beard,&nbsp;Charli S. Worth,&nbsp;Dinny Stevens,&nbsp;Amanda K. Charlton-Sevcik,&nbsp;John Hadynski,&nbsp;Joseph H. Taube,&nbsp;Souhail R. Al-Abed,&nbsp;Christie M. Sayes","doi":"10.1021/acs.chemrestox.6c00128","DOIUrl":"10.1021/acs.chemrestox.6c00128","url":null,"abstract":"<p>This study addresses current gaps in the 3D printingliteraturefor filament composition (polymer type, color, and brand), aerosolemissions, and human health risks. Six metals (aluminum, magnesium,manganese, chromium, iron, and copper) were found in nonmetal filamentsdepending on polymer type, color, and brand using inductively coupledplasma-mass spectrometry. For copper- and steel-filled filaments,scanning electron microscopy and elemental analysis indicated a highermetal concentration within the filaments than on the surface. MoreVOCs were emitted from acrylonitrile butadiene styrene (ABS) filamentscompared to polylactic acid (PLA) filaments, according to thermaldesorption unit samples analyzed by gas chromatography. Styrene, emittedfrom ABS filaments, appears to pose the greatest potential healthrisk among known VOCs, given its concentration and reported effects.Toluene and benzaldehyde were emitted in lower concentrations fromboth ABS and PLA filaments and may pose a potential risk to humanhealth. Based on three inflammatory markers across two exposure timesusing BEAS-2B epithelial lung cells, steel showed the highest proinflammatoryresponse, possibly due to chromium and overall particulate matter.3D printer users should minimize aerosolized emissions by taking properprecautions, such as ensuring adequate ventilation and wearing facemasks, particularly during extended exposure.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 8","pages":"1546–1558"},"PeriodicalIF":4.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ADMET-XSpec: A Tool for Systematic Cross-Species Data Integration in ADMET Prediction","authors":"Hubert Rybka,&nbsp;Konrad Masztalerz,&nbsp;Sabina Podlewska","doi":"10.1021/acs.chemrestox.5c00562","DOIUrl":"10.1021/acs.chemrestox.5c00562","url":null,"abstract":"<p>The rapid expansionof in silico methodologies has reshaped moderndrug discovery and toxicology research; however, robust predictionof ADMET endpoints remains limited by the scarcity and heterogeneityof experimental data. In particular, toxicological data sets are oftenfragmented across species, complicating the development of reliableand generalizable machine learning models. To address this challenge,we introduce a dedicated Python-based computational package, ADMET-XSpec,designed for the systematic development, training, and evaluationof ML models with an explicit consideration of interspecies data integration.The framework enables controlled incorporation of chemical space originatingfrom different species and different assay types, allowing users toflexibly construct single-species models, as well as models augmentedwith cross-species information. This design facilitates systematicinvestigation of how additional data from other organisms influencemodel performance without imposing assumptions inherent to specifictransfer learning paradigms. By supporting standardized preprocessing,scalable integration of heterogeneous data sets, and rigorous benchmarking,the proposed tool provides a unified environment for studying cross-specieseffects in ADMET modeling. Overall, this work delivers a practicalresource for the ADMET modeling community and offers insights intohow interspecies and interassay data integration can improve modelrobustness and generalizability while clarifying the conditions underwhich cross-species and cross-assay data information is beneficialfor predictive toxicology. The package is freely available at https://github.com/hubertrybka/admet-xspec. ADMET-XSpec advances the state of the art by providing the firstdedicated framework for controlled interspecies and interassay dataintegration in ADMET modeling, offering quantitative guidance on whenand how cross-species and cross-assay data improve predictive performance.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 8","pages":"1518–1531"},"PeriodicalIF":4.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148534540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nano- and Microplastics and Gastrointestinal Toxicity","authors":"Sarawut Sangkham,&nbsp;Anh Tuan Ta","doi":"10.1021/acs.chemrestox.6c00274","DOIUrl":"10.1021/acs.chemrestox.6c00274","url":null,"abstract":"<p>Increasing global plastic production has intensifiedhuman exposureto nano- and microplastics (NMPs) through food, water, and air. Emergingevidence links NMP exposure to oxidative stress, inflammation, microbiomedisruption, and metabolic dysfunction, although human exposure andhealth risk data remain limited.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 8","pages":"1465–1467"},"PeriodicalIF":4.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148519608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential Mutagenic Response of Rat Liver and Lung to Nicotine-Derived Nitrosamine Ketone (NNK)","authors":"Robert A. Jolly,&nbsp;Jessica Noteboom,&nbsp;Danielle P. M. LeBlanc,&nbsp;Francesco Marchetti,&nbsp;Katie L. Cavanagh,&nbsp;Sheroy Minocherhomji","doi":"10.1021/acs.chemrestox.6c00154","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00154","url":null,"abstract":"<p>Nitrosamines (NA) are chemical impurities that are presentin tobacco,foods, more recently in some pharmaceuticals and are associated withgenotoxicity and carcinogenicity. We evaluated the in vivo mutagenicityof nicotine-derived nitrosamine ketone (NNK) or 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone,a model compound used as an anchor molecule to estimate carcinogenicpotency of unknown nitrosamine impurities. Big Blue rats were treatedwith NNK at doses ranging from 0.001 to 30 mg/kg for 28 days, followingwhich liver and lung tissue were harvested 3 days later for nucleargenomic DNA isolation. Mutations in liver and lung were assessed withthe <em>cII</em> transgene assay and endogenous genomic lociusing Duplex Sequencing (DupSeq), a highly validated error-correctedsequencing (ECS) technology. The no genotoxic effect level (NOGEL)was 1 mg/kg in liver and 0.1 mg/kg in lung while the benchmark dose(BMD) analysis for <em>cII</em> mutagenicity determined aBMDL₅₀ of 1.3 mg/kg in liver and 0.12 mg/kg in lung, consistentwith lung being the more sensitive target organ for carcinogenicityfor NNK. ECS-derived mutagenicity was highly correlated with <em>cII</em>-derived mutagenicity. Interestingly, the types of mutationsformed appeared to be tissue-specific with higher <em>C</em> &gt; <em>T</em> transitions and lower <em>T</em> &gt;G transversions in lung compared to liver, differences that may reflecttissue-specific DNA repair capacity and/or metabolic differences.Collectively, these data support the use of in vivo mutagenicity data─fromboth TGR cII and ECS methods─for human health and cancer riskcharacterization of nitrosamines and for estimating acceptable dailyintakes for unknown nitrosamine drug substance related impurities.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 8","pages":"1571–1583"},"PeriodicalIF":4.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular Uptake, Intracellular Fate, and Cytotoxicity of Micro- and Nanoparticulate Nickel Substances in Human Lung Cells","authors":"Hanna L. Karlsson,&nbsp;Abishek Arora,&nbsp;Gunilla Herting,&nbsp;Luisa Path,&nbsp;Samuel Buxton,&nbsp;Tara Lyons-Darden,&nbsp;Inger Odnevall","doi":"10.1021/acs.chemrestox.6c00074","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00074","url":null,"abstract":"<p>Nickel (Ni) is utilized in a wide range of applications,includingthe production of austenitic stainless steel, superalloys, rechargeablebatteries, catalysts, and foundry products. Historically high exposureto mixed Ni dust has been associated with various health effects,including an increased risk of respiratory cancer. Different chemicalforms of Ni exhibit distinct physicochemical properties and biologicaleffects, and the role of these properties, including nanoparticles(NPs) vs microparticles (MPs), in the cellular uptake and fate isnot completely understood. This study aims to explore the uptake,intracellular fate, and cytotoxicity of eight well-characterized Nisubstances in BEAS-2B cells. Characterization was conducted usingscanning electron microscopy, X-ray photoelectron spectroscopy, anddynamic light scattering. Uptake in BEAS-2B cells was investigatedusing transmission electron microscopy, Newport Green staining incombination with super-resolution microscopy, and atomic absorptionspectroscopy. The characterization showed that the Ni substances differedin primary size but were all highly agglomerated under the conditionstested, with Ni₃S₂ having the largest size.At 48 h and based on the same mass of added Ni, Ni₃S₂ was the most cytotoxic, followed by the water-soluble saltNiSO₄·6H₂O and Ni metal NPs with a primarysize of 80 nm (Ni80), while nickel oxide (NiO) NPs were noncytotoxicunder the tested conditions. Biodissolution (released Ni per massNi added) in cell culture medium varied substantially across substancesand generally increased with time. At 48 h, Ni biodissolution followedthis order: Ni₃S₂ (55%) &gt; Ni80 (9%) &gt;NiO MPs(4%) &gt; Ni 20 nm and NiO 80 nm (3%), &gt; NiO 20 nm (2%) &gt; NiMPs (0.3%).All sparingly soluble Ni substances were clearly observable in intracellularmembrane-bound structures in BEAS-2B cells. A key observation fromthe quantitative uptake was the distinctly lower uptake of Ni ionsfrom the water-soluble NiSO₄·6H₂O comparedto the sparingly soluble Ni substances. There was thus no clear correlationbetween apparent uptake and cytotoxicity. After fractionation intocytosolic, nuclear, and particulate fractions, followed by analysisof dissolved Ni from the particles within the cells, the three substancesshowing the highest amount of Ni per added Ni mass (indicating bothuptake and intracellular Ni ion release) in both cytosol and nucleuswere Ni20 NPs, Ni MPs, and Ni₃S₂. Super-resolutionmicroscopy indicated increased Newport Green fluorescence, suggestiveof intracellular Ni accumulation, predominantly in cells exposed toNi MPs and Ni₃S₂. However, the findings werenot sufficiently robust to allow firm conclusions. These findingshighlight the complex interplay between biodissolution, cellular uptakeand cytotoxicity of Ni substances.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 8","pages":"1532–1545"},"PeriodicalIF":4.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Oxidative DNA Lesion 6-Oxo-M1dG is a Potent Replication Block, Inducing Deletions and Base Substitution Mutations In Vivo","authors":"Nina E. Gubina,&nbsp;Plamen P. Christov,&nbsp;Lawrence J. Marnett,&nbsp;John M. Essigmann,&nbsp;Bogdan I. Fedeles","doi":"10.1021/acs.chemrestox.6c00141","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00141","url":null,"abstract":"<p>One of the most prevalentexocyclic DNA adducts is 3-(2-deoxy-β-D-erythro-pentofuranosyl)pyrimido[1,2-α]purin-10(3H)-one (M₁dG), an oxidativeDNA lesion that forms by the reaction of guanines in nucleic acidsand pool nucleotides with oxidation-induced base propenals or withthe lipid peroxidation product, malondialdehyde. Further oxidationconverts M₁dG to 6-oxo-M₁dG, an even more deleteriouslesion whose genotoxic and mutagenic properties have been characterizedin vitro. The present work uses a site-specifically modified viralgenome to evaluate the biochemical consequences of 6-oxo-M₁dG in <em>Escherichia coli</em> cells and contrastthem with the properties of the M₁dG parent lesion. Wefound that 6-oxo-M₁dG strongly inhibited replication, witha bypass efficiency of 1–2%, relative to an unmodified guanine.By contrast, under the same experimental conditions, the bypass efficiencyof M₁dG was 30–40%. Beyond its low bypass rate,6-oxo-M₁dG was 20 times more mutagenic than M₁dG, with the majority of mutations being single base deletions. However,when the levels of bypass polymerases were increased by inducing theSOS response, the proportion of deletions decreased, at the expenseof additional single base substitutions, primarily G → T andG → C mutations. Finally, two DNA repair pathways─thedirect reversal dioxygenase AlkB and glycosylase MutY─wereinvestigated for their putative activity on 6-oxo-M₁dG.The results indicated that neither system was capable of repairingthis highly mutagenic lesion.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 8","pages":"1559–1570"},"PeriodicalIF":4.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}