Chemical Research in Toxicology最新文献

{"title":"L-System Transporters Control Uptake and Toxicity of Methylmercury Cysteine Complexes in Larval Zebrafish","authors":"Ashley K. James,&nbsp;Susan Nehzati,&nbsp;Natalia V. Dolgova,&nbsp;Tracy C. MacDonald,&nbsp;Kelly L. Summers,&nbsp;Graham N. George,&nbsp;Ingrid J. Pickering","doi":"10.1021/acs.chemrestox.6c00263","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00263","url":null,"abstract":"<p>Transport of methylmercury species has long been attributedtothe L-type large neutral amino acid transporters LAT1 and LAT2. However,the effects of perturbing this pathway on tissue-specific mercuryaccumulation <em>in vivo</em> have not been visualized directly.Here, we used synchrotron X-ray fluorescence imaging to examine theconsequences of competitive disruption of L-system transport on methylmercuryuptake in larval zebrafish (<em>Danio rerio</em>). Zebrafishlarvae were exposed to methylmercury-<span>l</span>-cysteine (MeHg-<span>l</span>-Cys) in the presence and absence of the LAT inhibitor 2-aminobicyclo-(2,2,1)-heptane-2-carboxylicacid (BCH) or the competing LAT substrates <span>l</span>-phenylalanineand <span>l</span>-methionine. Co-exposure with each LAT competitor resultedin markedly increased larval survival relative to MeHg-<span>l</span>-Cysalone, accompanied by decreased mercury accumulation in major targettissues, including the eye lens and brain. Exposure to methylmercury-<span>d</span>-cysteine (MeHg-<span>d</span>-Cys) also resulted in substantiallyreduced toxicity and altered tissue mercury distribution comparedwith exposure to MeHg-<span>l</span>-Cys. In contrast to previous observationswith methylmercury chloride, MeHg-<span>l</span>-Cys exposure did notcause significant selenium depletion, whereas MeHg-<span>d</span>-Cyscaused selenium depletion comparable to that observed for other mercuryforms. These findings demonstrate that L-system transport is a majordeterminant of methylmercury uptake and toxicological outcome <em>in vivo</em> and further indicate that the initial ligand environmentof methylmercury exerts a persistent influence on intracellular traffickingand downstream elemental modulation.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 10","pages":"2023–2030"},"PeriodicalIF":4.1,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210942","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":"Stronger Cytotoxicity is Exerted by Nano-/Microplastics Fibers in Lung and Intestinal Cells When Compared with Beads","authors":"Shibo Bao,&nbsp;Jiahui Wang,&nbsp;Puyang Huang,&nbsp;Hongfeng Li,&nbsp;Yuting Li,&nbsp;Jianjun Du,&nbsp;Kai Wang,&nbsp;Jiawei Song,&nbsp;Lingjun Yan,&nbsp;Wei Sun,&nbsp;Guowei Pan","doi":"10.1021/acs.chemrestox.6c00268","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00268","url":null,"abstract":"<p>Nano/micro-plastics (NMPs) have emerged as importantenvironmentalfactors due to their shape-dependent toxicity and potential threatto the environment and human health. Fibers, one of the most predominantshapes in the environment, tend to induce stronger damage when comparedwith beads. However, a lack of nanoscale fibrous NMP standards haslimited the full assessment of their health risks. Here, we preparedpolystyrene (PS)-Fibers (diameter = 500 nm and lengths of 5, 10, and20 μm). First, in respiratory and intestinal epithelial cells,PS-Fibers elicited greater cytotoxicity than PS-Beads, with 10 μmfibers having the most pronounced effects. Second, a pronounced reductionin cell viability and healing ability induced by PS-Fibers was possiblyattributed, at least in part, to length-dependent frustrated-phagocytosis-likeinteractions. These cytotoxic effects were associated with reactiveoxygen species (ROS), apoptosis, and mitochondrial damage. Furthermore,the effects were consistently more potent for fibers than beads, with10 μm fibers exhibiting the greatest toxicity. Fiber lengthwas another key factor in exerting different toxicity levels. Thus,fibrous NMPs enhanced greater cytotoxicity than spherical NMPs, withfiber length a key factor. Among fiber lengths (5/10/20 μm),10 μm PS-fibers induced the strongest cytotoxicity. ROS generationwas the primary cytotoxicity driver mediated by NMPs. Our fibrousNMP preparations may support the development of a standards databank,while our assays confirm that shape-dependent NMP toxicity could providetoxicological evidence for environmental contaminant control.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 10","pages":"2047–2062"},"PeriodicalIF":4.1,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210974","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":"A Memorial Tribute to John S. “Pete” Wishnok (1938–2026)","authors":"Peter Dedon,&nbsp;Ujjal Sarkar,&nbsp;Steven R. Tannenbaum","doi":"10.1021/acs.chemrestox.6c00360","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00360","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 9","pages":"1625–1626"},"PeriodicalIF":4.1,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149010630","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":"Refinement of Structural Alerts for Hepatic Steatosis","authors":"Anish Gomatam,&nbsp;James W. Firman,&nbsp;Georgios Chrysochoou,&nbsp;Larissa Camila Ribeiro de Souza,&nbsp;Steven J. Enoch,&nbsp;Judith C. Madden,&nbsp;Mark T. D. Cronin","doi":"10.1021/acs.chemrestox.6c00156","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00156","url":null,"abstract":"<p>With the growing focus upon application of new approachmethodologies(NAMs) within regulatory risk assessment of chemical substances, thereis a clear need for human-relevant <em>in silico</em> modelsto predict toxicity associated with chemical exposure. This work describesthe development of an <em>in silico</em> profiler for hepaticsteatosis, a condition that results from the excess accumulation offat within the liver. Toxicological data for chemicals were compiledfrom the literature, and expert judgments were made regarding theirpotential to induce steatosis. This list was used to test the 214rules developed in a previous study. Many of these rules, originallyderived from molecular initiating event (MIE)-based activation often nuclear receptor subtypes linked to liver injury, were found tobe overly general, thereby limiting their predictive utility. Thesewere supplemented with new fragments generated from the curated dataset, which, following refinement, yielded 12 alerts indicative ofsteatosis. These alerts, 10 of which had precision ≥80%, capturedchemicals with shared features and common toxicological profiles.Each was supported with a clear mechanistic rationale, by means ofan extensive literature search, and, where possible, was linked todocumented adverse outcome pathways (AOPs) describing steatosis. Ultimately,these were evaluated according to the established principles of uncertaintyanalysis and were shown to adhere to the findable, accessible, interoperable,and reusable (FAIR) Lite principles for data storage and sharing.The final collection of alerts has potential application in hazardidentification, read-across, and screening/prioritization to supporttiered assessment strategies targeting hepatic steatosis. To enableusage, a web-based implementation of the steatosis profiler that requiresonly chemical structures as input is available at https://steatosis-profiler.streamlit.app/.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 9","pages":"1756–1771"},"PeriodicalIF":4.1,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149003697","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":"Nicotine Induces Pyroptosis in Mouse Primary Pulmonary Arterial Endothelial Cells through Cx43-Mediated Activation of the NLRP3/Caspase-1/GSDMD Signaling Pathway","authors":"Xiaomin Hou,&nbsp;Xian Li,&nbsp;Guojiao Rao,&nbsp;Lingping Li,&nbsp;Liangjing Chen,&nbsp;Xiaoxia Ren,&nbsp;Ming Gao,&nbsp;Yong’e Liu,&nbsp;Yiwei Shi,&nbsp;Xiaojiang Qin","doi":"10.1021/acs.chemrestox.6c00208","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00208","url":null,"abstract":"<p>Pulmonaryarterial hypertension (PAH) is a progressive and life-threateningcardiovascular disorder characterized by pulmonary vascular remodeling,which is closely associated with pyroptosis of pulmonary arterialendothelial cells (PAECs). This study aimed to investigate whethernicotine induces pyroptosis in PAECs by regulating connexin 43 (Cx43)to activate the NLRP3/Caspase-1/GSDMD signaling pathway, thereby contributingto the pathogenesis of PAH. A nicotine-induced PAH model was establishedin C57BL/6J mice via intranasal instillation. Primary mouse PAECswere isolated and cultured for in vitro studies. Pulmonary vascularremodeling was evaluated using hemodynamic analyses and histopathologicalstaining. RT-qPCR, Western blot, and immunofluorescence were performedto assess Cx43 expression and the activation of the NLRP3/Caspase-1/GSDMDpathway in PAECs. Furthermore, endothelial-cell-specific Cx43 conditionalknockdown mice were employed to validate the essential role of Cx43in this process. We found that nicotine dose-dependently increasedright ventricular systolic pressure and induced pulmonary vascularremodeling in mice, accompanied by upregulated Cx43 expression inPAECs. Furthermore, nicotine-induced Cx43 upregulation enhanced theexpression of NLRP3, ASC, Caspase-1, and GSDMD. Nicotine also promotedNLRP3 inflammasome assembly, GSDMD cleavage, secretion of IL-1βand IL-18, and LDH release, ultimately leading to pyroptosis in PAECs.Notably, endothelial-cell-specific Cx43 knockdown significantly inhibitednicotine-induced activation of the NLRP3/Caspase-1/GSDMD pathway andattenuated downstream pyroptotic phenotypes in PAECs. Collectively,Cx43 acts as a partial mediator in nicotine-induced PAEC pyroptosis.Nicotine-mediated Cx43 upregulation largely contributes to the activationof the NLRP3/Caspase-1/GSDMD signaling pathway, thereby facilitatingpulmonary vascular remodeling and PAH progression. These findingssuggest that Cx43 may partially mediate nicotine-induced PAEC pyroptosisand PAH progression and may serve as a novel potential therapeutictarget for PAH.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 9","pages":"1821–1834"},"PeriodicalIF":4.1,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149003710","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":"Integrated Proteomic and Phosphoproteomic Profiling Reveals Mechanisms of Bisphenol A Induced Placental Toxicity","authors":"Ankit Biswas,&nbsp;Sandhini Saha,&nbsp;Naman Kharbanda,&nbsp;Tushar Kanti Maiti","doi":"10.1021/acs.chemrestox.6c00191","DOIUrl":"10.1021/acs.chemrestox.6c00191","url":null,"abstract":"<p>The global industrialization and rapid urbanization haveelevatedthe risk of toxic pollutant exposure, which affects human health,especially during pregnancy. Pregnant mothers are daily exposed tobisphenol A (BPA), a common plastic leachate and a prominent toxicpollutant present in our environment. BPA acts as an endocrine-disruptingchemical (EDC) by altering feto-placental homeostasis. This persistentand potent exposure to BPA during gestation can trigger placentaldamage, affecting trophoblast cell function and survival. BPA evendisrupts specific signaling cascades by altering post-translationalprotein phosphorylation. However, this BPA-mediated dysregulationof signaling nodes in the early trimester placenta remains unexplored.Therefore, this study investigates the global proteome changes inpost-BPA-exposed extravillous trophoblast (EVT) cells, which revealeda BPA-mediated dynamic regulation of phospho-proteome signatures andtheir associated kinases. Further inspection shows that the alteredphosphorylation of c-JUN (S63) and GSK3α (Y279) is associatedwith BPA toxicity in EVTs and the placenta. This altered phosphorylationaffects cellular signaling downstream, imparting damage upon the growingfeto-placental unit. This highlights an altered phosphorylation-mediatedmechanism of BPA toxicity in the placenta, which can cause the onsetof adverse pregnancy outcomes. Data are available via ProteomeXchangewith the identifiers PXD074780 and PXD080006.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 9","pages":"1801–1820"},"PeriodicalIF":4.1,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429387","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":"Transfer Learning Empowers the Development of Better-Performing Models for In Vivo Cardiotoxicity by Learning from In Vitro hERG Binding Data","authors":"Yuxuan Zhang,&nbsp;Yuwei Liu,&nbsp;Guijia Bi,&nbsp;Jingwen Chen","doi":"10.1021/acs.chemrestox.6c00190","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00190","url":null,"abstract":"<p>Evaluating chemical hazards, such as cardiotoxicity,is criticalfor sound chemical management but is challenging due to the labor-intensiveand time-consuming nature of <em>in vivo</em> testing. <em>In silico</em> models can efficiently and cost-effectively screenpotential cardiotoxic compounds from a large number of chemicals.However, the available small-scale <em>in vivo</em> toxicitydata sets prevent models from achieving superior prediction accuracy.Herein, a transfer learning-based graph neural network (TL-GNN) modelfor predicting <em>in vivo</em> cardiotoxicity was developedby fine-tuning from a pretrained model on a data set regarding thehuman <em>ether-a-go-go</em>-related gene binding, a molecularinitiating event that may ultimately cause cardiotoxicity. The TL-GNNmodel not only outperformed the GNN without TL and classic machinelearning models, but also those fine-tuned from GNN models pretrainedon a nonmechanistic octanol–water partition coefficient dataset and Bidirectional Encoder Representations from Transformers modelspretrained on a data set with over a million unlabeled compounds.A structure–activity landscape-based method was adopted tocharacterize the applicability domains of the TL-GNN model. The TL-GNNmodel with defined applicability domains was applied to screen approximately600,000 chemicals across diverse categories, identifying over 25,000as cardiotoxic. The robustness of the TL-GNN model suggests the potentialof the modeling strategy for complex <em>in vivo</em> toxicityby learning from adverse outcome pathway (AOP)-related <em>in vitro</em> targets.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 9","pages":"1787–1800"},"PeriodicalIF":4.1,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149003743","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":"HMGB1 and HMGB2 Are O4-Alkylthymidine-Binding Proteins","authors":"Xiaomei He,&nbsp;Xiaochen Liang,&nbsp;Pengcheng Wang,&nbsp;Junmin Chen,&nbsp;Yinsheng Wang","doi":"10.1021/acs.chemrestox.6c00155","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00155","url":null,"abstract":"<p>Exposure to endogenous and exogenous sources of alkylatingagentsleads to DNA lesions that can impair cell survival and confer genomeinstability by eliciting mutations during DNA replication and transcription.Among the DNA alkylation adducts, <em>O</em>⁴-alkylthymidine(<em>O</em>⁴-alkyldT) lesions are poorly repairedin mammalian cells, and not much is known about the cellular proteinsinvolved in the recognition of these lesions. Here, we found thatHMGB1 and HMGB2 bind directly and preferentially to <em>O</em>⁴-alkyldT-containing DNA. CRISPR-Cas9-mediated ablationof HMGB1 or HMGB2 led to an attenuated level of transcriptional bypassof these lesions, indicating diminished repair of <em>O</em>⁴-alkyldT lesions. Together, we identify HMGB1 and HMGB2as <em>O</em>⁴-alkyldT recognition proteins, andour work suggests the functions of these proteins in promoting therepair of <em>O</em>⁴-alkyldT lesions.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 9","pages":"1748–1755"},"PeriodicalIF":4.1,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149003747","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":"Shared and Distinct T-Cell Receptor Characteristics of CD4+ and CD8+ Drug-Specific T-Cells In Vitro Generated from Healthy Donors and Hypersensitive Patients","authors":"Kanoot Jaruthamsophon,&nbsp;Paul J. Thomson,&nbsp;Jirawat Pratoomwun,&nbsp;Qing Zhao,&nbsp;Mubarak Almutairi,&nbsp;Antida Sangiemchoey,&nbsp;Araya Yeunyongviwat,&nbsp;Kanitpong Phabphal,&nbsp;Hong Liu,&nbsp;Furen Zhang,&nbsp;Yonghu Sun,&nbsp;Chonlaphat Sukasem,&nbsp;Munir Pirmohamed,&nbsp;Dean J. Naisbitt","doi":"10.1021/acs.chemrestox.6c00152","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00152","url":null,"abstract":"<p>The initiation ofT-cell-mediated drug hypersensitivityreactionrequires the formation of a human leukocyte antigen (HLA)-peptide-drug-T-cellreceptor (TCR) complex. While specific interactions between HLA moleculesand drug antigens are well-defined, the characteristics of drug bindingto the TCR are unclear. Herein, we sequenced the TCR mRNAs of T-cellsthat express drug-specific HLAs (including <em>HLA</em>-<em>A*</em>31:01, <em>HLA</em>-<em>B*</em>15:02,and <em>HLA</em>-<em>B*</em>13:01) and exhibit drug-specificimmune responses against carbamazepine, sulfamethoxazole, and dapsone.This study included a total of 46 <em>in vitro</em>-generatedmonoclonal drug-specific (CD4+ and CD8+) T-cell clones. The T-cellclones were characterized for their drug-specific immune response,including HLA restriction properties, interferon-γ secretion,and cross-reactive responses. RNA isolated from these cells was usedfor TCR library preparation and subsequent long-read sequencing analyses.T-cell characterization studies showed different drug-responsivenessproperties among the clones. TCR sequencing revealed wide heterogeneityamong drug-specific T-cells. Only TCR Vβ (<em>TRBV</em>) and TCR Jβ (<em>TRBJ</em>) segments of CD4+ T-cellclones displayed noticeable shared characteristics. A YEQYF residueon CDR3β, which correlates with the preferential use of <em>TRBJ</em>2–7, was identified in 5 out of 16 CD4+ carbamazepine-specificclones. However, CD8+ drug-specific clones showed no preferentialusage of TCR α/β. Sequence alignment analyses among cloneswith similar or different drug-responsiveness properties also showedno evidence of structure–function correlation. In summary,TCR specificity against drug antigens appears to be nonrestrictive,suggesting that the extent of possible binding and its key determinantsare not rigid.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 9","pages":"1735–1747"},"PeriodicalIF":4.1,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149003749","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":"Glyoxalase 1 Regulates Methylglyoxal-Derived Nucleic Acid Adduct Burden","authors":"Alana Battad,&nbsp;Francisco Nunez,&nbsp;Seigmund W. T. Lai,&nbsp;Elise Desjarlais,&nbsp;Sarah C. Shuck","doi":"10.1021/acs.chemrestox.6c00169","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00169","url":null,"abstract":"<p>Increased metabolic stress associated with diabetes andcancerincreases the level of reactive dicarbonyl molecules that covalentlymodify nucleic acids. Methylglyoxal (MG), one of the most abundantendogenous dicarbonyl electrophiles, reacts with guanine bases inDNA and RNA to form covalent adducts that compromise genomic and RNAintegrity. The primary MG-derived adduct in DNA is <em>N</em>²-carboxyethyl deoxyguanosine (CEdG), and in RNA, it is <em>N</em>²-carboxyethyl guanosine (CEG). CEdG is mutagenic,while CEG decreases mRNA stability and impairs translation. To preventadduct formation, cells utilize the glyoxalase pathway, which is theprimary pathway for detoxifying MG. Glyoxalase 1 (GLO1) is the firstenzyme in this pathway. While GLO1 is frequently dysregulated in metabolicdisease and cancer, its role in regulating MG-induced nucleic acidadduct burden and the downstream functional consequences remains incompletelydefined. Here, we demonstrate that the genetic ablation of GLO1 significantlyincreases the accumulation of MG-derived DNA and RNA adducts. We foundthat an elevated CEdG adduct burden is associated with increased DNAstrand breaks, whereas increased CEG modifications are associatedwith reduced translational efficiency. These findings establish GLO1as a critical regulator of the endogenous nucleic acid modificationburden and mechanistically link metabolic stress-derived chemicallesions to genome instability and translational dysfunction.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 9","pages":"1772–1779"},"PeriodicalIF":4.1,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149010638","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}