Chemical Research in Toxicology最新文献

{"title":"Bisphenol A and Its Substitutes Bisphenol S/Bisphenol F in Combined Exposure Collectively Exacerbate Hepatotoxicity by Triggering Oxidative Stress and Inflammatory Responses via the PI3K-Akt/NF-κB Axis","authors":"Jianjin Guo,&nbsp;Shaojie Li,&nbsp;Junlei Hao,&nbsp;Zhou Xu,&nbsp;Yao Gao,&nbsp;Chao Fang,&nbsp;Hao Wang,&nbsp;Jiayin Wang","doi":"10.1021/acs.chemrestox.6c00348","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00348","url":null,"abstract":"<p>BisphenolA (BPA) and its substitutes bisphenol S (BPS) and bisphenolF (BPF) are environmental endocrine-disrupting chemicals that frequentlyco-occur. However, the hepatotoxic effects and underlying mechanismsof their combined exposure remain unclear. This study integrated networktoxicology, bioinformatics, molecular modeling, and <em>in vivo</em>/<em>in vitro</em> experiments to investigate how combinedexposure to BPA, BPS, and BPF collectively exacerbates hepatotoxicityin association with the PI3K-Akt/NF-κB signaling pathway. Networktoxicology identified 127 common targets of BPA, BPS, and BPF, ofwhich 19 were closely associated with liver injury. KEGG enrichmentanalysis significantly pointed to the PI3K-Akt and NF-κB pathways.Molecular docking and dynamics simulations revealed that each individualcompound exhibited favorable binding energy to core targets, formingstable complex conformations. <em>In vivo</em> experimentsdemonstrated that continuous gavage administration of BPA, BPS, BPF,or their mixture induced liver tissue damage, oxidative stress, andinflammatory responses in mice, with the mixture group showing themost pronounced effects. <em>In vitro</em> experiments usingprimary hepatocytes and HepG2 cells further confirmed that combinedexposure additively inhibited cell viability, increased reactive oxygenspecies (ROS) levels, activated the PI3K-Akt/NF-κB pathway,and upregulated the expression of pro-inflammatory factors. Althoughformal synergy assessment is lacking, this study reveals that combinedexposure to BPA, BPS, and BPF produces greater-than-single-compoundtoxicity, which is associated with oxidative stress and inflammatoryresponses alongside the PI3K-Akt/NF-κB signaling pathway. Thesefindings provide a new theoretical basis for the risk assessment ofcombined exposure to bisphenol analogues.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 10","pages":"2117–2136"},"PeriodicalIF":4.1,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210935","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":"Hazard Prioritization and Transcriptomic Characterization of PFASs Based on Machine Learning and Human Liver Spheroids","authors":"Shiyuan Wang,&nbsp;Li Cui,&nbsp;Huifeng Yue","doi":"10.1021/acs.chemrestox.6c00344","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00344","url":null,"abstract":"<p>Becauseof their pervasiveness and ongoing toxicity,particularlyto the liver, perfluorinated and polyfluoroalkyl substances (PFASs)present an increasingly serious threat to human health and the environment.On the basis of high-throughput bioactivity data, we developed a quantitativestructure–activity relationship (QSAR) model based on the XGBoostalgorithm and an operational four-tier scheme for bioactivity-basedprioritization of PFAS hepatotoxicity-related hazards. Public transcriptomicdata from human liver spheroids (GSE145239) exposed to 19 PFAS compoundswere subsequently analyzed to provide biological context for the model-derivedhazard prioritization tiers. Transcriptomic response patterns differedamong PFASs assigned to different hazard tiers. Transcriptomic profilingfurther suggested that lipid metabolism disruption and cellular stressresponses were among the major biological processes associated withPFAS-induced hepatic perturbations. FABP1, PLIN2, and GDF15 were identifiedas shared responsive genes across PFAS exposure groups. This integratedcomputational and in vitro framework links molecular hazard prioritizationto transcriptomic responses, providing a potential strategy for prioritizingdata-scarce PFAS.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 10","pages":"2109–2116"},"PeriodicalIF":4.1,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210945","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":"Fine Brown Carbon Aerosol Emitted by Wood Pyrolysis - New Harmful Tracers and Cytotoxicity in Human Lung Cells","authors":"Nadira Zendi,&nbsp;Vinh Nguyen,&nbsp;Bartłomiej Witkowski,&nbsp;Anna Pogorzelska,&nbsp;Małgorzata Milczarek,&nbsp;Tomasz Gierczak","doi":"10.1021/acs.chemrestox.6c00273","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00273","url":null,"abstract":"<p>Biomass burning (BB)is a major global source of light-absorbingorganic aerosols, the so-called atmospheric brown carbon (BrC), whichnegatively affects human health. However, the interplay between themolecular composition and toxicity of BB emissions remains ambiguous.In this study, cytotoxicity analyses and molecular-level characterizationof fine BrC generated by wood pyrolysis at 350 °C, representativeof smoldering combustion during vegetation fires, were performed.Solvent-extractable BrC was analyzed using UHPLC-ESI-ToF-MS coupledwith a nontarget analysis (NTA) workflow, and cytotoxicity was evaluatedon the A549 (CCL-185) human lung carcinoma cell line. In the dissolvedBrC, 776–1132 unique molecular features were detected. Theaqueous fraction was dominated by lignin-derived phenols and aromaticacids, whereas organic solvents (methanol and acetone) preferentiallyextracted less oxidized, more hydrophobic compounds, such as terpenoid-and sterol-like species, including several emerging BB tracers. Furthermore,reduction in metabolic activity, cellular membrane damage, death phenotype,and morphology were investigated. Cytotoxicity of solvent-extractableBrC increased in the order water &lt; methanol &lt; acetone. Descriptor-basedscreening showed that cytotoxicity was likely associated with lipophiliccompounds capable of membrane partitioning and redox-active moieties,contributing to oxidative stress. The harmful BrC tracers identifiedincluded benzoic and cinnamic acids, methoxyphenols, quinols, andnatural compounds such as flavonoids, coumarins, indoles, and plantsterols. The highest contributors to baseline narcosis were 3-hydroxybenzoic,salicylic, <em>p</em>-coumaric acids, benzene-1,2,4-triol,methylxanthoxylin, methyl ester of heteropeucenin, coniferylaldehyde,and agelasine. These results demonstrate that chemical compositionstrongly governs BrC toxicity. Moreover, by combining comprehensivemolecular-level characterization with simple descriptors, it is possibleto identify potentially harmful compounds within complex BB emissions.The presented approach provides a framework for identifying potentiallyharmful components of BrC aerosols and supports improved assessmentof their health impacts.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 10","pages":"2063–2077"},"PeriodicalIF":4.1,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210930","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":"Respiratory Health Effects of Organophosphate Ester Exposure: From Toxicological Mechanisms to Epidemiological Associations","authors":"Tianlei Sun,&nbsp;Jianzhong Cao,&nbsp;Xiangyu Zhu,&nbsp;Mingyue Wang,&nbsp;Xinyu Wang,&nbsp;Yang Song","doi":"10.1021/acs.chemrestox.6c00372","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00372","url":null,"abstract":"<p>Organophosphate esters (OPEs), particularly organophosphateflameretardants (OPFRs), have become ubiquitous environmental contaminantssince the phase-out of brominated flame retardants. As additives thatare not chemically bound, OPFRs migrate into dust and air and aredetected in over 90% of the general population, with the highest intakesin young children. This review integrates toxicological and epidemiologicalevidence linking OPFR exposure to respiratory health, presenting themechanistic findings first. In population studies, prenatal and early-lifeexposure is associated with childhood asthma and wheeze; the highesthousehold-dust quartile of tris(2-butoxyethyl) phosphate (TBOEP) carriednearly 4-fold higher asthma odds (odds ratio 3.85, 95% confidenceinterval 1.92–7.74), whereas chlorinated OPFRs show the mostconsistent associations with reduced lung function. These associationsare constrained by exposure misclassification, co-pollutant confounding,and reverse causation in cross-sectional designs, and the availablemeta-analysis rates the overall evidence as low. Toxicologically,OPFR exposure is associated with oxidative stress, inflammation, andallergic sensitization, with chlorinated and aryl compounds most cytotoxicand alkyl compounds acting as immune adjuvants at the human tolerabledaily intake. This convergence, reinforced by detection of OPFRs inhuman lung tissue, strengthens biological plausibility without provingcausality. Major gaps regarding chronic obstructive pulmonary disease(COPD), occupational exposure, and long-term trajectories warrantprecautionary regulation and prospective study.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 10","pages":"1919–1939"},"PeriodicalIF":4.1,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210965","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":"Maternal Glyphosate Exposure Induces Transgenerational Testicular Fibrosis and Dysfunction in Male Offspring Mediated by Sperm-Borne piRNAs","authors":"Jinfa Zheng,&nbsp;Ling Yu,&nbsp;Shulan Li,&nbsp;Ruijia Li,&nbsp;Shunqing Xu,&nbsp;Wei Xia","doi":"10.1021/acs.chemrestox.6c00241","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00241","url":null,"abstract":"<p>Glyphosate, the most widely used herbicide worldwide,has experienceda more than 12-fold increase in application over the past decade,raising substantial public health concerns regarding its potentialreproductive toxicity. Previous toxicological studies have primarilyfocused on the effects of high-dose exposures, while the impacts oflong-term, low-dose, and transgenerational exposure, which more closelyreflect real-world environmental exposure, remain poorly understood.A three-generation rat model of continuous maternal glyphosate exposurewas established. Pregnant F0 dams were administered glyphosate (5μg/kg bw/day) in drinking water, and the exposure was maintainedthrough their female offspring (F1 and F2) during gestation and lactationand continued in all offspring postweaning. Male offspring from eachgeneration (F1–F3) were assessed for testicular histology,serum testosterone levels, and sperm quality. Transcriptomic profilingwas performed by RNA sequencing, and sncRNA-seq was conducted to characterizesperm miRNA and piRNA expression profiles. Key molecules and signalingpathways were further examined by RT-qPCR and molecular docking analyses.Significant reproductive alterations were observed in F3 males atpostnatal day 90 (PND 90), including reduced body weight, decreasedsperm count, lower serum testosterone levels, and disrupted seminiferoustubule morphology. Transcriptomic analysis showed progressive dysregulationof extracellular matrix (ECM) and collagen formation-related pathwaysacross generations, with the most pronounced changes in F3 males.This dysregulation was related to the activation of the TGF-βsignaling pathway, as protein–protein interaction network analysisidentified the TGF-β receptor 2(Tgfbr2) and its downstream mediator(Ccn2) as central hubs, together with the major collagen gene Col1a1.Moreover, sperm sncRNA-seq identified differentially expressed miRNAsand piRNAs, among which piR-rno-2217383_L2 was bioinformatically predictedto target Tgfbr2 and Ccn2, and molecular docking indicated stablebinding of glyphosate to TGFBR2 and CCN2 proteins. These findingssuggest the possibility that the piR-rno-2217383_L2/TGFBR2 and CCN2/Col1a1axis may contribute to testicular fibrosis, although functional validationis required to confirm this regulatory cascade.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 10","pages":"2000–2012"},"PeriodicalIF":4.1,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210943","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":"Nanopore Sequencing Identification of DNA Aristolochic Acid Adducts","authors":"Ran Liu,&nbsp;Yezhuang Shen,&nbsp;Jie Mao,&nbsp;Chunzheng Li,&nbsp;Yawei Zhang,&nbsp;Mandong Hu,&nbsp;Yizhe Zhang,&nbsp;Qiuying Han,&nbsp;Weili Gong,&nbsp;Liang Chen,&nbsp;Kun He,&nbsp;Tao Zhou,&nbsp;Weihua Li,&nbsp;Xianxing Xie","doi":"10.1021/acs.chemrestox.6c00264","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00264","url":null,"abstract":"<p>Aristolochicacid (AA) is a Group I carcinogen that forms covalentDNA adducts following metabolic activation, inducing characteristicmutational signatures and driving carcinogenesis. Liquid chromatography–massspectrometry (LC–MS/MS) provides highly sensitive and specificdetection of AA-derived DNA adducts, but commonly relies on enzymaticallydigested DNA, which does not retain positional and sequence-contextinformation along individual DNA molecules. Here, we explored nanoporesequencing as a novel strategy for characterizing aristolactam II–deoxyadenosineDNA adducts (AL-II-dA) in a defined synthetic DNA context via thedetection of intrinsic signal deviations. Using chemically synthesizedAL-II-dA incorporated at defined sites, we show that the adduct inducesconsistent and localized alterations in normalized signal levels anddwell time across two independent sequencing platforms. These deviationswere accompanied by changes in base-calling outcomes, including elevatederror-specific base (ESB) values, increased odds ratios, and reducedbase-calling quality scores (Q-scores), collectively forming a multidimensionalsignature associated with adduct presence. Building on these observations,we further explored a signal-based analytical approach to identifycharacteristic signal changes associated with the adduct directlyfrom normalized signal levels. Our results show that nanopore sequencingcan detect and localize a site-specifically incorporated AL-II-dAadduct in a defined sequence context through characteristic deviationsin normalized signal levels, dwell time, and base-calling features.This study supports the potential of nanopore sequencing as a newapproach for investigating DNA-adduct-associated signal characteristics.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 10","pages":"2031–2046"},"PeriodicalIF":4.1,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210972","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":"Stress-Induced Reprogramming of tRNA Epitranscriptome in the Industrially Important Yeast Komagataella phaffii","authors":"Alex Reading,&nbsp;Chi-Kong Chan,&nbsp;Rahul Raman,&nbsp;Michael S. DeMott,&nbsp;Thomas J. Begley,&nbsp;Peter C. Dedon","doi":"10.1021/acs.chemrestox.6c00393","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00393","url":null,"abstract":"<p>Transfer RNA (tRNA) modifications regulate codon-biasedtranslationand enable rapid translational adaptation to environmental stressesin diverse organisms. While these mechanisms have been extensivelycharacterized in <em>Saccharomyces cerevisiae</em>, littleis known about the epitranscriptomic landscape of nonconventionalindustrial yeasts such as <em>Komagataella phaffii</em>. Here,we combined comparative genomics and liquid chromatography-coupledtandem mass spectrometry (LC-MS/MS) to define the tRNA epitranscriptomeof <em>K. phaffii</em> and compare its stress-responsive remodelingto that of <em>S. cerevisiae</em> under oxidative and alkylatingstresses. Comparative genomic analysis identified 65 shared tRNA-modifyingorthologs, consistent with broad conservation of core modificationmachinery. LC-MS/MS profiling identified 33 modified ribonucleosidesin small RNA isolated from <em>S. cerevisiae</em> and 35 in <em>K. phaffii</em>, including two modifications, lysidine (k²C) and 5,2′-<em>O</em>-dimethylcytidine (m⁵Cm), uniquely detected in <em>K. phaffii</em>. Furthersupporting lysidine biology in <em>K. phaffii</em> was theidentification of a putative lysidine synthase in its genome. Exposureto equitoxic doses of methyl methanesulfonate and hydrogen peroxideinduced extensive and structured remodeling of tRNA modification levelsin both species. Several wobble uridine modifications associated withcodon-biased translation exhibited stress- and species-dependent responses,while hierarchical clustering revealed distinct modification signaturesthat segregated primarily by stress type and secondarily by yeastspecies. Although the overall architecture of the tRNA modificationsystem was conserved, the magnitude and direction of stress-inducedremodeling differed substantially between species. These findingssupport a model in which conserved epitranscriptome machinery is differentiallyregulated to shape species-specific codon-biased translation duringstress adaptation, which has implications for industrial applicationsof the yeast species.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 10","pages":"2137–2149"},"PeriodicalIF":4.1,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210973","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":"Comparative Analysis of Genotoxic Modes of Action and Underlying Molecular Mechanisms of Four Classes of Unregulated DBPs in Human Uroepithelial (SV-HUC-1) Cells","authors":"Yingnan Han,&nbsp;Shuo Zhang,&nbsp;Xiaohong Zhou,&nbsp;Mei Ma","doi":"10.1021/acs.chemrestox.6c00291","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00291","url":null,"abstract":"<p>Increasing evidence suggests thatthe contribution ofunregulateddisinfection by-products (UR-DBPs) to the overall toxicity of disinfectedwater is underestimated. However, the molecular mechanisms by whichthey promote bladder carcinogenesis remain largely unexplored. Usingthe nontumorigenic human uroepithelial cell line SV-HUC-1, we soughtto elucidate the potential genotoxic mechanisms underlying the bladdercancer risk associated with four classes of typical UR-DBPs: haloacetonitriles(HANs), haloacetamides (HAMs), halobenzoquinones (HBQs), and halobenzoquinoneimines (HQCs). Genotoxicity was evaluated by the SOS/<em>umu</em> assay and the micronucleus assay. Only three of the eight UR-DBPsgave positive SOS/<em>umu</em> responses. However, all testedUR-DBPs showed clear cytotoxicity and micronucleus effects, with aconsistent toxicity order: HANs &gt; HAMs &gt; HBQs and HQCs. Principalcomponent analysis (PCA) of transcriptomic data indicated that theeight UR-DBPs may act through two distinct modes of action (MOAs).Gene set variation analysis (GSVA) further revealed that HANs andHAMs activated DNA repair pathways, including base excision repair(BER) and nonhomologous end-joining for double-strand break repair(DSBR-NHEJ), while HBQs and HQCs suppressed DNA damage repair pathwaysor the regulatory pathways involved in nucleotide excision repair(NER), mismatch repair (MMR), and double-strand break repair (DSBR).Western blotting confirmed that HBQs and HQCs significantly downregulatedproteins critical for DNA damage repair regulation. This is possiblyattributable to their stronger protein-binding capacities relativeto other UR-DBPs. Collectively, these findings argue that the impairmentof DNA repair regulation constitutes a distinct genotoxic mechanismthat should be integrated into DBP risk evaluation alongside directDNA damage.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 10","pages":"2087–2098"},"PeriodicalIF":4.1,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149211017","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":"Correction to “Engineered PS and PAN Microplastic Fibers Elicit Stronger A549 Epithelial Responses than Spherical Polystyrene Particles”","authors":"Sewoon Kim,&nbsp;David M. Cwiertny,&nbsp;Dongkeun Lee,&nbsp;Jong Sung Kim,&nbsp;Jon A. Doering,&nbsp;Qinglin Wu","doi":"10.1021/acs.chemrestox.6c00471","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00471","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 10","pages":"2150–2150"},"PeriodicalIF":4.1,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210952","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":"Pulmonary Injury, Functional Impairment, and Transcriptomic Responses Following Phosphine Inhalation in Mice: Implications for Therapeutic Development","authors":"Esraa Mohamed,&nbsp;Andrea Adamcakova-Dodd,&nbsp;Xuefang Jing,&nbsp;David K. Meyerholz,&nbsp;Mohammad Al-Natour,&nbsp;Peter S. Thorne,&nbsp;Aliasger K. Salem","doi":"10.1021/acs.chemrestox.6c00223","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00223","url":null,"abstract":"<p>Phosphine (PH₃) is a highly lethal gas that is widelyused as an agricultural fumigant. Human exposure occurs through inhalationof accidentally released gas or phosphide-containing pesticides. Itshigh lethality, combined with its ready accessibility, makes it achemical threat agent. Although its toxic mechanism remains unclear,PH₃ is known to induce oxidative stress, leading to celldeath. With no available antidote, this study examines the pulmonaryeffects of acute PH₃ inhalation exposure in order to supportfuture treatment strategies and identifies key biological pathwaysaffected in the lungs and hearts. Female mice were exposed acutelyto one of three PH₃ doses in a dynamic whole-body exposurechamber. Following exposure, respiratory function, total protein levelsin bronchoalveolar lavage fluid (BALF), and lung pathology were evaluated.Bulk RNA sequencing of PH₃-exposed lungs and hearts wasperformed, and differentially expressed genes (DEGs) in tissues fromexposed versus nonexposed mice were analyzed. Animals exposed to highPH₃ doses experienced a significant decrease in respiratoryrate and had to be euthanized within 5 h postexposure. There was asignificant increase in total protein and cell counts in BALF of PH₃-exposed mice at the medium and high doses, and histopathologicalevaluation of lungs showed foci of hypercellularity and scatteredvessels filled with platelet aggregates and neutrophils, indicativeof early pulmonary thrombi formation. Gene expression analysis revealedupregulation of genes involved in protein synthesis, inflammation,cell cycle, and apoptosis. The MAPK, IL-17, and atherosclerosis pathwayswere among the most impacted pathways in lung and heart tissues. <em>Fos, Fosb, Jun</em>, and <em>Junb</em> were significantlyupregulated following exposure; all of them are components of theAP-1 protein complex, a potentially key element in inducing injuriessubsequent to PH₃ exposure and therefore a promising therapeutictarget.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 10","pages":"1985–1999"},"PeriodicalIF":4.1,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149211009","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}