Archives of Toxicology最新文献

{"title":"Pro-inflammatory response of human iPSC-derived intestinal epithelial monolayers towards microbial toxins LPS and nigericin.","authors":"Germaine Aalderink, Hugo Brouwer, Jingxuan Wang, Aafke W F Janssen, Meike van der Zande, Coen Govers, Tamara Hoppenbrouwers, Hans Bouwmeester, Mathias Busch","doi":"10.1007/s00204-025-04215-9","DOIUrl":"https://doi.org/10.1007/s00204-025-04215-9","url":null,"abstract":"<p><p>The intestinal epithelium forms a selective barrier between the intestinal lumen and the subepithelial layer. Intestinal epithelium plays a critical role in initiating inflammatory tissue responses in vivo, which remains challenging to emulate in vitro. Caco-2 cells are commonly used models of the intestinal epithelium, but lack crucial receptors and pathways associated with pro-inflammatory reactions. Human-induced pluripotent stem cell (iPSC)-based in vitro models are assumed to provide a system that better emulates in vivo responses. This study evaluated the inflammatory response of iPSC-derived intestinal epithelial cells (IEC) and Caco-2-derived intestinal epithelial cells to the microbial toxins lipopolysaccharide (LPS) and nigericin. Here, iPSCs were differentiated towards enterocyte, goblet- and Paneth-like cells without using three-dimensional culture techniques. The formed monolayer barriers were exposed to a combination of 0-100 µM nigericin and 100 ng/mL LPS on either the apical or basolateral side. The treatment-induced expression of cytokine genes and cytokine secretion were compared between the iPSC-derived cell model and differentiated Caco-2 cell layers. Nigericin exposure in combination with LPS significantly reduced transepithelial electrical resistance in the iPSC-derived model, and resulted in a tenfold increased secretion of the pro-inflammatory cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha compared to the negative control. A similar increase was observed for the mRNA expression of these cytokines. No significant effect on TEER, cytokine secretion, or mRNA expression was observed in the Caco-2 model. Overall, this study shows that iPSC-IECs are a more sensitive model compared to Caco-2 to emulate inflammatory perturbations of the human intestinal epithelium.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthetic cannabinoid receptor agonists containing silicon: exploring the metabolic pathways of ADMB- and Cumyl-3TMS-PrINACA in human urine specimens and post mortem material compared to in vitro and in silico data.","authors":"Annette Zschiesche, Jeremy Carlier, Jörg Pietsch, Martin Scheu, Jasmin Seibt, Francesco P Busardò, Volker Auwärter, Laura M Huppertz","doi":"10.1007/s00204-025-04204-y","DOIUrl":"https://doi.org/10.1007/s00204-025-04204-y","url":null,"abstract":"<p><p>The rapid emergence of synthetic cannabinoid receptor agonists (SCRAs) poses challenges for drug testing, particularly when analyzing urine samples due to the rapid metabolization of the parent compounds. In early 2023, two novel SCRAs were reported to the European Union Drugs Agency (EUDA): ADMB-3TMS-PrINACA and Cumyl-3TMS-PrINACA, which are both indazole SCRAs featuring a trimethylsilyl propyl moiety connected to the tertiary indazole nitrogen. Peaks corresponding to metabolites of ADMB-BINACA (also known as ADB-BUTINACA) and Cumyl-4CN-BINACA observed with retention time shifts in a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for detecting SCRAs were later identified as metabolites of ADMB- and Cumyl-3TMS-PrINACA. Pooled human liver microsome (pHLMs, 25 µmol/L) and pooled human hepatocyte (PHH, 20 µmol/L) assays were performed to generate metabolites. Additionally, human urine samples were analyzed by reversed phase liquid chromatography-quadrupole-time-of-flight-mass spectrometry (LC-QToF-MS), assisted by GLORYx and BioTransformer 3.0 for in silico metabolite prediction. Gas chromatography-mass spectrometry (GC-MS) was used to identify substances in seized materials. In total, 34 metabolites for ADMB-3TMS-PrINACA and 38 for Cumyl-3TMS-PrINACA were tentatively identified. Major biotransformations included side chain monohydroxylation (specific markers) and TMS-group cleavage, likely initiated by oxidative Si-demethylation followed by further hydroxylation resulting in an N-3-OH-propyl metabolite and further oxidation to the respective N-propionic acid. Most of these biomarkers were detected in the blood, urine, and stomach content of a deceased poly-drug user exposed to ADMB-3TMS-PrINACA. Overall, Cumyl-3TMS-PrINACA was more prevalent than ADMB-3TMS-PrINACA in Germany according to routine urine testing. This work provides the first investigation of the metabolic fate and suggests biomarkers for these new SCRAs.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenges and advances in the development of antidotes against A-series nerve agents.","authors":"Rajan K Tripathy, Khushi Goyal, Prakash Y Khandave, Janek Bzdrenga, Xavier Brazzolotto, Florian Nachon, Abhay H Pande","doi":"10.1007/s00204-025-04216-8","DOIUrl":"https://doi.org/10.1007/s00204-025-04216-8","url":null,"abstract":"<p><p>A novel series of toxic nerve agents called Novichok agents (A-agents and their binary form) was developed in the Soviet Union during the 70s-90s under the FOLIANT program. These agents, including A-230, A-232, and A-234, are structurally distinct from earlier G- and V-series agents and pose significant challenges due to their high environmental persistence, poor aqueous degradation, and rapid irreversible inhibition of acetylcholinesterase (AChE). Current medical countermeasures, such as atropine and oxime reactivators, show limited efficacy against A-agents, particularly due to the low reactivity of A-agent-AChE conjugates. Surrogate-based studies have provided partial insights into the reactivation and decontamination strategies, but they do not fully replicate the behavior of actual A-agents. Developing efficient reactivators against A-agents appears challenging. Emerging skin decontamination strategies, including Reactive Skin Decontamination Lotion and metal-organic framework catalysts, show some success. In this context, enzymatic biocatalysts such as engineered variants of paraoxonase (PON1) and phosphotriesterase (PTE) are valuable antidotes, although their catalytic efficiencies against A-agents remain suboptimal. The development of broad-spectrum bioscavengers with prolonged circulatory half-life, like butyrylcholinesterase, or other recombinant enzyme candidates, enhanced through fusion protein engineering and mutagenesis, represents a promising avenue. However, significant knowledge gaps persist due to limited availability and high-risk handling of these agents. Advancing countermeasures requires continued integration of computational modeling, biochemical engineering, and surrogate validation strategies to overcome these biochemical and therapeutic challenges.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhalation exposure to cigarette smoke promotes neointimal formation in mouse model of arterial injury.","authors":"Yoon-Seok Seo, Kwang-Hoon Park, Jung-Min Park, Jae-Hyeong Kim, Seong-Jin Choi, Min-Seok Kim, Kyuhong Lee, Moo-Yeol Lee","doi":"10.1007/s00204-025-04210-0","DOIUrl":"https://doi.org/10.1007/s00204-025-04210-0","url":null,"abstract":"<p><p>Smoking is a well-established risk factor for cardiovascular diseases, yet direct evidence linking cigarette smoke (CS) exposure to neointimal formation remains limited. To address this gap, we investigated the effects of CS exposure on neointimal formation using an injury-induced arterial mouse model. Neointimal formation was induced in the femoral artery via mechanical injury with a guidewire, and mice were exposed to CS generated from 3R4F reference cigarettes at a total particulate matter concentration of 600 µg/L for 2 h daily. CS exposure commenced three days prior to injury induction and continued until euthanasia on days 7 or 14 post-injury. CS exposure significantly exacerbated neointimal formation; however, in the absence of injury, it did not induce structural alterations in the femoral artery. In vitro, cigarette smoke extract (CSE) at 0.1%-corresponding to approximately 50 ng/mL nicotine, a clinically relevant concentration in smokers-enhanced the proliferation of aortic smooth muscle cells, a critical process in neointimal development. However, CSE exhibited minimal effects on other cellular processes involved in neointimal formation, including phenotype switching, adhesion, migration, and extracellular matrix deposition. Mechanistically, CSE exposure increased Akt and FOXO3a phosphorylation, leading to a downregulation of p27 and an upregulation of CDK2 and cyclin E, ultimately promoting Rb phosphorylation and cell cycle progression. In conclusion, although CS alone does not appear sufficient to initiate neointimal formation, it significantly exacerbates or accelerates its progression in a primed vascular environment. The promotion of vascular smooth muscle cell proliferation via cell cycle progression may underlie this effect.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The synthetic cannabinoid THJ-2201 modulates mitochondrial activity and enhances mitochondrial recruitment to newly-forming neurites during neurodifferentiation of NG108-15 cells.","authors":"Rui Filipe Malheiro, Ana Catarina Costa, Helena Carmo, Félix Carvalho, João Pedro Silva","doi":"10.1007/s00204-025-04217-7","DOIUrl":"https://doi.org/10.1007/s00204-025-04217-7","url":null,"abstract":"<p><p>Synthetic cannabinoids (SCs) have been increasingly associated with neurodevelopmental impairment; however, the underlying mechanisms remain poorly understood. In particular, the impact of SCs on mitochondria during neurodifferentiation remains largely unexplored, despite the central role of these organelles in this process. Building upon our previous findings that THJ-2201, a widely used SC, enhances neurite outgrowth in NG108-15 neuroblastoma-glioma cells at biologically relevant concentrations (1 pM-1 μM), we investigated whether this SC influences mitochondrial function, morphology, and dynamics during neurodifferentiation. THJ-2201 exposure caused a 30-40% reduction in intracellular ATP levels in a CB1-dependent manner, along with a 20-30% decrease in TMRE retention during NG108-15 neurodifferentiation. Cells treated with 1 μM THJ-2201 failed to sustain the expected increase in VDAC levels (an indirect marker of mitochondrial mass) during regular differentiation. Concurrently, THJ-2201 elevated PGC-1α levels, a key regulator of mitochondrial biogenesis, by disrupting its translocation to the nucleus. Expression of both fusion (Opa1, Mfn1, and Mfn2) and fission (Drp1 and Fis1) markers exhibited a less pronounced increase between 24 and 72 h in THJ-2201-treated cells. Mitochondrial morphology exhibited alterations in mean area, perimeter, branching, and circularity in the soma after 72 h exposure. Additionally, THJ-2201 reduced mitochondrial mobility in neurites without affecting their average speed or run length and led to a mitochondrial accumulation within neurites, as indicated by decreased Miro1 expression. Overall, these findings suggest that THJ-2201-induced mitochondrial remodelling and redistribution may transiently enhance local energy supply for neurite outgrowth, but at the expense of somatic mitochondrial function, resulting in an overall bioenergetic imbalance.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estimating safe doses of perfluorooctane sulfonate (PFOS): an international collaboration.","authors":"Michael L Dourson, Laura C Green, Edmund A C Crouch, Harvey J Clewell, Thomas Colnot, Tony Cox, Wolfgang Dekant, Linda D Dell, James A Deyo, Bernard K Gadagbui, Helmut Greim, Mahesh Rachamalla Gupta, Tamara House-Knight, Ashish Jachak, Vijayavel Kannappan, Travis R Kline, Therese Manning, Ravi Naidu, Paul Nathanail, Chijioke Onyema, Frank Pagone, Andrew Pawlisz, Tiago Severo Peixe, Katie Richardson, Anurag Sharma, James S Smith, Nitin Verma, Andrea Wojtyniak, Jackie Wright","doi":"10.1007/s00204-025-04134-9","DOIUrl":"https://doi.org/10.1007/s00204-025-04134-9","url":null,"abstract":"<p><p>Many government agencies and expert groups have estimated a safe dose (aka a \"reference dose,\" [RfD]) for perfluorooctane sulfonate (PFOS). Notably, these agencies have derived safe doses that vary over at least 600-fold range. The range is larger still if one includes the U.S. Environmental Protection Agency (USEPA) current science-policy position under the Safe Drinking Water Act, which is that the only safe dose of PFOS is zero. This wide range in safe dose-estimates is surprising, since PFOS is a relatively well-studied, and ubiquitous, chemical. The Steering Committee of the Alliance for Risk Assessment (ARA) called for health-scientists interested in attempting to understand and, if possible, narrow this range of estimates. An advisory committee of eight scientists from four countries was selected from nominations received, and a subsequent invitation to scientists internationally led to the formation of three teams comprised of 24 scientists from nine countries. Each team independently reviewed toxicologic and epidemiologic data, and developed PFOS safe dose-estimates. All three teams concluded that currently available epidemiologic data could not form a reliable basis for PFOS safe dose-assessments. In contrast, results of bioassays of PFOS in laboratory monkeys and rats did provide usable bases from which serum-concentration-based \"points of departure\" were derived. After applying several, necessarily imprecise, uncertainty factors, the three groups derived PFOS safe dose-estimates that ranged, narrowly, from 20 to 100 nanograms (ng) of PFOS/kg body weight/day. In contrast, USEPA's current (United States Environmental Protection Agency (USEPA) (2024) Human health toxicity assessment for perfluorooctane sulfonic acid (PFOS) and Related Salts. EPA Document No. 815R24007.) estimate of the safe dose is 0.1 ng of PFOS/kg-day.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Dapagliflozin protects against doxorubicin-induced cardiotoxicity by restoring STAT3.","authors":"Wei-Ting Chang, Jhih-Yuan Shih, Yu-Wen Lin, Zhih-Cherng Chen, Wei-Chih Kan, Tsung-Hsien Lin, Chon-Seng Hong","doi":"10.1007/s00204-025-04190-1","DOIUrl":"https://doi.org/10.1007/s00204-025-04190-1","url":null,"abstract":"","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping the ethical and sustainable transition in toxicology: a bibliometric analysis and a review of new approach methodologies.","authors":"Ruxandra Malina Petrescu-Mag, Mathieu Vinken, Dacinia Crina Petrescu","doi":"10.1007/s00204-025-04209-7","DOIUrl":"https://doi.org/10.1007/s00204-025-04209-7","url":null,"abstract":"<p><p>Toxicology is undergoing a paradigm shift, driven by the ethical imperative to reduce animal testing, the pursuit of sustainability, and regulatory transitions toward new approach methodologies (NAMs). This study systematically maps the integration of ethics and sustainability into NAMs-related toxicological research, using a mixed-methods design that combines bibliometric analysis with a review of scientific and policy literature. Our findings reveal a steep increase in NAMs publications since 2015, with in vitro and in silico approaches at the forefront. Bibliometric clustering identified three dominant thematic domains-regulatory testing, methodological performance factors, and human cell culture innovation-each reflecting varying degrees of engagement with ethical, scientific, and sustainability principles. A qualitative matrix was also developed to link the bibliometric clusters to key ethical and methodological dimensions, highlighting the growing centrality of themes such as the 3Rs, sustainability, and regulatory reform. Notably, the scientific and political discourse is shifting from merely \"symbolic\" ethics, used primarily to signal alignment with funding priorities or public expectations, toward more deeply embedded and actionable ethical frameworks. Initiatives emphasize operational ethics through concepts such as the fourth R (responsibility), with more expanded models including 12Rs, the 3C model (cell culture, computer simulation, and clinical trials), and ethics-driven AI tools. These developments signal a maturing field where ethics is becoming a methodological imperative. By mapping these shifts, the study offers an integrated perspective on how ethical values shape scientific innovation in toxicology. It provides evidence-based directions for accelerating a responsible transition to animal-free, human-relevant, and resource-efficient risk assessment.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vivo and in vitro metabolism of the designer benzodiazepine, bretazenil: a comparison of pooled human hepatocytes and liver microsomes with postmortem urine and blood samples.","authors":"Prince S Gameli, Johannes Kutzler, Laura M Huppertz, Diletta Berardinelli, Livio Tronconi, Giuseppe Basile, Jeremy Carlier, Francesco P Busardò, Volker Auwärter","doi":"10.1007/s00204-025-04213-x","DOIUrl":"https://doi.org/10.1007/s00204-025-04213-x","url":null,"abstract":"<p><p>Benzodiazepines are often used with other drugs like opioids, potentially leading to severe intoxications. Bretazenil, an imidazo-tetrahydropyrrolo-1,4-benzodiazepine, developed in the 1980s but never marketed as a medicine, has recently appeared on the illicit drug market. Given its high potency, short elimination half-life, and potential for rapid metabolism, it is essential to identify markers for bretazenil consumption for clinical and forensic purposes. Our study aimed to thoroughly explore bretazenil's metabolism using web-based in silico prediction tools, in vitro incubation with pooled human liver microsomes and hepatocytes, and to compare these results with authentic postmortem blood and urine samples. The in silico prediction revealed 16 metabolites, mainly formed by hydroxylation (phase I) and further O-glucuronidation, sulfation, and methylation (phase II) reactions. High-resolution mass spectrometry and software-aided data processing of in vitro and in vivo samples identified a total of 26 metabolites. Eight metabolites were detected in vitro, 15 in postmortem urine, and 11 in postmortem blood. Hydroxylation on the pyrrolidine ring was predominant. Other phase I reactions, including combinations of dihydroxylation, hydroxylation, reduction, and carboxylation as well as phase II glucuronidation and sulfation on the pyrrolidine ring, imidazole ring, or the tert-butyl chain, were also identified. Additionally, we discovered a new benzodiazepine biotransformation pathway via hydroxylation and cysteine conjugation in both human hepatocytes and blood. Due to bretazenil's extensive metabolism, we recommend hydroxy-bretazenil (B14), reduced hydroxy-bretazenil (B6), and reduced dihydroxy-bretazenil (B1) as significant markers for detecting bretazenil use.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dexamethasone alters the cornea transcriptome to confer protection against ocular sulfur mustard exposure via regulating NFκB and TGFβ signaling in an in vivo rabbit model.","authors":"Neha Mishra, Laura Saba, Chapla Agarwal, Rajesh Agarwal","doi":"10.1007/s00204-025-04207-9","DOIUrl":"https://doi.org/10.1007/s00204-025-04207-9","url":null,"abstract":"<p><p>Ocular exposure to sulfur mustard (SM), infamously called \"King of Battle Gases\", may occur during warfare, terrorist activities, or accidentally from improperly discarded munitions/stockpiles. Eyes, particularly corneas, are exceptionally vulnerable to SM toxicity. Notably, SM is a potent genotoxicant that causes damage to proteins, lipids, and nucleic acids. Currently, no approved therapeutics are available for ocular SM injuries. We developed a dexamethasone (DEX; 0.1%) treatment plan (application initiation 2 h post-exposure and every 8 h thereafter for 28 days) that effectively countered mustard vesicant-induced corneal injuries. However, the mechanistic aspects of SM toxicity and DEX efficacy remain elusive. Thus, rRNA-depletion RNA sequencing was performed on day 14 and day 28 post-SM exposure (neat) to assess the progression of SM toxicity and DEX efficacy at the transcriptome level in corneas (in vivo rabbit studies) from control, SM-exposed, and DEX-treated tissues. Transcripts significantly differentially expressed between all three groups (omnibus FDR < 0.01) were further analyzed based on pairwise differences between treatment groups. Further, network analyses and functional enrichment studies were performed to decipher SM toxicity and DEX efficacy-associated effects as a function of time. Twenty-day treatment was found to be more effective than 4-day DEX treatment. Main mechanisms associated with DEX efficacy included NFκB and TGFβ signaling. The most prominent functional aspects associated with SM toxicity and DEX efficacy were preservation of the corneal structural integrity via regulating collagen networks and angiogenesis. These novel outcomes provide in-depth mechanistic insights into DEX efficacy for treating SM-induced corneal injuries.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}