Chemical Research in Toxicology最新文献

{"title":"Di-2-ethylhexyl Phthalate Reprograms Epithelial–Mesenchymal Transition and Lenvatinib Responsiveness in Hepatoma Cells via SPAG4-Dependent MAPK/ERK Signaling","authors":"QiWei Yang,&nbsp;Lin Yu,&nbsp;Ran Tang,&nbsp;YiShan Peng,&nbsp;Tao Huang,&nbsp;HaoQi Chen,&nbsp;WenFeng Zhu,&nbsp;Qing Yuan,&nbsp;Wei Wang,&nbsp;Xiaojian Jiang,&nbsp;ZhiLi Ma,&nbsp;Lei Yuan,&nbsp;SuMei Wang*,&nbsp;XiaoWen Wang* and GenShu Wang*,&nbsp;","doi":"10.1021/acs.chemrestox.6c00105","DOIUrl":"10.1021/acs.chemrestox.6c00105","url":null,"abstract":"<p >Environmental chemical exposure has emerged as an important modulator of cancer progression and therapeutic outcomes. Di-2-ethylhexyl phthalate (DEHP), a ubiquitous environmental plasticizer, has been widely recognized for its endocrine-disrupting effects; however, its impact on intracellular signaling reprogramming and cancer drug responsiveness remains incompletely understood. In this investigation, we aimed to elucidate the toxicological mechanisms by which DEHP alters cellular phenotypes and therapeutic sensitivity in hepatocellular carcinoma (HCC) cells. We demonstrate that DEHP exposure does not primarily promote cancer cell proliferation but instead induces epithelial–mesenchymal transition (EMT), leading to enhanced migratory and invasive capacities and reduced responsiveness to the tyrosine kinase inhibitor lenvatinib. Notably, integrative bioinformatic analyses combined with functional validation identified sperm-associated antigen 4 (SPAG4) as a key DEHP-responsive regulator mediating toxicant-induced cellular reprogramming. Mechanistic studies revealed that DEHP-induced upregulation of SPAG4 activates the MAPK/ERK signaling pathway, thereby driving EMT and attenuating lenvatinib responsiveness. Genetic silencing of SPAG4 or pharmacological inhibition of MAPK/ERK signaling effectively reversed DEHP-induced EMT and drug resistance. In conclusion, we highlight DEHP as a signaling-disrupting environmental toxicant that reprograms cancer cell states and modulates therapeutic responses through a SPAG4-dependent MAPK/ERK pathway. These findings provide mechanistic insight into how environmental chemical exposure can reshape intracellular signaling networks and influence cancer treatment outcomes, underscoring a previously underappreciated aspect of chemical toxicology.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 6","pages":"1207–1217"},"PeriodicalIF":3.8,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147924822","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":"Gold Nanoparticles Size Dependence on DNA Damage under X-rays","authors":"Alaa Huwaidi*,&nbsp;Redha-Alla Abdo,&nbsp;François Lessard,&nbsp;Brigitte Guérin,&nbsp;Léon Sanche* and J. Richard Wagner*,&nbsp;","doi":"10.1021/acs.chemrestox.6c00037","DOIUrl":"10.1021/acs.chemrestox.6c00037","url":null,"abstract":"<p >Combining gold nanoparticles (AuNPs) with 10–100 keV X-rays has shown considerable potential for radiotherapy. The uptake of AuNPs in cancer tissues is influenced by their size, with smaller sizes exhibiting enhanced penetration capabilities into deeper layers of cancer tissue compared to larger AuNPs. In this study, we examine the effect of nanoparticle (NP) size with respect to the formation of various types of DNA damage upon X-ray exposure of dried AuNP-oligo-DNA mixtures. The type and yield of DNA damage is measured using LC-MS/MS. The most important type of damage involves the release of nucleobases (Cyt &gt; Ade ≈ Thy &gt; Gua), which accounts for 82% of the total measured damage. The remaining 18% includes reduction products of pyrimidines (5,6-dihydrothymidine and 5,6-dihydro-2’-deoxyuridine), oxidative products (8-oxo-7,8-dihydro-2′-deoxyguanosine (8oxoG) and 5-hydroxymethyl-2′-deoxyuridine (5hmU)), and novel electron-specific products, including eight 2’,3′- and 2’,5′-dideoxynucleosides (ddNs). The presence of AuNP in close contact with DNA results in a shift of radiation-induced damage toward that mediated by electrons. Moreover, the yield of damage depends on the size of the NP, with much more damage (7–10-fold) observed for NPs with a small diameter (5 nm) compared to those with a large diameter (110 nm). The dependence of DNA damage with NP size is partly attributed to the energy of electrons emitted from the surface of AuNPs and the distance required to reach available sites of electron attachment. This study contributes to elucidate the mechanisms of AuNP radiosensitization and should aid in designing optimal NP sizes for radiotherapy.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 6","pages":"1141–1151"},"PeriodicalIF":3.8,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147924849","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":"AB-Free Kava and Dihydromethysticin Inhibit Chronic Hexavalent Chromium Exposure-Induced Cell Malignant Transformation through Down-Regulating RNA Splicing Factor SNRPA1 Expression","authors":"Emily Li,&nbsp;Tengfei Bian,&nbsp;Matthew Finkelberrg,&nbsp;Zulong Liu,&nbsp;Zhuoyue Bi,&nbsp;David Carlson,&nbsp;Chengguo Xing,&nbsp;Chengfeng Yang and Zhishan Wang*,&nbsp;","doi":"10.1021/acs.chemrestox.6c00147","DOIUrl":"10.1021/acs.chemrestox.6c00147","url":null,"abstract":"<p >Hexavalent chromium [Cr(VI)] is a common occupational and environmental toxicant and an established carcinogen causing lung cancer in humans. The mechanism through which Cr(VI) exposure causes lung cancer remains to be clearly defined. No effective strategies are currently available to prevent lung cancer resulting from chronic Cr(VI) exposure. Kava is traditionally consumed by South Pacific Islanders to reduce anxiety. Epidemiology and experimental studies suggest that kava has anticancer potential and may be used as a preventive agent to reduce the risk of various cancers including lung cancer. The purpose of this study is to determine the effect of AB-Free Kava and its active component dihydromethysticin (DHM) on chronic Cr(VI) exposure-induced cell malignant transformation and the underlying mechanism. The study was performed by pretreating immortalized but nontumorigenic human bronchial epithelial cells (BEAS-2B) with AB-Free Kava (25 μg/mL) or DHM (10 μM) followed by exposing cells to 0.25 μM Cr(VI) (K₂Cr₂O₇) for 20 weeks to determine the impact of AB-Free Kava or DHM on chronic Cr(VI) exposure-induced cell transformation, cancer stem cell (CSC)-like properties, and tumorigenesis. The extent of cell transformation was evaluated by soft agar colony formation assays, Western blot analysis of cancer stemness marker expression levels, and nude mouse xenograft tumorigenesis assays. It was found that AB-Free Kava or DHM pretreatment significantly reduces Cr(VI)-induced cell transformation, CSC-like properties, and tumorigenesis. Mechanistically, it was determined that AB-Free Kava or DHM impairs Cr(VI)-induced cell transformation by down-regulating RNA splicing factor small nuclear ribonucleoprotein polypeptide A′ (SNRPA1) expression to reduce the protooncogene, cancer stemness marker, and driver c-MYC expression. It was further determined that DHM and SNRPA1 regulate c-MYC expression through affecting c-MYC protein stability. It was concluded that AB-Free Kava or DHM inhibits Cr(VI)-induced cell transformation, CSC-like properties, and tumorigenesis by down-regulating RNA splicing factor SNRPA1 expression to increase the protooncogene c-MYC protein degradation.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 6","pages":"1234–1245"},"PeriodicalIF":3.8,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147939000","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":"Democratizing Artificial Intelligence in Toxicology: Real-World Applications and Automated Computational Workflows","authors":"Kamel Mansouri*,&nbsp;José Teófilo Moreira-Filho,&nbsp;Ricardo S Tieghi and Nicole Kleinstreuer,&nbsp;","doi":"10.1021/acs.chemrestox.6c00093","DOIUrl":"10.1021/acs.chemrestox.6c00093","url":null,"abstract":"<p >Artificial intelligence (AI) and machine learning are transforming toxicological research and chemical safety assessment. Although user-friendly computational toxicology platforms are increasingly available, integrating, customizing, and deploying AI methods within end-to-end workflows still often requires programming expertise. This barrier increases the time to adoption of new methods and slows regulatory uptake. To address this limitation, we survey recent initiatives democratizing computational toxicology through no-code/low-code pipelines, automated workflows, and open-source tools. We emphasize solutions for four computational needs: (i) data extraction and access, (ii) data mining and curation, (iii) data analysis and visualization, and (iv) modeling and prediction. These initiatives transform complex computational methods into guided and web-accessible applications that enable toxicologists, regulators, and researchers to leverage AI without coding expertise. The broad applicability of computational methods will be essential for supporting and scaling federal initiatives that advance human-relevant alternatives to animal testing. We also offer practical considerations for domain-specific tool development, including large language model-based information extraction, chemical structure standardization, interactive chemical grouping, and the development of validated machine learning models, as used in the Modeling and Visualization (MoVIZ) pipeline. The authors map the future of computational toxicology and cheminformatics, one that does not require scientists to become programmers but rather makes sophisticated AI tools more broadly accessible, transparent, and guided through thoughtful interface design, transparent workflows, and open science initiatives.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 6","pages":"1072–1083"},"PeriodicalIF":3.8,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.6c00093","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148050943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physicochemical Characterization and Metabolites Identification of the Synthetic Cannabinoid MDMB-5′Br-PINACA Using In Silico and In Vitro Approaches","authors":"Alexandre B. Godoi,&nbsp;Natalícia J. Antunes*,&nbsp;Júlio C. C. da Silva,&nbsp;Gabriel Cordeiro,&nbsp;Tássia F. D. Castro and Jose L. Costa,&nbsp;","doi":"10.1021/acs.chemrestox.6c00107","DOIUrl":"10.1021/acs.chemrestox.6c00107","url":null,"abstract":"<p >MDMB-5′Br-PINACA is a recently identified brominated synthetic cannabinoid that was detected in herbal materials seized in Brazil in 2025, raising concerns regarding further potential intoxication cases. In this sense, the evaluation of physicochemical properties and metabolic fate may improve its analytical detectability. Therefore, an integrated <i>in silico</i> and <i>in vitro</i> approach was employed to investigate the physicochemical properties and phase I metabolism of MDMB-5′Br-PINACA. Physicochemical parameters and predicted metabolic pathways were first evaluated using BioTransformer 3.0 and XenoSite, providing complementary insights into likely sites of metabolism. <i>In vitro</i> metabolism was subsequently assessed using pooled human liver microsomes associated with liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) analysis. MS²-based molecular networking (MN) was applied as an exploratory and confirmatory strategy to guide metabolite annotation by clustering structurally related features and prioritizing candidates linked to MDMB-5′Br-PINACA. A total of twenty-seven metabolites were level 2 annotated, encompassing aliphatic and aromatic hydroxylation, sequential alcohol oxidation to ketone, aldehyde, and carboxylic acid derivatives, ester hydrolysis, intramolecular lactone formation, and <i>N</i>-dealkylation with loss of the pentyl side chain. Hydroxylations of the pentyl chain and <i>tert</i>-butyl moiety and secondary oxidative reactions emerged as the predominant pathways under the experimental conditions, in agreement with <i>in silico</i> predictions. However, lactone formation was exclusively revealed by <i>in vitro</i> experiments, demonstrating limitations of current <i>in silico</i> prediction approaches. The integration of computational prediction, LC-HRMS, and MN substantially enhanced metabolite coverage and confidence of structural assignment. These findings provide a detailed metabolic map of MDMB-5′Br-PINACA and underscore the value of combining <i>in silico</i> and <i>in vitro</i> approaches to improve metabolite identification, supporting forensic and clinical investigations of intoxication involving this synthetic cannabinoid.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 6","pages":"1190–1206"},"PeriodicalIF":3.8,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.6c00107","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148003877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"QSAR in the AI Era: Reflections for Advancing Chemical Safety Assessment","authors":"Simona Kovarich,&nbsp;Andrea Gissi,&nbsp;Patience Browne,&nbsp;Mojca Fuart-Gatnik,&nbsp;Salvador Moncho,&nbsp;Aleksandra Mostrag-Szlichtyng,&nbsp;Glenn Myatt,&nbsp;Manuela Pavan and Arianna Bassan*,&nbsp;","doi":"10.1021/acs.chemrestox.6c00079","DOIUrl":"10.1021/acs.chemrestox.6c00079","url":null,"abstract":"<p >Quantitative Structure–Activity Relationship (QSAR) models are increasingly discussed in the broader context of artificial intelligence (AI). Indeed, they formally meet certain regulatory definitions of AI as data-driven inference systems. However, in the context of chemical safety assessment, QSARs represent a distinct, domain-specific class of models shaped by decades of dialogue between computational toxicology and regulatory science. This work summarizes roundtable discussions from the 21st International workshop on QSAR in Environmental and Health Sciences (QSAR2025) held in Milan in June 2025, addressing structural similarity and local performance assessment, model selection, integration of multiple predictions, and challenges posed by black-box models that demand careful consideration of the balance between predictive performance and explainability. These discussions highlight the experience of integrating QSAR approaches into regulatory frameworks, supported by internationally harmonized OECD principles, standardized reporting formats (QMRF, QPRF, QRRF), and the OECD QSAR Assessment Framework (QAF). The QAF provides a structured basis for evaluating the reliability and regulatory relevance of QSAR predictions through transparent documentation, consideration of applicability domain, and expert-driven interpretation. The discussion is then broadened to examine how modern AI, particularly Large Language Models, may support toxicological risk assessment beyond QSAR modeling itself. Building on both the conference insights and this extended analysis, this work reflects on how principles established through decades of QSAR development and regulatory integration (including considerations on data quality, applicability domain, uncertainty, and expert judgment) may inform the governance of emerging AI applications in chemical safety assessment.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 6","pages":"1059–1071"},"PeriodicalIF":3.8,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147968677","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":"Sensitive Quantification of the Ethylene Oxide Hemoglobin Adduct N-(2-Hydroxyethyl)-l-valine from Minimal Blood Volumes","authors":"Chih-Wei Liu,&nbsp;Jiahao Feng,&nbsp;Jingya Peng,&nbsp;Haoduo Zhao,&nbsp;Xueying Wang,&nbsp;B. Bhaskar Gollapudi,&nbsp;Abby A. Li,&nbsp;James S. Bus,&nbsp;Christopher Kirman and Kun Lu*,&nbsp;","doi":"10.1021/acs.chemrestox.6c00200","DOIUrl":"10.1021/acs.chemrestox.6c00200","url":null,"abstract":"<p >Ethylene oxide (EtO) assessment relies on detecting the hemoglobin adduct <i>N</i>-(2-hydroxyethyl)-<span>l</span>-valine (HE-V). However, current methods require large blood volumes, limiting small-animal exposure studies and reliable detection of endogenous background levels of HE-V. We optimized a highly sensitive analytical workflow including hemoglobin extraction from microliter-scale blood samples, HE-V purification, and targeted LC-MS/MS quantitative analysis. This workflow reliably quantifies endogenous HE-V levels of unexposed mice from only 50 μg of purified hemoglobin (10 μL of blood) and is demonstrated to detect significant HE-V increases at EtO exposures as low as 0.05 ppm. Our platform enables practical EtO biomonitoring in volume-constrained experimental and environmental settings.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 6","pages":"1084–1087"},"PeriodicalIF":3.8,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148003847","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":"Nitrogen Mustard Disrupts Bioenergetics and Activates Oxidative Stress-Induced Cell Death Pathways in Human Keratinocytes","authors":"Yi-Hua Jan,&nbsp;Bozena Michniak-Kohn,&nbsp;Laurie B. Joseph,&nbsp;Debra L. Laskin and Jeffrey D. Laskin*,&nbsp;","doi":"10.1021/acs.chemrestox.6c00099","DOIUrl":"10.1021/acs.chemrestox.6c00099","url":null,"abstract":"<p >Nitrogen mustard (HN2) is a highly reactive bifunctional alkylating agent that causes severe skin injury. To define its impact on keratinocyte bioenergetics and stress responses, we examined mitochondrial function, metabolism, and cell death signaling in human HaCaT cells. Seahorse analysis showed that HN2 caused time- and concentration-dependent suppression of oxidative phosphorylation, including reductions in basal, adenosine 5′-triphosphate-linked, and maximal oxygen consumption. Glycolytic activity was similarly impaired, with decreased extracellular acidification, reduced glucose-stimulated glycolysis, and loss of glycolytic capacity and reserve, indicating broad metabolic dysfunction. HN2-induced bioenergetic impairment triggered rapid nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulation of antioxidant and mitochondrial regulatory genes (HO-1, NQO1, GSTA4, and PGC1α). In parallel, HN2 activated multiple programmed cell death pathways, including apoptosis, autophagy, and ferroptosis, as evidenced by corresponding alterations in Bax, Bcl-xL, LC3-II, SQSTM1/p62, caspase-2, caspase-9, GPx4, TFRC, and ACSL4. Cell cycle analysis identified cells in G2/M as particularly susceptible to HN2, which exhibited enhanced apoptotic signaling. <i>N</i>-acetylcysteine attenuated Nrf2 activation, preserved mitochondrial and glycolytic function, and reduced activation of cell death pathways, demonstrating a central role for oxidative and electrophilic stress in HN2 toxicity. These findings reveal a novel mechanism by which HN2 disrupts keratinocyte bioenergetics to drive stress-dependent cell death and highlight antioxidant intervention as a potential strategy to mitigate HN2-induced skin injury.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 6","pages":"1178–1189"},"PeriodicalIF":3.8,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.6c00099","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148040113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutralization Kinetics and Transport Define the Dermal Decontamination Window for Warfare and Industrial Toxicants","authors":"Laurent Simon*,&nbsp; and ,&nbsp;Ishita Kulkarni,&nbsp;","doi":"10.1021/acs.chemrestox.5c00540","DOIUrl":"10.1021/acs.chemrestox.5c00540","url":null,"abstract":"<p >Chemical warfare agents that are moderately to highly volatile can readily permeate the skin, posing an acute systemic toxicity risk. Effective decontamination depends on how intervention timing and chemical reactivity jointly shape dermal absorption, evaporation, and neutralization. While earlier finite-dose models characterized dermal uptake, they lacked decontaminant reactivity and failed to quantify how neutralization competes with diffusion and surface clearance. This work presents a unified, dimensionless framework integrating diffusion, evaporation, and reactive neutralization. The system behavior is governed by two dimensionless groups: a surface-loss number (<i>π_surf</i>) that captures combined evaporation and interfacial reaction and a Damköhler number (<i>Da</i>) that quantifies bulk neutralization relative to diffusion. Analytical solutions yield characteristic time constants describing the relative rates of absorption, surface clearance, and neutralization. Three distinct kinetic regimes emerge: (i) low <i>Da</i> (&lt;3), where slow internal reaction leaves surface loss as the primary clearance mechanism; (ii) intermediate <i>Da</i> (3–8), characterized by competitive transport and reaction rates; and (iii) high <i>Da</i> (&gt;8), where rapid bulk neutralization renders surface-based interventions progressively less effective. The framework identifies a critical decontamination window during which the applied decontaminant neutralizes the agent faster than it can enter the bloodstream, thereby minimizing systemic exposure. Implemented as open-source Python software, this tool can help emergency responders and regulatory agencies predict decontamination windows for chemical warfare agents and industrial toxicants.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 5","pages":"920–928"},"PeriodicalIF":3.8,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.5c00540","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147669156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of ER Stress via cAMP Signaling: Protective Role of Rolipram in Paracetamol-Induced Liver Injury","authors":"Saziye Sezin Palabiyik-Yucelik,&nbsp;, ,&nbsp;Nagihan Demirtas,&nbsp;, ,&nbsp;Nevra Aydemir Celep,&nbsp;, ,&nbsp;Ayse Bozkurt,&nbsp;, ,&nbsp;Zekai Halici,&nbsp;, and ,&nbsp;Elif Cadirci*,&nbsp;","doi":"10.1021/acs.chemrestox.6c00126","DOIUrl":"10.1021/acs.chemrestox.6c00126","url":null,"abstract":"<p >This investigation sought to assess the potential protective function of the phosphodiesterase-4 (PDE) enzyme inhibitor rolipram (ROL) against paracetamol (PARA) induced liver damage, as well as any potential underlying mechanism through modulation of endoplasmic reticulum (ER) stress via cAMP signaling. Fifty-six rats were randomly divided into 7 groups (<i>n</i> = 8). Following 24 h of fasting, animals received three different dosages of ROL (1.25, 2.5, and 5 mg/kg, i.p.) or <i>N</i>-acetylcysteine (140 mg/kg, orally). One hour later, 2 g/kg PARA orally was administered to induce hepatotoxicity. The ELISA method was used to evaluate GSH, PDE4D, and cAMP levels in liver tissue, as well as PDE4D and cAMP levels in serum. In addition, serum levels of liver injury biomarkers, including ALT and AST, were measured. GRP78, IRE1, and CHOP mRNA expressions in tissue samples were assessed using the Real Time PCR technique. The liver tissue’s histopathological parameters, including necrosis, bleeding, and mononuclear cell infiltration, were evaluated. The PARA group had higher serum and tissue PDE4 levels, lower cAMP and GSH levels, higher ALT and AST levels, and higher expressions of the ER stress markers GRP78, IRE1, and CHOP mRNA. Histopathological evaluation also revealed severe histopathological damage with PARA toxicity. These changes improved with dose dependent increase of ROL dose. It was evaluated that the protective effect of PDE4 enzyme inhibition on liver injury caused by PARA toxicity could be regulated by intracellular secondary communication signals and ER stress inhibition. These findings also suggested that these pathways might be studied in relation to other liver injuries.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 5","pages":"1015–1023"},"PeriodicalIF":3.8,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.6c00126","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147727761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}