Toxicology最新文献

{"title":"PM2.5 induces cardiac defects by triggering endoplasmic reticulum stress mediated through the impairment of SIRT6 deacetylase activity","authors":"Jianhui Liu ,&nbsp;Yuan Wang ,&nbsp;Shaofei Su ,&nbsp;Ruixia Liu ,&nbsp;Jiajia Wang ,&nbsp;Shuanghua Xie ,&nbsp;Chenghong Yin ,&nbsp;Enjie Zhang","doi":"10.1016/j.tox.2026.154404","DOIUrl":"10.1016/j.tox.2026.154404","url":null,"abstract":"<div><div>A growing body of research suggests that maternal exposure to fine particulate matter (PM2.5) is linked to congenital heart disease in the offspring. Endoplasmic reticulum stress (ERS) has been established as a cause of the cardiac developmental toxicity of PM2.5. Silent information regulator 6 (SIRT6) which serves as a protective element against environmental pollutants, was closely associated with cardiovascular conditions. However, the precise underlying molecular mechanisms remain unclear. Pregnant mice were exposed to PM2.5 or sterile saline through oropharyngeal aspiration, proteomic analysis of fetal cardiac tissue was performed. Co-immunoprecipitation analysis was used to examine the interaction of SIRT6 and PERK. We observed that maternal exposure to PM2.5 caused abnormal cardiac development in offspring, accompanied by a marked reduction in the expression of NKX2.5. In the AC16 cardiomyocyte model, exposure to PM2.5, contributed to a marked increase in cardiomyocyte apoptosis. Moreover, proteomic analysis revealed a significant disruption in protein processing in the endoplasmic reticulum. We further demonstrated that the expression of PERK and activity of the PERK/eIF2α/CHOP signaling pathway were significantly upregulated, along with a notable increase in PERK acetylation levels. More importantly, we confirmed the interaction between SIRT6 and PERK. Concurrently, a significant reduction in SIRT6 expression was detected alongside elevated H3K9 acetylation after exposure to PM2.5. The treatment of AC16 cells with the SIRT6 activator UBCS039 significantly attenuated PM2.5-induced PERK activation and cardiomyocyte apoptosis. Our results reveal that PM2.5 induces the downregulation of SIRT6, which promotes PERK hyperacetylation and activates the PERK/eIF2α/CHOP pathway, triggering ERS, ultimately resulting in abnormal cardiac development in offspring.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154404"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145978153","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":"In vivo high-throughput toxicity screening of brominated flame retardants using a Caenorhabditis elegans transcription factor RNAi platform","authors":"Siyeol Ahn ,&nbsp;Elizabeth Dufourcq Sekatcheff ,&nbsp;Jinhee Choi","doi":"10.1016/j.tox.2026.154395","DOIUrl":"10.1016/j.tox.2026.154395","url":null,"abstract":"<div><div>Brominated flame retardants (BFRs) such as tetrabromobisphenol A (TBBPA), hexabromocyclododecane (HBCDD), and decabromodiphenyl ethane (DBDPE) are extensively used in a variety of consumer products, including electronics, textiles, and furniture. However, their environmental persistence and potential for neurodevelopmental toxicity have raised increasing concern. Legacy compounds such as TBBPA and HBCDD are undergoing regulation or being phased out, while alternatives like DBDPE remain poorly characterized, leaving uncertainties regarding their suitability as replacements. In order to rapidly fill knowledge gaps on these data poor substances and avoid regrettable substitutions, we established a high-throughput, mechanism-based <em>in vivo</em> toxicity screening platform. A RNAi approach on <em>Caenorhabditis elegans</em> Transcription Factors (TF) was used to assess biological pathways that were triggered by BFR exposure, leading to neurotoxicity (assessed via locomotion behavior). Using a 384-TF RNAi library, we identified 44 TFs modulating TBBPA-induced neurotoxicity. Pathway analyses (Reactome and CTD) highlighted retinoic acid receptor signaling as a key event, which mapped to four neurodevelopmental AOPs (AOP 520, 523, 532, and 533). Gene expression analysis of <em>sex-1</em> and <em>unc-55</em> confirmed retinoic acid signaling pathway activation. Application of the same framework to HBCDD and DBDPE revealed partially conserved behavioral and molecular responses, supporting the cross-chemical applicability of the TBBPA-derived AOP network. These findings demonstrate the utility of <em>C. elegans</em>-based TF RNAi screening as a fit-for-purpose New Approach Methodology (NAM) for mechanistic toxicology. By linking molecular initiating events to adverse outcomes, this strategy enables early hazard identification and read across strategy via AOP-informed, animal-free chemical risk assessment within next-generation risk assessment (NGRA) frameworks.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154395"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896921","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 exposure to polypropylene nanoplastics disrupts sex- and region-specific lipid metabolism in the brains of C57BL/6N mouse offspring","authors":"Jangjae Lee ,&nbsp;Subin Park ,&nbsp;Da Yong Lee ,&nbsp;Sung-Hee Cho","doi":"10.1016/j.tox.2025.154392","DOIUrl":"10.1016/j.tox.2025.154392","url":null,"abstract":"<div><div>Polypropylene nanoplastics (PPNPs), produced through the degradation of widely used plastic products, are increasingly recognized as emerging environmental contaminants with potential neurodevelopmental toxicity. However, the long-term biochemical consequences of prenatal PPNP exposure on brain development remain poorly understood. In this study, we performed a region- and sex-specific targeted lipidomic analysis to examine how maternal oral exposure to PPNPs during pregnancy and lactation alters brain lipid composition in offspring at postnatal day 21. Using liquid chromatography–tandem mass spectrometry (LC–MS/MS), we profiled lipid classes in the hippocampus (HP), cortex (CTX), cerebellum (CB), and dorsal raphe nucleus (DR) of both male and female mice. Our findings revealed distinct, region-specific lipid remodeling patterns in response to PPNP exposure. Females exhibited consistent reductions in neuroprotective lipids, including lysophosphatidylethanolamines (LPEs) and plasmalogens, most prominently in the hippocampus. Males, in contrast, displayed elevated triglyceride levels and region-specific alterations in phospholipid composition, such as reduced phosphatidylcholines in the hippocampus and dorsal raphe. These results indicate that maternal nanoplastic exposure, even without postnatal contact, can cause persistent, sex-specific disturbances in brain lipid metabolism. To our knowledge, this study provides the first targeted lipidomic characterization of offspring brains following maternal PPNP exposure and highlights the importance of brain region–specific lipid analysis for identifying localized disruptions in neurodevelopment caused by environmental pollutants.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154392"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893146","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":"Development and analysis of the adverse outcome pathway network for neurotoxicity","authors":"Xinyue Hui ,&nbsp;Xingying Li ,&nbsp;Sisi Liu ,&nbsp;Guang-Guo Ying ,&nbsp;Chang-Er Chen","doi":"10.1016/j.tox.2026.154397","DOIUrl":"10.1016/j.tox.2026.154397","url":null,"abstract":"<div><div>Adverse Outcome Pathways (AOPs) and their networks offer a structured framework for understanding toxicological mechanisms and supporting non-animal testing strategies. This study developed a neurotoxicity-focused AOP network (NT-AOPn) based on AOP-Wiki data and analyzed its topological properties using graph theory. We identified key events with high connectivity and centrality—such as oxidative stress and decreased thyroxine—and determined the two most prevalent adverse outcomes: Impairment of Learning and Memory (ILM) and Decreased Cognitive Function (CFD). Further analysis of their subnetworks revealed system-level perturbations spanning metabolic, neurological, and reproductive systems, and uncovered two novel AOP pathways linking molecular initiating events to adverse outcomes. Additionally, chemical stressors including heavy metals and pesticides were associated with these pathways. Our findings enhance the mechanistic understanding of neurotoxicity and provide a foundation for in vitro assays and computational modeling in risk assessment.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154397"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918628","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":"Could cannabigerol protect against neuroinflammation? Insights from an in vitro microglial study","authors":"Júlia Maiara dos Santos ,&nbsp;Amanda Kolinski Machado ,&nbsp;Djenifer Leticia Ulrich Bick ,&nbsp;Michele Rorato Sagrillo ,&nbsp;Elaine Aparecida Del Bel ,&nbsp;Alencar Kolinski Machado ,&nbsp;Antonio Cardozo dos Santos","doi":"10.1016/j.tox.2026.154406","DOIUrl":"10.1016/j.tox.2026.154406","url":null,"abstract":"<div><div>Cannabigerol (CBG), a non-psychotropic cannabinoid from <em>Cannabis sativa</em>, has been investigated for its anti-inflammatory potential. However, its toxicological profile and the mechanisms underlying its effects are still poorly understood. This experimental study evaluated the safety and anti-inflammatory efficacy of CBG in BV-2 microglial cells, in a model of neuroinflammation. BV-2 cells were exposed to CBG concentrations ranging from 0.01 to 100 μM for 24 h to investigate non-cytotoxic doses. Colorimetric and fluorometric assays were performed in triplicate to assess cellular viability (MTT), the production of reactive oxygen species (ROS) and nitric oxide (NO), genotoxicity (GEMO and Alkaline Comet assay), and Caspase-1 gene expression. Cell morphology was also monitored microscopically. The results revealed that CBG 100 μM was highly cytotoxic, reducing cell viability by about 80 % and significantly increasing NO (approximately 400 %) and ROS (approximately 900 %) levels. Additionally, CBG was shown to be genotoxic in the GEMO assay at various concentrations, with 10 μM and 100 μM inducing DNA damage of approximately 200 % and 300 %, respectively. However, no genotoxicity was identified in the Comet assay. At higher concentrations, CBG also promoted the activation of microglia, altering their morphology. In a neuroinflammation model, CBG was unable to attenuate the increase in ROS levels induced by NLRP3 activation and promoted an increase in Caspase-1 gene expression. Despite a favorable safety profile at low doses, CBG exhibits inconsistent anti-inflammatory effects and can be genotoxic depending on the dose and exposure conditions.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154406"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145978152","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":"PPAR subtypes determine distinct modes of action of phthalate esters (PAEs) and per- and polyfluoroalkyl substances (PFAS) in disrupting human macrophage alternative activation","authors":"Zhisen Zhuang ,&nbsp;Lijuan You ,&nbsp;Jianbo Kong ,&nbsp;Yaru Tian ,&nbsp;Yongning Li ,&nbsp;Yuan Zhi ,&nbsp;Bo Zhang ,&nbsp;Yi Wan ,&nbsp;Xudong Jia ,&nbsp;Hui Yang","doi":"10.1016/j.tox.2025.154387","DOIUrl":"10.1016/j.tox.2025.154387","url":null,"abstract":"<div><div>Phthalate esters (PAEs) and per- and polyfluoroalkyl substances (PFAS) are ubiquitous pollutants tied to metabolic and immune disorders. The peroxisome proliferator-activated receptor (PPAR) pathway has been indicated to mediate their toxic effects, but the specific functions of PPAR subtypes and their mediating roles remain unclear. In this study, we generated PPARα-, δ-, and γ-specific knockout THP-1 cell lines by using CRISPR/Cas9 system and then differentiated them into interleukin-4 (IL-4) and interleukin-13 (IL-13)-polarized macrophages (alternative activation). During the induction process, the cells were exposed to 0, 6.25, 12.5, 25, 50, 100 μM of five PAE metabolites: Mono-(2-ethylhexyl) phthalate (MEHP), Monocyclohexyl phthalate (MCHP), Monoisonyl phthalate (MINP), Monoisobutyl phthalate (MIBP), and Monobenzyl phthalate (MBzP); and five PFAS: Perfluoroundecanoic acid (PFUnDA), Perfluorodecanoic acid (PFDA), Perfluorooctanoic acid (PFOA), Potassium perfluorooctanesulfonate (PFOS-K), and Potassium 9-chlorohexadecafluoro-3-oxanonane-1-sulfonate (F53B) for 48 h. The results showed that PPARδ deletion abolished CD209 expression, confirming its essential role, whereas PPARα deletion reduced and PPARγ deletion enhanced CD209, indicating PPARα promotes and PPARγ restrains alternative activation. Compounds displayed subtype-selective actions: MEHP activated PPARα/γ; MBzP/MCHP inhibited PPARδ yet activated PPARγ; MINP activated PPARγ only. Among PFAS, PFOS-K activated PPARδ/γ; F53B inhibited PPARα; PFOA activated PPARγ; PFDA inhibited PPARα/δ. Transcriptomics revealed compound-specific enrichments—cholesterol (MEHP), fatty-acid (MCHP), glycolysis (PFOS-K), TCA cycle (PFOA)—despite common PPAR pathway engagement. In conclusion, PAEs and PFAS disrupt macrophage plasticity through distinct PPAR-subtype signatures, providing molecular landmarks for future hazard assessment of environmental pollutants.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154387"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850303","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":"PFHxS exposure causes osteoarthritis through the innate immune signaling pathway mediated by lipid peroxidation","authors":"Xicong Chen ,&nbsp;Huiliang Zeng ,&nbsp;Guocai Chen ,&nbsp;Haiyun Yang","doi":"10.1016/j.tox.2026.154403","DOIUrl":"10.1016/j.tox.2026.154403","url":null,"abstract":"<div><div>PFHxS have been widely used and detected in the environment. The toxicological effects of PFHxS exposure on cartilage tissues and cells are not fully clear. The objective of this work was to study the toxicological effects of PFHxS on cartilage. We investigated these effects using both in-vitro and in-vivo models. In the in-vitro model, we exposed chondrocytes to environmentally relevant concentrations of PFHxS. In the in-vivo model, we assessed cartilage damage using various staining methods, including toluidine blue, alcian blue, and safranin-fast green staining. In chondrocytes, PFHxS exposure decreased cell viability and induced inflammatory and oxidative stress responses.Further experiments showed that PFHxS induced lipid peroxidation, increased Fe²⁺ levels, and significantly decreased the expression of GPX4 and xCT, indicating the induction of ferroptosis. Oxidative stress also led to large-scale production of ds-DNA and activation of the cGAS-STING signaling pathway.In the in-vivo model, PFHxS exposure caused damage to cartilage tissues, as evidenced by the tissue staining.Similarly, in vivo findings showed that PFHxS induced ferroptosis-like characteristics in cartilage tissues, including decreased GPX4 and xCT and increased iron ion levels. This study is the first to reveal that the environmental pollutant PFHxS causes extracellular matrix degradation and functional damage to chondrocytes by inducing ferroptosis and activating the cGAS-STING inflammatory pathway. These findings establish a theoretical basis for a potential association between PFHxS environmental exposure and cartilage-degenerative diseases.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154403"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145960445","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":"NOX4/Keap1/Nrf2/ROS signaling drives ferroptosis in trimethyltin chloride-induced cardiac developmental malformations","authors":"Jin Chen ,&nbsp;Hanwen Hu ,&nbsp;Jing Fu ,&nbsp;Yaolin He ,&nbsp;Hui Zhou ,&nbsp;Jingwei Lei ,&nbsp;Ming Huang ,&nbsp;Jianqi Wang ,&nbsp;Anfei Liu ,&nbsp;Zhenzhong Liu","doi":"10.1016/j.tox.2026.154394","DOIUrl":"10.1016/j.tox.2026.154394","url":null,"abstract":"<div><div>Trimethyltin chloride (TMT), a pervasive environmental organic tin pollutant, has been implicated in cardiac injury, though its underlying mechanisms remain unclear. TMT exposure triggers excessive reactive oxygen species (ROS) generation, a key inducer of ferroptosis—a regulated form of cell death driven by iron-dependent lipid peroxidation. NADPH oxidase 4 (NOX4), highly expressed during cardiac development, plays a critical role in myocardial ROS production, while the Keap1/Nrf2 pathway regulates cellular ROS homeostasis. We hypothesized that TMT induces cardiac developmental defects by activating NOX4/Keap1/ROS-mediated ferroptosis. TMT exposure induced cardiac malformations, pericardial edema, and reduced heart rate in zebrafish embryos. Further studies revealed that TMT upregulated nox4 expression in embryonic hearts. Notably, pharmacological inhibition or genetic knockdown of nox4 markedly attenuated TMT-induced cardiac defects. Moreover, nox4 suppression antagonized TMT-triggered dysregulation of the Keap1/Nrf2 axis, ROS overaccumulation, mitochondrial damage, and ferroptosis-related abnormalities—including Fe²⁺ accumulation, elevated lipid peroxidation, and downregulated glutathione peroxidase 4 (GPX4) expression. Crucially, inhibition or knockdown of keap1 similarly mitigated TMT-induced ROS bursts, mitochondrial injury, and ferroptosis progression. Intervention with ferroptosis-specific inhibitors (Liproxstatin-1 and Myricetin) confirmed that ferroptosis directly contributes to TMT-induced cardiac developmental defects. This study demonstrates that TMT induces cardiac malformations by activating ferroptosis via the nox4/Keap1/Nrf2/ROS signaling axis. These findings reveal a novel mechanism underlying TMT cardiotoxicity, provide theoretical insights for assessing TMT exposure as a risk factor for congenital heart disease, and identify potential molecular targets for therapeutic intervention.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154394"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900904","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 scalable human liver-on-a-chip platform for predictive safety assessment","authors":"Gauri Kulkarni ,&nbsp;Lizao Chen ,&nbsp;Jing Sang ,&nbsp;Ji Hye Seo ,&nbsp;Romain Grall ,&nbsp;Yunfang Wang ,&nbsp;Paige Gilbride ,&nbsp;Yu-Chieh Yuan ,&nbsp;Matthew Albaum-Getzen ,&nbsp;Jenna McCormack ,&nbsp;Jingzhe Ma ,&nbsp;Alyssa Fanelli ,&nbsp;Lingjun Meng ,&nbsp;Beibei Xu ,&nbsp;XuHai Huang ,&nbsp;Thomas Marshall ,&nbsp;Hardeep Singh ,&nbsp;Xiaohua Qian ,&nbsp;Zhiyong Xie ,&nbsp;Hui Bai ,&nbsp;Haiqing Bai","doi":"10.1016/j.tox.2025.154378","DOIUrl":"10.1016/j.tox.2025.154378","url":null,"abstract":"<div><div>Non-animal methods, including advanced <em>in-vitro</em> approaches such as liver-on-a-chip models, hold promise for hepatotoxicity testing but remain limited in pharmaceutical and regulatory adoption due to high costs, poor scalability, low reproducibility, and insufficient validation. To address these challenges, we introduce a drug-induced liver injury (DILI) model based on the commercially available and highly adaptable OC-Plex microfluidic platform. Primary human hepatocytes (PHHs) maintained long-term viability and metabolic competence, confirmed by albumin and urea production as well as cytochrome P450 gene expression. The system reliably detected acetaminophen (APAP) - induced hepatotoxicity across six mechanistic readouts—albumin, viability, cytokeratin-18 (CK18), urea, CYP3A4 activity, and mitochondrial function. As an initial proof-of-concept, we tested 17 compounds, including both drugs and cosmetic ingredients. Among 13 compounds with known toxicity liabilities in humans, our model shows a high predictive performance (85.7 % sensitivity, 100 % specificity, and 92.3 % accuracy). Together, these findings demonstrate the feasibility of a cost-effective, scalable, and human-relevant liver-on-a-chip system for predictive hepatotoxicity testing. With future development and validation, this model holds great potential to replace animal testing in chemical safety assessment.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154378"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145805556","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":"Nickel refining fumes activate glutamine metabolism via the HIF‐1α/Notch pathway to drive epithelial-mesenchymal transition in Beas‐2B cells","authors":"Qian-Qian Sun ,&nbsp;Han-Nong Yu ,&nbsp;Rui-Ze Wu ,&nbsp;Bo Zhang ,&nbsp;Wen-Xue Yao ,&nbsp;Wei-Yang Liu ,&nbsp;Jia Han ,&nbsp;Li-Yan Ju ,&nbsp;Yu-Lin Pan ,&nbsp;Yong-Hui Wu","doi":"10.1016/j.tox.2025.154390","DOIUrl":"10.1016/j.tox.2025.154390","url":null,"abstract":"<div><div>Occupational exposure to nickel refining fumes (NiRF) represents a critical risk factor for respiratory diseases; however, the molecular mechanisms governing NiRF-induced epithelial-mesenchymal transition (EMT) in bronchial epithelial cells remain incompletely elucidated. In vitro experiments using the human bronchial epithelial cell line Beas-2B as a model demonstrated that NiRF exposure robustly activated the hypoxia-inducible factor-1α (HIF-1α)/Notch signaling pathway, while concomitantly triggering glutamine metabolic reprogramming. This reprogramming phenotype was characterized by the upregulated expression of the glutamine transporter SLC1A5 and enhanced expression of glutaminase 1 (GLS1). Functional validation assays revealed that small interfering RNA (siRNA)-mediated silencing of HIF-1α (siHIF-1α) or Notch1 (siNotch1) significantly downregulated GLS1 expression, and reversed NiRF-induced glutamine metabolic activation. Furthermore, pharmacological inhibition of glutamine metabolism via treatment with a GLS1 inhibitor effectively abrogated the EMT process in Beas-2B cells, as evidenced by the upregulated expression of the epithelial marker E-cadherin and the downregulated expression of the mesenchymal markers N-cadherin and vimentin. In vivo experiments further confirmed that NiRF promoted EMT in lung tissue cells in a dose-dependent manner, accompanied by activation of the HIF-1α/Notch signaling pathway and enhanced glutamine metabolism (as reflected by the upregulated expression of both SLC1A5 and GLS1). Collectively, these findings verify that glutamine metabolic activation, mediated by the HIF-1α/Notch pathway, constitutes the core mechanism underlying NiRF-driven EMT in Beas-2B cells. This study provides novel theoretical insights and potential therapeutic targets for elucidating the pathogenesis of occupational NiRF-associated respiratory injury and developing targeted intervention strategies.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154390"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888943","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}