Toxicology最新文献

{"title":"Bisphenol AP promotes pulmonary fibrosis by regulating macrophage function in a bleomycin-induced mouse model","authors":"Ze Chen ,&nbsp;Zhenying Lin ,&nbsp;Meng Ni ,&nbsp;Baihe Li ,&nbsp;Qianqian Zhang ,&nbsp;Zelin Cao ,&nbsp;Wei Li ,&nbsp;Yanan Tang ,&nbsp;Dongting Yao ,&nbsp;Chunyu Cheng ,&nbsp;Yi Hu ,&nbsp;Xiaorui Liu ,&nbsp;Jiuru Zhao ,&nbsp;Zhiwei Liu","doi":"10.1016/j.tox.2026.154396","DOIUrl":"10.1016/j.tox.2026.154396","url":null,"abstract":"<div><div>Bisphenols are extensively used in industrial and consumer products and may pose potential risks to human health. Previous studies have shown that bisphenol A (BPA) induces chronic inflammation and lung toxicity. Bisphenol AP (BPAP), a structural analogue of BPA, has also been associated with adverse health outcomes, including metabolic disorders and mood disturbances. However, its role in pulmonary diseases remains poorly characterized. In this study, a bleomycin (BLM)-induced pulmonary fibrosis (PF) model in C57BL/6 mice was employed to investigate the effects of BPAP on pulmonary pathology. Although BPAP exposure alone did not induce PF-related pathological changes, pretreatment with BPAP (0.4 mg/kg/day) initiated 14 days before BLM administration significantly aggravated BLM-induced histopathological alterations, inflammation, and collagen deposition. This exacerbation of fibrosis was accompanied by a marked upregulation of the M2 macrophage marker arginase-1. Further <em>in vitro</em> assays showed that 24-hour BPAP exposure inhibited macrophage proliferation, increased oxidative stress, and enhanced both phagocytic and chemotactic activities in the RAW 264.7 mouse macrophage cell line. Mechanistic analyses revealed that BPAP modulated several key molecules involved in cell cycle regulation, phagocytosis, and chemotaxis, specifically Ttk, Fcgr1, and Ccl5. These findings indicate that BPAP exacerbates BLM-induced PF by dysregulating macrophage function. This study provides new insights into the pulmonary toxicity of BPAP and underscores the potential health risks associated with its exposure.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154396"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900911","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 and in vitro toxicokinetics including metabolism, isozyme mapping, and monoamine oxidase inhibition of three (2-aminopropyl)benzo[b]thiophene (APBT) psychedelics","authors":"Lea Wagmann ,&nbsp;Simon D. Brandt ,&nbsp;Pierce V. Kavanagh ,&nbsp;Markus R. Meyer","doi":"10.1016/j.tox.2026.154402","DOIUrl":"10.1016/j.tox.2026.154402","url":null,"abstract":"<div><div>3-(2-Aminopropyl)benzo[<em>b</em>]thiophene (3-APBT), 5-APBT, and 6-APBT are recently identified psychedelics and entactogens that activate serotonin 2 receptor subtypes and lead to a head-twitch response in mice. The present study characterized their toxicokinetics, metabolism, and monoamine oxidase (MAO) inhibition using liquid chromatography-high-resolution tandem mass spectrometry. Metabolites were tentatively identified in urine from male Wistar rats collected over 24 h after oral administration (2 mg/kg body weight) and in incubations with pooled human liver S9 fraction (25 µM after 1 and 6 h). Phase I isoenzyme mapping and MAO inhibition were assessed using individual incubations with 11 human monooxygenases or recombinant human MAO-A and MAO-B. Hydroxylation was the predominant phase I biotransformation, primarily catalyzed by cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A4, and CYP3A5, while <em>N</em>-acetylation, glucuronidation, and sulfation were observed as phase II reactions. The metabolic patterns were similar to those of related 5- and 6-(2-aminopropyl)benzofuran analogues, and the involvement of multiple CYP isozymes suggested a reduced toxicity risk e.g., by CYP-mediated drug-drug interactions. However, all three APBT isomers strongly inhibited MAO-A (IC₅₀ of 5-APBT 0.4 µM, 6-APBT 0.6 µM, and 3-APBT 4 µM) but only weakly MAO-B (IC₅₀ 23–49 µM). Given that the MAO-A inhibition strengths of 5-APBT and 6-APBT were in the range of model inhibitors, clinically relevant MAO-A inhibition and associated interaction risks and toxic effects cannot be excluded. These data provide a toxicokinetic basis to support the clinical and forensic interpretation of exposures to APBT and related sulfur-based psychedelics.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154402"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145939759","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":"Transcriptomic analysis of BPA alternative chemicals in primary human mammary epithelial cells","authors":"Geronimo Matteo ,&nbsp;Andrea Rowan-Carroll ,&nbsp;Lauren M. Bradford ,&nbsp;Matthew J. Meier ,&nbsp;Andrew Williams ,&nbsp;J. Christopher Corton ,&nbsp;Carole L. Yauk ,&nbsp;Ella Atlas","doi":"10.1016/j.tox.2025.154375","DOIUrl":"10.1016/j.tox.2025.154375","url":null,"abstract":"<div><div>Some everyday consumer products contain endocrine disruptors like bisphenol A (BPA) and its replacements. To date, most <em>in vitro</em> chemical screening to evaluate these compounds has been accomplished using immortalized cell lines, which differ significantly from human tissues. Our goal was to test BPA and select alternatives previously screened in breast cancer cells for toxicological potency and mechanism of action in human mammary epithelial cells (HMECs). HMECs from three human donors were exposed to BPA and four alternative chemicals (in concentration response format from 0.001 to 50 µM) for 48 h and global transcriptomic changes were quantified. Transcriptomic biomarker analysis was employed to explore chemically induced estrogen receptor alpha (ERα) activation and alterations in stress response pathways. Benchmark concentration (BMC) analysis was applied to gene expression data to derive transcriptomic points of departure (tPODs) to compare chemicals for potency. Pathway and upstream regulator analysis was applied among the genes fitting BMCs. All chemicals had tPODs within a single order of magnitude. Bisphenol AF (BPAF) was the most potent, followed by tetramethyl bisphenol F (TMBPF), bisphenol C (BPC), 4,4’-bisphenol S (BPS), and BPA. None of the chemicals activated the ERα biomarker. Some stress response biomarkers were activated at high exposure concentrations. Genes fitting BMCs clustered chemicals into two groups, with one group (BPAF and TMBPF) primarily inhibiting expression patterns and the other (BPC, BPS, and BPA) mostly activating. These data suggest that the BPA alternatives tested have similar toxicological potencies in HMECs and oppositely enrich various gene sets.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154375"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145811034","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":"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}