Toxicology and applied pharmacology最新文献

{"title":"Muscone ameliorates osteoarthritis progression by inhibiting M1 macrophages polarization via Nrf2/NF-κB axis and protecting chondrocytes","authors":"Zhuang Qian ,&nbsp;Jie Xu ,&nbsp;Lei Zhang ,&nbsp;Zheng Miao ,&nbsp;Ziyan Lv ,&nbsp;Hongwei Ji ,&nbsp;Qian Deng ,&nbsp;Zhuangwei Lv ,&nbsp;Heqin Zhan ,&nbsp;Yang Yu ,&nbsp;Zichuan Liu ,&nbsp;Wenjie Ren","doi":"10.1016/j.taap.2025.117494","DOIUrl":"10.1016/j.taap.2025.117494","url":null,"abstract":"<div><div>Osteoarthritis (OA) is a common and chronic joint condition marked by the deterioration of cartilage, osteophyte formation, and synovial inflammation (synovitis), severely impairing physical function and quality of life. The synovitis is crucial for initiation and exacerbation of OA. Muscone, the main bioactive compound found in musk, exhibits anti-inflammatory, antioxidant, and neuroprotective effects. Nevertheless, it is still uncertain whether Muscone alleviates the progression of OA by suppressing inflammation. Our research investigated how Muscone affected M1 macrophage polarization and joint inflammation in vitro, as well as its effects on OA progression in vivo. Our findings showed that Muscone significantly inhibited pro-inflammatory cytokine secretion and M1 polarization in LPS-induced RAW264.7 macrophages. Moreover, Muscone suppressed synovitis by impeding pro-inflammatory and M1-related factors in synovium of OA mice. Mechanistic investigations revealed Muscone directly bound Nrf2 and promoted its nuclear translation in LPS-induced RAW264.7 cells, while also simultaneously suppressing the phosphorylation of P65 and IκBα within the NF-κB signaling pathway. Moreover, the pharmacological blockade of Nrf2 partially mitigated the influence of Muscone on LPS-triggered M1 macrophage polarization and the NF-κB pathway. Furthermore, Muscone slowed down the degeneration of articular cartilage in OA mice by promoting chondrocyte anabolism and simultaneously inhibiting inflammation, catabolic processes, and apoptosis of chondrocytes. Overall, our findings indicate that Muscone mitigates the advancement of OA through the inhibition of M1 macrophage polarization and the protection of chondrocytes, thus highlighting its potential as a therapeutic candidate for OA treatment.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"503 ","pages":"Article 117494"},"PeriodicalIF":3.4,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144750571","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":"Flame retardant tricresyl phosphate gestational exposure induced endocrine and metabolic disruptions in rat","authors":"S.A. Valentino ,&nbsp;J.-P. Sabaté ,&nbsp;M. Perceau ,&nbsp;S. Viton ,&nbsp;S. Grossmann ,&nbsp;M. Mascherin ,&nbsp;D. Rousseau-Ralliard ,&nbsp;D. Ndiaye ,&nbsp;F. Cosnier ,&nbsp;L. Gaté","doi":"10.1016/j.taap.2025.117493","DOIUrl":"10.1016/j.taap.2025.117493","url":null,"abstract":"<div><div>Organophosphate flame retardants (OPFRs), including tricresyl phosphate (TCP), are incorporated into a wide variety of polymers to give them fire resistance. They are therefore present in numerous industrial and consumer products such as electrical and electronic appliances, building materials, furnishings and textiles. TCP induces disturbed fertility, intracellular lipid accumulation and disrupts fatty acid metabolism. The toxicological profiles of these molecules, combined with the lack of data, led to interest in their effects on male reproductive function and lipid metabolism.</div><div>Sprague-Dawley rats were exposed to increasing doses of TCP from days 12 to 19 of gestation, a critical period for reproductive masculinization and genital development. Organs and biological fluid samples were collected from the mother and from the fetus. Maternal physiology, <em>via</em> weight monitoring and blood biochemistry, was analyzed, as were gestation parameters. Fetal testosterone production was measured, with the expression of genes involved in steroidogenesis. Fatty acid profiles in maternal and fetal livers and maternal adrenals were analyzed in association with measurements of the expression of genes involved in cholesterol and fatty acid metabolism.</div><div>TCP demonstrated endocrine and metabolic disruption, inducing maternal adverse impact at 300 mg/kg, with reduced weight gain, liver weight and increased adrenal weight. Furthermore, at fetal level, <em>in utero</em> exposure to TCP induced a significant decrease in testosterone production without disruption of steroidogenesis gene expression. TCP exposure disrupted fatty acid profiles in maternal and fetal livers and maternal adrenals. These results shed new light on the toxicological properties of OPFRs following different mechanisms of action.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"503 ","pages":"Article 117493"},"PeriodicalIF":3.4,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757946","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":"Dental enamel following maternal exposure to different fluoride concentrations: Physicochemical and functional approaches in rats offspring","authors":"Victória Santos Chemelo ,&nbsp;Maria Karolina Martins Ferreira ,&nbsp;Leonardo Oliveira Bittencourt ,&nbsp;Liliana Carolina Báez-Quintero ,&nbsp;Juliano Pelim Pessan ,&nbsp;Alan Rodrigo Leal Albuquerque ,&nbsp;Rômulo Simões Angélica ,&nbsp;Sofia Pessanha ,&nbsp;Aline Dionizio ,&nbsp;Marília Afonso Rabelo Buzalaf ,&nbsp;Rafael Rodrigues Lima","doi":"10.1016/j.taap.2025.117495","DOIUrl":"10.1016/j.taap.2025.117495","url":null,"abstract":"<div><div>Excessive fluoride (F) exposure is associated with adverse effects at different life stages and can affect various biological systems, including the mineralized tissues of the oral cavity. However, there is limited evidence that early F exposure during pregnancy and lactation impairs the development of offspring dental enamel. From a translational perspective, this study aimed to investigate the effects of F at different concentrations on the ultrastructural, physicochemical, and functional properties of dental enamel in the offspring of rats exposed during the prenatal and lactation periods. Pregnant Wistar rats were divided into: control (deionized water), 10 mg F/L, and 50 mg F/L. F exposure was conducted from the first day of pregnancy until the 21st day of lactation. Enamel samples from the offspring's upper incisors were collected to evaluate F levels, ultrastructural characteristics, and physicochemical composition through scanning electron microscopy (SEM), Fourier Transform Infrared Spectroscopy (FTIR), Raman spectroscopy, and X-ray diffraction (XRD). The results showed that increased levels of F triggered changes in phosphate and carbonate contents, with no alterations in the ultrastructure of the prisms or enamel crystallinity. Nevertheless, a significant increase in enamel hardness was observed in F exposed groups. These findings suggest that while F exposure did not affect the ultrastructure integrity of enamel, it significantly altered its chemical composition and mechanical properties. Our data suggest that maternal exposure to excessive levels of F during the prenatal and lactation periods leads to increased enamel hardness, which could impact enamel friability.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117495"},"PeriodicalIF":3.4,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144761430","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":"Ceritinib (LDK378) inhibits laryngeal squamous cell carcinoma progression via regulating ROS-induced mitochondrial apoptosis and inducing oxidative stress","authors":"Yue Wang ,&nbsp;Xiaoli Ren ,&nbsp;Pengyan Liu ,&nbsp;Ran An ,&nbsp;Wenjing Li ,&nbsp;Licheng Xu ,&nbsp;Yaoyao Dong ,&nbsp;Xiaolin Xu ,&nbsp;Yi wang ,&nbsp;Lei Zhang ,&nbsp;Linli Tian","doi":"10.1016/j.taap.2025.117489","DOIUrl":"10.1016/j.taap.2025.117489","url":null,"abstract":"<div><div>Laryngeal squamous cell carcinoma (LSCC) is a prevalent malignant tumor of the head and neck with unfavorable outcomes. Ceritinib, an FDA-approved tyrosine kinase inhibitor targeting the insulin-like growth factor 1 receptor (IGF1R), has not been thoroughly explored for its therapeutic potential in LSCC. In this study, we demonstrated that Ceritinib significantly inhibits the growth of LSCC cells (TU686 and AMC-HN8), disrupts oxidative stress homeostasis, and induces mitochondrial-mediated apoptosis. Ceritinib triggered ROS overload, and the apoptotic effects were reversed by <em>N</em>-acetylcysteine, confirming ROS-dependent mitochondrial apoptosis. Transcriptome sequencing and Western blot analysis revealed that Ceritinib suppresses PI3K/Akt signaling to promote apoptosis. Ceritinib triggered mitochondria mediated apoptosis via ROS-PI3K/AKT axis to inhibit the progression of LSCC. Furthermore, using Chou-Talalay's method, we calculated the combination index (CI) for Ceritinib and cisplatin, demonstrating that their combination synergistically suppressed the malignant behavior of LSCC cells, exacerbated mitochondrial dysfunction, and enhanced oxidative stress in vitro. In vivo, Ceritinib (25 mg/kg) alone or in combination with cisplatin (2 mg/kg) significantly inhibited LSCC tumor growth without affecting bodyweight. Overall, our findings highlight that Ceritinib, both as a monotherapy and in combination with cisplatin, effectively inhibits LSCC progression in vitro and in vivo—with the combination more potently promoting apoptosis and suppressing tumor cell proliferation, consistent with our in vitro results—underscoring its potential as a promising therapeutic strategy for LSCC treatment.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"503 ","pages":"Article 117489"},"PeriodicalIF":3.4,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144750569","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":"Plumbagin activates NLRP3/caspase-1/GSDMD-mediated pyroptosis by decreasing DUSP4 expression to exhibit anticancer property in cholangiocarcinoma","authors":"Fei Song ,&nbsp;Lingxiao Wei ,&nbsp;Junchao Wu ,&nbsp;Guoyi Zhu ,&nbsp;Jigui Zhang ,&nbsp;Hongyang Li","doi":"10.1016/j.taap.2025.117492","DOIUrl":"10.1016/j.taap.2025.117492","url":null,"abstract":"<div><h3>Background</h3><div>Plumbagin is effective in treating cholangiocarcinoma (CCA), however, the potential mechanism of plumbagin therapy is still unclear. This study aims to uncover the anti-tumor nature of plumbagin and the specific mechanism by which plumbagin alleviates NLRP3/caspase-1/GSDMD-induced pyroptosis.</div></div><div><h3>Methods</h3><div>Human CCA cells lines HuCCT1 and RBE and the CCA mouse model injected with HuCCT1 cells were used for the mechanism exploration. Different concentrations of plumbagin were incubated with the cells or injected to the CCA mouse to investigate the anti-tumor role of pumbagin. CCK-8 and Transwell was used to detect the cell viability and migration, respectively. ELISA kits were used to detect the ROS, LDH, IL-1β, and IL-18 levels. SEM was used for pyroptosis condition observation. qRT-PCR and WB were used to detect the expression levels of DUSP4, NLRP3, GSDMD-N, and cle-caspase-1 levels. Immunohistochemical staining was used for detection of tumor tissue injury.</div></div><div><h3>Results</h3><div>In CCA cells, plumbagin inhibited the cell viability and migration. In CCA mouse model, plumbagin inhibited the tumor growth. Along with the plumbagin treatment, the decreased DUSP4 expression, and increased ROS, LDH, NLRP3, clecaspase-1, GSDMD-N proteins, and pyroptosis degree, were investigated. After addition of NLRP3 inhibitor MCC950 and transfection of oe-DUSP4, the promoted pyroptosis and inhibited tumor growth induced by plumbagin were reversed, indicating that the plumbagin treatment inhibited the CCA progression through decreasing the DUSP4 expression and thus activating the pyroptosis.</div></div><div><h3>Conclusion</h3><div>DUSP4/NLRP3/caspase-1/GSDMD-mediated pyroptosis is demonstrated to be the therapeutic mechanism of plumbagin in CCA.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117492"},"PeriodicalIF":3.4,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144761431","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":"Miconazole alleviates colitis by suppressing colonic senescence, NF-κB Signaling and gut microbiota modulation","authors":"Fuxing Li ,&nbsp;Shujia Song ,&nbsp;Mingming Huang ,&nbsp;Yaxing Xu ,&nbsp;Bingxiang Zhao ,&nbsp;Zhenlin Liu ,&nbsp;Bin Fu ,&nbsp;Huilai Zhang ,&nbsp;Hanying Zou ,&nbsp;Min Zhou ,&nbsp;Lihua Li ,&nbsp;Xiaobo Wang","doi":"10.1016/j.taap.2025.117488","DOIUrl":"10.1016/j.taap.2025.117488","url":null,"abstract":"<div><div>Ulcerative colitis (UC) is a chronic relapsing non-transmural inflammatory bowel disease characterized by bloody diarrhea, closely associated with intestinal epithelial cell senescence and chronic inflammation. This study reveals novel mechanisms of the imidazole antifungal drug Miconazole (MCZ) in UC treatment. Through compound library screening, we found that MCZ effectively inhibits dextran sulfate sodium (DSS)-induced senescence in colonic epithelial NCM460 cells. Although clinically used for over 40 years, its anti-senescence and anti-inflammatory mechanisms remain unclear. Experiments confirmed that MCZ significantly reduces DSS-induced SA-β-Gal-positive cell proportion and P16/P21 expression. In animal models, MCZ ameliorated DSS-induced weight loss, bloody stools, and colonic tissue damage. Mechanistic studies demonstrated that MCZ specifically modulates microbiota composition (enriching beneficial bacteria Adlercreutzia, Lactobacillus, Ligilactobacillus, and Limosilactobacillus, while suppressing the relative abundance of Mycoplasma, Oscillibacter, and Streptococcus), and inhibits inflammatory progression by blocking the phosphorylation cascade of the NF-κB signaling pathway. These findings not only reveal MCZ's novel anti-senescence and anti-inflammatory functions but also provide potential new strategies for UC treatment.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"503 ","pages":"Article 117488"},"PeriodicalIF":3.4,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144750570","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":"Exploring the mechanism of cinobufagin on gastric cancer based on proteomics, molecular dynamics, in vitro and in vivo experiment","authors":"Pin Wang ,&nbsp;Xia Zhang ,&nbsp;Hanwei Ma ,&nbsp;Youcheng Zhang","doi":"10.1016/j.taap.2025.117490","DOIUrl":"10.1016/j.taap.2025.117490","url":null,"abstract":"<div><div>Cinobufagin as one of the primary bioactive components of Chansu, which is a widely used traditional remedy in China, has been employed in the treatment of various malignant tumors, including gastric cancer. However, its antitumor effects on gastric cancer and the underlying mechanisms have not yet been fully elucidated. This study aims to comprehensively investigate the effects of cinobufagin on AGS gastric cancer cells both in vitro and in vivo, and to further explore its mechanism of action. AGS gastric cancer cells were treated with cinobufagin. A series of assays and analyses were conducted, and an in vivo gastric cancer model, to examine changes in AGS cell characteristics and to elucidate the molecular mechanisms underlying the effects of cinobufagin. Our data demonstrate that cinobufagin exhibits multiple anti-gastric cancer activities, including suppression of proliferation, induction of apoptosis, cell cycle arresting at the G0/G1 phase, and inhibition of migration and invasion in AGS gastric cancer cells. Furthermore, proteomic analysis, bioinformatics analysis, molecular docking, and molecular dynamics simulation suggest that decorin (DCN) is the most probable target of cinobufagin. Western blot and immunohistochemistry (IHC) assays confirmed that cinobufagin significantly upregulated DCN expression in both AGS cells and xenograft tumors. Moreover, cinobufagin effectively reduced the levels of EGFR and active EGFR, and inhibited Erk phosphorylation, which may contribute to its anti-gastric cancer effects. Cinobufagin is capable of suppressing gastric tumor growth in mice likely through the DCN/EGFR pathway and may serve as a potential treatment option for gastric cancer.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"503 ","pages":"Article 117490"},"PeriodicalIF":3.4,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144722001","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":"Systemic toxicity induced by topical application of the sulfonic acids, perfluorobutane sulfonic acid (PFBS) and perfluoropentane sulfonic acid (PFPeS), in a murine model","authors":"Madison P. Cooper ,&nbsp;Lisa M. Weatherly ,&nbsp;Ewa Lukomska ,&nbsp;Laurel G. Jackson ,&nbsp;Stacey E. Anderson","doi":"10.1016/j.taap.2025.117487","DOIUrl":"10.1016/j.taap.2025.117487","url":null,"abstract":"<div><div><em>Per</em>- and polyfluoroalkyl substances (PFAS) are a large group of synthetic surfactants incorporated into products for their chemical and physical properties. Studies have associated PFAS with adverse health effects. Although there is a high potential for dermal exposure, toxicity studies related to this route of exposure are lacking. The present study evaluated the systemic toxicity following a sub-chronic 28-day dermal exposure to perfluorobutane sulfonic acid (PFBS) (1.25–5 %) or perfluoropentane sulfonic acid (PFPeS) (1.25–5 %) in a murine model. Elevated levels of both PFAS were detected in the serum and urine, suggesting that absorption occurs through the skin. Additionally, both PFAS induced significantly increased relative liver weight, altered serum chemistries, altered skin and liver histopathology, and significantly decreased relative spleen weight (PFPeS only). Gene expression changes were observed in the liver and skin for genes involved in fatty acid metabolism, inflammation, and skin integrity. In general, the PFPeS-induced changes in the endpoints examined were observed more frequently compared to PFBS, supporting the concept that longer-chain PFAS are more toxic. These findings support PFAS absorption through the skin, leading to liver damage and systemic toxicity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"503 ","pages":"Article 117487"},"PeriodicalIF":3.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718730","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":"Triclosan (TCS) promotes lipid accumulation in the mouse adipocyte (3T3-L1) cell line via peroxisome proliferator activated receptor gamma (PPARγ) pathway","authors":"Konrad A. Szychowski ,&nbsp;Bartosz Skóra ,&nbsp;Anna K. Wójtowicz","doi":"10.1016/j.taap.2025.117482","DOIUrl":"10.1016/j.taap.2025.117482","url":null,"abstract":"<div><div>Triclosan (TCS) is one of the most widely used antibacterial agents and is commonly detected not only in the environment but also in the human body. Epidemiological studies have associated TCS exposure with increased body weight and metabolic alterations. The aim of this study was to elucidate the molecular mechanisms by which TCS promotes lipid accumulation and differentiation in preadipocytes, using the murine 3T3-L1 cell model. Our experiments demonstrate that low concentrations of TCS (1 μM) promote lipid accumulation and induce adipogenic differentiation in 3T3-L1 cells. This process involves PPARγ-related pathways, as confirmed using rosiglitazone, a well-characterized PPARγ agonist. TCS further potentiates rosiglitazone-induced differentiation, leading to the formation of mature adipocytes with large lipid droplets. This phenotype is associated with reduced levels of GLUT4 and IGF-1R, <em>i.e.</em> key regulators of glucose uptake and insulin signaling. Additionally, TCS modulated the expression of adipogenic and metabolic regulators, including <em>FABP4</em>, <em>Resistin</em>, <em>DLK1</em>, <em>Adipoq</em>, <em>Serpin E1</em>, and <em>VEGF-A</em>. TCS also altered the activity of signaling proteins such as PI3K, STAT3, and GSK3β. Notably, at the tested concentration, TCS did not affect the IκBα/NFκB axis, suggesting it does not trigger inflammatory signaling in this model. Our findings indicate that TCS enhances 3T3-L1 differentiation toward a metabolically compromised adipocyte phenotype, supporting its classification as a potential pro-obesogenic compound. These results provide new insights into how TCS may contribute to adipose tissue dysfunction and the development of insulin resistance. Further <em>in vivo</em> studies are warranted to assess the systemic impact of chronic TCS exposure.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"503 ","pages":"Article 117482"},"PeriodicalIF":3.3,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144703358","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":"PFAS-exposed zebrafish embryos show impaired innate immune response after infection with mycobacteria","authors":"Maxim P. Carlier ,&nbsp;Theo Verboom ,&nbsp;Laura Cuijpers ,&nbsp;Lisa Baumann ,&nbsp;Wilbert Bitter ,&nbsp;Timo Hamers","doi":"10.1016/j.taap.2025.117484","DOIUrl":"10.1016/j.taap.2025.117484","url":null,"abstract":"<div><div>The <em>Per</em>- and polyfluoroalkyl substances PFNA, PFOA, PFOS and PFHxS have been regulated in the EU based on their interference with immune system functions. For many more environmental pollutants possible effects on immune function are unknown, so quick screening methods are required to determine which compounds are of highest immunotoxic concern. The aim of the present study was to optimize a test protocol to assess effects of chemicals on the innate immune system using zebrafish (<em>Danio rerio</em>) embryos. In a second step, the protocol was used to determine the immunotoxic effects of 11 PFAS on the innate immune response to pathogen infection. In the final protocol, zebrafish embryos were manually dechorionated 24 h after fertilization and subsequently infected with a transgenic strain of <em>Mycobacterium marinum</em> expressing the fluorescent protein mCherry. To avoid interference by systemic toxic effects that are not specific to the immune system, embryos were exposed to test compound concentrations that caused no developmental effects. Exposure was started immediately after infection. At 120 h after fertilization, the bacterial load, <em>i.e.</em> the integrated fluorescence intensity of bacteria in embryos exposed to the PFAS was compared to the integrated fluorescence intensity in infected vehicle-treated (control) embryos. In our optimized immunotoxicity assay, exposure to PFHxS and PFOA resulted in increased bacterial loads compared to vehicle treated embryos, indicating an increase in infection severity. Thus, the present study demonstrates that this zebrafish embryo immunotoxicity assay is useful to detect suppression of the innate immune system after chemical exposure.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"503 ","pages":"Article 117484"},"PeriodicalIF":3.3,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144694423","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}