Archives of Toxicology最新文献

{"title":"In silico studies and in vitro evaluation of isatin-pyridine oxime hybrids as novel reactivators of acetylcholinesterase inhibited by an A-230 surrogate.","authors":"Leandro B Bernardo, Leandro A Vieira, Caio V N Borges, Pedro A G Buitrago, Kamil Kuča, Tanos C C França, Samir F A Cavalcante, Roberto B Sousa, Antônio L S Lima, Daniel A S Kitagawa","doi":"10.1007/s00204-025-03976-7","DOIUrl":"https://doi.org/10.1007/s00204-025-03976-7","url":null,"abstract":"<p><p>Recent events involving nerve agents of the A-Series, a once elusive class of chemical warfare agents, have provoked a great concern in the international community. In this paper, continuing our research efforts in Medicinal Chemistry at the Brazilian Institute of Chemical, Biological, Radiological and Nuclear Defense (IDQBRN) (an OPCW-designated Laboratory for environmental samples), we explore ANMP, an A-230 surrogate, in the search for new treatment options for intoxications caused by these chemicals. Five isatin-pyridine oxime hybrids were evaluated as acetylcholinesterase (AChE) reactivators using a modified Ellman's assay. Our results indicate that monocationic hybrids with five methylene units, as well as its oxa-analog, are promising compounds for the design of new AChE reactivators.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human and rat renal proximal tubule in vitro models for ADME applications.","authors":"Olivia C Klatt, Lenya de Brouwer, Femke Hendriks, Eva-Maria Dehne, Beren Ataç Wagegg, Paul Jennings, Anja Wilmes","doi":"10.1007/s00204-025-03987-4","DOIUrl":"https://doi.org/10.1007/s00204-025-03987-4","url":null,"abstract":"<p><p>The kidney is a major organ dictating excretion rates of chemicals and their metabolites from the body and thus renal clearance is frequently a major component of pharmaco-(toxico)-kinetic profiles. Within the nephron, the proximal tubule is the major site for xenobiotic reabsorption from glomerular filtrate and xenobiotic secretion from the blood into the lumen via the expression of multiple inward (lumen to interstitium) and outward transport systems (interstitium to lumen). While there exist several human proximal tubular cell culture options that could be utilized for modelling the proximal tubule component of renal clearance, they do not necessarily represent the full complement of xenobiotic transport processes of their in vivo counterparts. Here, we review available human and rat renal proximal tubule in vitro models, including subcellular fractions, immortalized cell lines, primary cell cultures, induced pluripotent stem cell (iPSC)-derived models and also consider more organotypic cell culture environments such as microporous growth supports, organoids and microfluidic systems. This review focuses on expression levels and function of human and rat renal transporters and phase I and II metabolizing enzymes in these models in order to critically assess their usefulness and to identify potential solutions to overcome identified limitations.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro-in silico analysis reveals that loss of tankyrase1/2 improves bile acid handling in genetically engineered HepG2 cultures.","authors":"Kristof De Vos, Raf Mols, Yeghig Armoudjian, Patrick Augustijns, Pieter Annaert","doi":"10.1007/s00204-025-03979-4","DOIUrl":"https://doi.org/10.1007/s00204-025-03979-4","url":null,"abstract":"<p><p>Modelling and simulation of hepatic bile acids (BA) kinetics is instrumental to understand mechanisms underlying drug-induced cholestasis (DiCho). A recent study has shown that the loss of tankyrase1/2 (TNKS1/2) matured the hepatic phenotype in vitro in terms of cellular respiration rate and metabolism. However, whether this phenotype was accompanied with more in vivo relevant hepatic BA handling was not investigated. The present study explored whether tankyrase1/2 loss improved hepatic BA handling through an integrated in vitro-in silico approach. To do so, double knockout (DKO) TNKS1/2 HepG2 cells were exposed to a 10 µM BA mixture containing chenodeoxycholic acid (CDCA), cholic acid, deoxycholic acid, and lithocholic acid. BA levels and their metabolites were subsequently quantified in medium and cell extracts using liquid chromatography-tandem mass spectrometry (LC-MSMS). The in vitro data were then used as input in an ordinary differentially equation (ODE)-based kinetics model that was solved in R, using CDCA and its metabolites as index. The analyses revealed that glycine and taurine conjugation were enhanced by 1.5- and 2.2-fold, respectively, in the HepG2-DKO cells compared to the control. Further, the mechanistic model unveiled that efflux of taurochenodeoxycholic acid was elevated. In conclusion, HepG2-DKO cells provide a robust foundation for building a sensitive in vitro model for DiCho studies. Furthermore, this study discovered that tankyrase1/2 loss improved BA metabolism and kinetics, promoting the utility of tankyrase1/2 inhibitors, like XAV-939, in future pre-clinical BA disposition interaction studies.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"7-Hydroxycannabidiol and 7-carboxycannabidiol induced cytotoxicity via apoptosis and endoplasmic reticulum stress in human hepatic cells.","authors":"Yuxi Li, Xilin Li, Qiangen Wu, Montserrat Puig, Frederic Moulin, Supratim Choudhuri, Jeremy Gingrich, Lei Guo, Si Chen","doi":"10.1007/s00204-025-04001-7","DOIUrl":"https://doi.org/10.1007/s00204-025-04001-7","url":null,"abstract":"<p><p>Cannabidiol (CBD), a major component of extract from the plant Cannabis sativa L., has demonstrated efficacy in treating childhood-onset epilepsy; however, animal studies and clinical trials have reported elevated liver enzymes after CBD use, suggesting potential liver toxicity. In a previous study, we demonstrated that CBD caused cytotoxicity with apoptosis and endoplasmic reticulum (ER) stress in human hepatic cells. In the present study, we investigated the toxicity profile of the two main metabolites of CBD, 7-hydroxy-CBD and 7-carboxy-CBD, in primary human hepatocytes and HepG2 cells. Our findings indicated that both metabolites induced cellular damage similar to the parent drug in these cells. 7-Hydroxy-CBD and 7-carboxy-CBD also caused cell cycle disturbances, apoptosis, and ER stress in HepG2 cells. Additionally, we explored the role of cytochrome P450 (CYP) in the metabolism of 7-hydroxy-CBD and 7-carboxy-CBD using HepG2 cell lines expressing 14 individual CYPs. We determined that 7-hydroxy-CBD is metabolized by CYP2D6, and CYP2D6-mediated metabolism attenuated the cytotoxicity, apoptosis, and ER stress induced by 7-hydroxy-CBD. The CYPs did not metabolize 7-carboxy-CBD. In summary, our findings highlight the mechanisms underlying cytotoxicity induced by 7-hydroxy-CBD and 7-carboxy-CBD in hepatic cells.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Click-chemistry-derived oxime library reveals efficient reactivators of nerve agent-inhibited butyrylcholinesterase suitable for pseudo-catalytic bioscavenging.","authors":"Tena Čadež, Nikolina Maček Hrvat, Goran Šinko, Jarosław Kalisiak, Zoran Radić, Valery V Fokin, Karl Barry Sharpless, Palmer Taylor, Zrinka Kovarik","doi":"10.1007/s00204-025-03985-6","DOIUrl":"https://doi.org/10.1007/s00204-025-03985-6","url":null,"abstract":"<p><p>A library of 100 click-chemistry-derived oximes was evaluated as reactivators of butyrylcholinesterase (BChE) inhibited by the nerve agents (NAs) sarin, cyclosarin, VX, and tabun. While reactivation efficiency was highly dependent on the structure of both the NA and the oxime, for each NA-BChE conjugate, we identified reactivators more effective than currently approved oximes for NA poisoning. Detailed kinetic analysis indicated that this enhancement results from both improved molecular recognition-specifically, enhanced binding affinity of the phosphylated conjugates for the oximes-and increased maximal reactivation rates. Molecular modeling of oximes in a near-attack conformation within inhibited BChE revealed critical interactions for productive reactivation. Among all tested oximes, 5B [1-hexyl-2-((hydroxyimino)methyl)pyridinium chloride] emerged as a particularly efficient reactivator for BChE phosphorylated with cyclosarin, with the highest observed overall reactivation rate of 34,120 M^-1 min^-1, which is 525-fold and 44-fold higher than the reference oximes 2-PAM and HI-6, respectively. In general, three mono-pyridinium mono-oximes demonstrated more efficient recovery of BChE activity than bis-pyridinium triazole-annulated click-chemistry bis-oximes, which were previously identified as potent reactivators for inhibited acetylcholinesterase (AChE). Ex vivo assessment of reactivation potency demonstrated that the combined addition of BChE with one efficient reactivator for BChE and another for AChE achieved > 90% reactivation of cyclosarin-inhibited cholinesterases in whole blood (WB), demonstrating near-complete degradation of a 100-fold excess of cyclosarin within 6 min. These results confirm that oxime-assisted catalysis is feasible for NA bioscavenging in blood and underscore BChE's potential as a target for developing therapies against NA poisoning.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imbalance of human CD4+ T lymphocyte subsets following atrazine treatment","authors":"Mahdieh Naghavi Alhosseini,&nbsp;Ambra Maddalon,&nbsp;Luigi Cari,&nbsp;Simona Ronchetti,&nbsp;Graziella Migliorati,&nbsp;Emanuela Corsini,&nbsp;Giuseppe Nocentini","doi":"10.1007/s00204-025-03974-9","DOIUrl":"10.1007/s00204-025-03974-9","url":null,"abstract":"<div><p>While being banned in the European Union, the herbicide atrazine (ATR) is still one of the most used herbicides in the world. ATR is classified as an endocrine disruptor, but the immunotoxic effects of ATR may also be due to its direct impact on immune cells. To study the effects of ATR on human T cells, we activated T cells present in PBMCs of 8 healthy donors in the presence of ATR (0.1–100 μM). After 4 days of culture, T cells were stained to evaluate cell growth and phenotype by flow cytometry. The results demonstrated that ATR treatment exerts an antiproliferative activity on CD4⁺ T cells and decreases their activation, including the percentage of cytokine-producing CD4⁺ T cells. Among these, the percentage of interferon (IFN)-<b><i>γ</i></b>- and interleukin (IL)-22-producing CD4⁺ T cells decreased within total CD4⁺ T cells. Moreover, IL-4-, IL-10- and IL-17-producing CD4⁺ T cells decreased within cytokine-producing CD4⁺ T cells. Consequently, ATR caused a dose-related decrease in Th1/Th2 ratio. Many of the effects of ATR treatment were quantitatively different in males and females, with more pronounced effects observed in females. tSNE analysis demonstrated that ATR strongly inhibited the differentiation of two subsets of IFN-<b><i>γ</i></b>⁺IL-4⁺CD4⁺ T cells from each of the healthy donors tested and promoted greater differentiation of the CD25⁺FoxP3⁺CD4⁺ T cell subset from seven out of the eight healthy donors tested. In conclusion, the study suggests that ATR skews CD4⁺ T cell activation towards Th2, a phenotype that may promote reduced immunosurveillance and increased risk of cancer, as well as Th2-related diseases such as asthma, thereby presenting an environmental and occupation-related risk to human health.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 4","pages":"1455 - 1469"},"PeriodicalIF":4.8,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-025-03974-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perfluorooctanoic acid increases serum cholesterol in a PPARα-dependent manner in female mice.","authors":"G Nielsen, D D Gondim, M C Cave, W J Heiger-Bernays, T F Webster, J J Schlezinger","doi":"10.1007/s00204-025-03984-7","DOIUrl":"https://doi.org/10.1007/s00204-025-03984-7","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFAS) are a large group of persistent chemicals that are pervasive in the environment leading to widespread exposure for humans. Perfluorooctanoic acid (PFOA), one of the most commonly measured PFAS in people, disrupts liver and serum lipid homeostasis as shown in animal toxicity and human epidemiological studies. We tested the hypothesis that the effects of PFOA exposure in mice expressing mouse PPARα (mPPARα) are driven largely through PPARα-dependent mechanisms while non-PPARα dependent mechanisms will be more apparent in mice expressing human PPARα (hPPARα). Female and male mPPARα, hPPARα, and PPARα null mice were exposed to PFOA (0.5, 1.4 or 6.2 mg PFOA/L) via drinking water for 14 weeks. Concurrently, mice consumed an American diet containing human diet-relevant amounts of fat and cholesterol. Here, we focused on the effects in female mice, given the dearth of data reported on PFAS-induced effects in females. Increasing the duration of PFOA exposure reduced weight gain in all genotypes of female mice while end-of-study body fat was lower in PFOA exposed hPPARα and PPARα null mice. Serum cholesterol, but not triacylglyceride, concentrations were increased by PFOA exposure in a PPARα-dependent manner. Hepatic triacylglycerides were higher in vehicle-exposed mPPARα and PPARα null mice than hPPARα mice, and PFOA significantly reduced concentrations in mPPARα and PPARα null mice only. In contrast, PFOA increased hepatic cholesterol content in a PPARα-dependent manner. Changes in liver and serum cholesterol may be explained by a strong, PPARα-dependent downregulation of Cyp7a1 expression. PFOA significantly increased PPARα target gene expression in mPPARα mice. Other nuclear receptors were examined: CAR target gene expression was only induced by PFOA in hPPARα and PPARα null mice. PXR target gene expression was induced by PFOA in all genotypes. Results were similar in male mice with two exceptions: (1) vehicle-exposed male mice of all genotypes were equally susceptible to diet-induced hepatic steatosis; (2) male mice drank less water, resulting in lower serum PFOA levels, which may explain the less significant changes in lipid endpoints. Overall, our results show that PFOA modifies triacylglyceride and cholesterol homeostasis independently and that PPARα plays an important role in PFOA-induced increases in liver and serum cholesterol.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic activation and cytotoxicity of ibudilast mediated by CYP3A4.","authors":"Lingwen Dong, Xialing Hao, Minglu Liu, Yanjie Zhai, Xu Wang, Xiaobao Tian, Weiwei Li, Ying Peng, Jiang Zheng","doi":"10.1007/s00204-025-03995-4","DOIUrl":"https://doi.org/10.1007/s00204-025-03995-4","url":null,"abstract":"<p><p>Ibudilast (IBD) is a relatively nonselective inhibitor of phosphodiesterase, commonly used for treating asthma, progressive multiple sclerosis and other neuropathological pain conditions. Although IBD was considered safe and harmless to human health, its clinical use might be associated with reported increases of serum AST and ALT as well as liver weight. However, the mechanisms behind such liver injury are still unknown. The purpose of this work was to investigate metabolic activation of IBD and to define correlation between bioactivation and hepatotoxicity of IBD. Two oxidative metabolites, IBD-derived glutathione (GSH) conjugates (M1, M2), N-acetyl-L-cysteine (NAC) conjugates (M3, M4), and cysteine (Cys) conjugates (M5, M6) were detected in mouse liver microsomes fortified with IBD (100 μM) and trapping agents GSH, NAC, or Cys, respectively, and two GSH conjugates (M1 and M2), one NAC conjugate (M4) and one Cys conjugate (M5) were detected. Similar observation was obtained in human liver microsomal incubations. The formation of M1-M6 was NADPH-dependent. Moreover, biliary GSH conjugates and urinary NAC conjugates derived from IBD were detected in mice given IBD intragastrically at 100 mg/kg. The metabolism study suggested the formation of an epoxide intermediate. In addition, the epoxide intermediate was found to react with cysteine residues of hepatic protein in a dose-dependent manner. Further studies indicate that CYP3A4 dominated the metabolic activation of IBD. Exposure of primary hepatocytes to IBD resulted in decreased cell survival. Pretreatment of mice hepatocytes with ketoconazole attenuated the susceptibility to the cytotoxicity of IBD (25-400 μM). The reactive epoxide intermediate might correlate the hepatotoxicity induced by IBD. This work revealed the reactive epoxide intermediate might correlate the hepatotoxicity induced by IBD, and would provide new insights into the mechanisms behind the adverse reactions taking place in clinical use of IBD, especially for the reported liver injury.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure to polystyrene nanoplastics causes anxiety and depressive-like behavior and down-regulates EAAT2 expression in mice.","authors":"Ziyang Su, Rui Kong, Chengqing Huang, Kun Wang, Chenhao Liu, Xiaozhen Gu, Hui-Li Wang","doi":"10.1007/s00204-025-04002-6","DOIUrl":"https://doi.org/10.1007/s00204-025-04002-6","url":null,"abstract":"<p><p>Microplastics exposure can induce brain dysfunction like cognitive impairment, Parkinson's disease, and autism spectrum disorders. In this study, we aimed to investigate the effects of Polystyrene nanoplastics (NPS) on anxiety and depression in mice. First, Polystyrene nanoplastics (NPS) (10 mg/kg) were administered orally daily for two months starting at PND 21. Subsequently, behavioral tests about anxiety and depression were conducted, including the open field test, the elevated plus maze, the forced swimming test, and the tail suspension test. The results showed that NPS induced anxiety and depression-like behaviors in mice. The mPFC played a pivotal role in the etiology of anxiety and depression, in which nanoplastics led to impaired synaptic transmission and reduced neuronal activity in vivo in mPFC. Furthermore, the astrocyte marker GFAP was abnormally increased as observed in mPFC. The abnormal activation of astrocytes results in impaired glutamate recycling through decreasing the expression of the glutamate transporter protein EAAT2 after NPS exposure. In order to ascertain the function of EAAT2, the EAAT2 activator (LDN-212320) was employed to stimulate the expression of EAAT2. Following the activation of EAAT2, synaptic transmission, and anxiety and depressive behavior were rescued in the mice. Polystyrene nanoplastics induce anxiety and depressive-like behavior in mice possibly inhibiting astrocyte EAAT2 expression. Specific activation EAAT2 of astrocytes rescue anxiety and depressive behavior in nanoplastics exposed mice.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T-2 toxin-induced splenic injury by disrupting the gut microbiota-spleen axis via promoting IL-6/JAK/STAT1 signaling-mediated inflammation and apoptosis and its mitigation by elemental nano-selenium.","authors":"Meng Liu, Xue-Wu Li, Hua Sun, Yi-Qin Yan, Zhi-Yuan Xia, Alainaa Refaie, Ni-Ya Zhang, Shuai Wang, Chen Tan, Lv-Hui Sun","doi":"10.1007/s00204-025-04005-3","DOIUrl":"https://doi.org/10.1007/s00204-025-04005-3","url":null,"abstract":"<p><p>T-2 toxin is one of the most toxic A trichothecene mycotoxins prevalent in the environment and food chain, which brings severe health hazards to both animals and humans and it can significantly damage immune function. In this study, we comprehensively explained the impact of T-2 toxin on the spleen through gut microbiota-spleen axis by integrating the transcriptome and microbiome. Our results revealed that dietary T-2 toxin ≥ 1.0 mg/kg exposure significantly inhibited the growth performance and caused spleen injury in broilers chicks, accompanied by oxidative stress and histopathological damage. Cecal microbiome analysis suggested that T-2 toxin exposure caused gut microbial dysbiosis, especially leading to the decrease of some beneficial bacteria genera that enhanced gut barrier and reduced inflammation, including Blautia, Coprococcus, Lachnospira and Anaerostipes belonging to Lachnospiraceae family. Transcriptome analysis suggested that T-2 toxin exposure directly caused splenic inflammation and immune-related signaling, such as cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway, NOD-like receptor signaling pathway and JAK-STAT signaling pathway. Furthermore, by integrating the transcriptome and microbiome analysis, we found that spleen damage induced by T-2 toxin was associated with the abnormal activation of IL-6/JAK/STAT1 signaling pathway-mediated inflammation and apoptosis, which was further verified by western bolt analysis. Notably, dietary selenium supplementation could protect chicks from T-2 toxin-induced adverse effects on growth performance and spleen injury by inhibiting the expression of the IL-6/JAK/STAT1 signaling-related genes. In summary, our findings provided new insights into the immunotoxicity mechanisms of T-2 toxin in the chickens' spleen and highlighted the potential of selenium to alleviate T-2 toxin-induced immunotoxicity.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}