Archives of Toxicology最新文献_第7页

Cell identity uncertainty and exposure heterogeneity in germ cell-resolved comet assays. 生殖细胞分辨彗星测定中的细胞身份不确定性和暴露异质性。

IF 10.9 2区医学

Archives of Toxicology Pub Date : 2026-07-28 DOI: 10.1007/s00204-026-04516-7

Man Sun, Dan Zang, Jun Chen

引用次数: 0

No clear evidence of PFAS-induced immunomodulation in SARS-CoV-2-specific human T cell responses following vaccination 没有明确的证据表明，接种疫苗后，pfas诱导的sars - cov -2特异性人T细胞反应具有免疫调节作用。

IF 10.9 2区医学

Archives of Toxicology Pub Date : 2026-07-23 DOI: 10.1007/s00204-026-04511-y

Hermann-Josef Thierse, Katharina Sommerkorn, Moustapha Sy, Patrick Tarnow, Andreas Luch, Katherina Siewert

引用次数: 0

How structural variations in synthetic cannabinoids affect their metabolism: A pilot study on the in vivo metabolism of 8 synthetic cannabinoid receptor agonists. 合成大麻素的结构变化如何影响其代谢：8种合成大麻素受体激动剂体内代谢的初步研究。

IF 10.9 2区医学

Archives of Toxicology Pub Date : 2026-07-23 DOI: 10.1007/s00204-026-04517-6

María Mata-Pesquera, David Fabregat-Safont, Manuela Barneo-Muñoz, María José Sánchez-Catalán, Ferran Martinez-Garcia, Marie Mardal, Juan V Sancho, María Ibáñez

{"title":"How structural variations in synthetic cannabinoids affect their metabolism: A pilot study on the in vivo metabolism of 8 synthetic cannabinoid receptor agonists.","authors":"María Mata-Pesquera, David Fabregat-Safont, Manuela Barneo-Muñoz, María José Sánchez-Catalán, Ferran Martinez-Garcia, Marie Mardal, Juan V Sancho, María Ibáñez","doi":"10.1007/s00204-026-04517-6","DOIUrl":"https://doi.org/10.1007/s00204-026-04517-6","url":null,"abstract":"The structural diversity and continuous emergence of synthetic cannabinoid receptor agonists (SCRAs) pose an important challenge to forensic and clinical toxicology. Understanding their metabolic pathways is essential for identifying reliable consumption biomarkers and improving toxicological screening strategies. This pilot study has investigated the influence of chemical structure on the metabolism of eight structurally diverse SCRAs: AMB-FUBINACA, ADB-FUBINACA, SDB-005, APINACA, CUMYL-4CN-BINACA, 5 F-AMB-PINACA, 5 F-AB-PINACA, and THJ-2201. The compounds were administered to male Sprague-Dawley rats from which serum and urine samples were analysed using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). Metabolite identification was achieved through different analytical strategies. Following structural elucidation, the in vivo metabolism for each SCRA was evaluated, and the corresponding metabolic pathways were proposed. A comparative analysis of the different metabolic reactions was subsequently performed, classifying biotransformations according to the site of occurrence within the molecule, to highlight both shared features and compound-specific pathways. The results demonstrated significant variability in the number and type of metabolites identified, underscoring the substantial influence of chemical structure on SCRA metabolism. Despite this variability, consistent biotransformations across compounds were also observed. Notably, this in vivo study allowed the detection of several metabolites not previously reported in in vitro models, demonstrating the added value of in vivo approaches in profiling the complete metabolic fate of SCRAs.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560680","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}

引用次数: 0

The aryl hydrocarbon receptor is downregulated in MASLD while its activation attenuates steatosis in human hepatocytes through an IGFBP1-associated pathway. 在MASLD中，芳烃受体下调，而其激活通过igfbp1相关途径减弱人肝细胞脂肪变性。

IF 10.9 2区医学

Archives of Toxicology Pub Date : 2026-07-22 DOI: 10.1007/s00204-026-04513-w

Marta Del Pozo-Medina, Polina Soluyanova, Eugenia Pareja, Marta Moreno-Torres, Ramiro Jover

{"title":"The aryl hydrocarbon receptor is downregulated in MASLD while its activation attenuates steatosis in human hepatocytes through an IGFBP1-associated pathway.","authors":"Marta Del Pozo-Medina, Polina Soluyanova, Eugenia Pareja, Marta Moreno-Torres, Ramiro Jover","doi":"10.1007/s00204-026-04513-w","DOIUrl":"https://doi.org/10.1007/s00204-026-04513-w","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a growing global health concern; however, its multiple pathogenic mechanisms remain incompletely understood. The role of the aryl hydrocarbon receptor (AHR) in MASLD is controversial, as it has been described as either pro- or anti-steatotic depending on the experimental context. Through whole-genome expression profiling and RT-qPCR analysis of human liver biopsies from two independent MASLD patient cohorts, we demonstrate that AHR expression and its canonical activity-assessed by CYP1A1 mRNA levels-are inversely correlated with hepatic steatosis. The role of AHR was further investigated in cultured human Upcyte® hepatocytes from different donors treated with a 2:1 oleate:palmitate mixture (0.6 mM) to induce steatosis, in combination with the exogenous AHR agonist β-naphthoflavone (BN, 25 µM) or the endogenous agonist 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE, 25 µM). Activation of AHR resulted in a statistically significant reduction of intracellular lipid levels, as determined by triglyceride quantification and AdipoRed staining. Microarray analysis of AHR-activated human hepatocytes identified IGFBP1 as a robustly induced target gene. Consistently, IGFBP1 expression was diminished in the livers of both MASLD cohorts and positively correlated with AHR expression levels. Furthermore, treatment of human hepatocytes with recombinant IGFBP1, alone or in combination with IGF1, reduced lipid accumulation, supporting IGFBP1 as a potential downstream effector within the anti-steatotic AHR pathway. Collectively, these findings support a role for AHR and its target IGFBP1, as key negative regulators of hepatic lipid accumulation in human hepatocytes and suggest that activation of this pathway may be taken into account in the therapeutic approaches for MASLD.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547623","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}

引用次数: 0

Learning the assay, not the hazard: how computational toxicity models inherit the artifacts of their high-throughput training data. 学习分析，而不是危险：计算毒性模型如何继承其高通量训练数据的工件。

IF 10.9 2区医学

Archives of Toxicology Pub Date : 2026-07-22 DOI: 10.1007/s00204-026-04512-x

Muhammad Javid Iqbal, Tooba Amjad, Cristian Paz

引用次数: 0

Does fluoridated toothpaste induce genotoxicity and cytotoxicity in human oral epithelial cells? 含氟牙膏会对人口腔上皮细胞产生遗传毒性和细胞毒性吗？

IF 10.9 2区医学

Archives of Toxicology Pub Date : 2026-07-22 DOI: 10.1007/s00204-026-04510-z

Gabriel Carvalhal de Aguiar, Antonio Silva, Daniel Araki Ribeiro

引用次数: 0

Molecular characterization of the uterotrophic assay: temporal gene expression changes in uterus and pituitary gland following ethinylestradiol. 子宫营养测定的分子特征：炔雌醇后子宫和垂体的时间基因表达变化。

IF 10.9 2区医学

Archives of Toxicology Pub Date : 2026-07-20 DOI: 10.1007/s00204-026-04507-8

M Pavkovic, A Mahringer, U Bach, A Freyberger, H Ellinger-Ziegelbauer

{"title":"Molecular characterization of the uterotrophic assay: temporal gene expression changes in uterus and pituitary gland following ethinylestradiol.","authors":"M Pavkovic, A Mahringer, U Bach, A Freyberger, H Ellinger-Ziegelbauer","doi":"10.1007/s00204-026-04507-8","DOIUrl":"https://doi.org/10.1007/s00204-026-04507-8","url":null,"abstract":"The uterotrophic bioassay is a recognized tool for assessing estrogenic activities of chemicals, relying on estrogen-induced uterine growth. This study employed the assay in immature female rats using ethinyl estradiol (EE) to explore temporal gene expression dynamics in the uterus and pituitary gland, both estrogen-responsive organs. Gene expression changes were evident as early as 2 h post-EE administration in the uterus, with early responses indicating increased proliferation, macromolecule synthesis, and immune responses-notably through WNT/β-catenin signaling and cholesterol biosynthesis. Estrogen's influence on inflammation was observed, with macrophage polarization shifting from anti-inflammatory M2 to pro-inflammatory M1 types over time. In the pituitary gland, early gene upregulation suggested proliferative and metabolic responses to estrogen. The findings enhance understanding of estrogen's effects on uterine and pituitary function during the uterotrophic assay, offering avenues for assay optimization, improved in vitro models, and refined adverse outcome pathways (AOPs).","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148519679","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}

引用次数: 0

Revisiting cannabinoid receptor-2: a key regulator of hepatic steatosis, inflammatory cascades, and fibrotic progression. 大麻素受体-2：肝脂肪变性、炎症级联反应和纤维化进展的关键调节因子。

IF 10.9 2区医学

Archives of Toxicology Pub Date : 2026-07-20 DOI: 10.1007/s00204-026-04499-5

Shilpa Kumari, Biswanath Nayak, Preeti Garg, Rahul Deshmukh

{"title":"Revisiting cannabinoid receptor-2: a key regulator of hepatic steatosis, inflammatory cascades, and fibrotic progression.","authors":"Shilpa Kumari, Biswanath Nayak, Preeti Garg, Rahul Deshmukh","doi":"10.1007/s00204-026-04499-5","DOIUrl":"https://doi.org/10.1007/s00204-026-04499-5","url":null,"abstract":"Liver diseases constitute a major global health challenge, affecting over 25% of the world's population, with metabolic dysfunction-associated steatotic liver disease (MASLD) emerging as the most prevalent chronic liver disorder and a leading cause of cirrhosis, hepatocellular carcinoma, and liver-related mortality. Despite its increasing burden, effective and targeted pharmacological therapies remain limited, highlighting a critical need to identify novel molecular targets and mechanistic pathways for therapeutic intervention. The endocannabinoid system, comprising cannabinoid receptors, endogenous ligands, and the enzymes involved in their synthesis and degradation, has gained significant attention as a regulator of hepatic physiology and disease. Although cannabinoid receptor 1 (CB1) has been extensively characterized, cannabinoid receptor 2 (CB2), previously considered predominantly immunomodulatory, is now recognized as a key regulator of hepatic lipid metabolism, inflammatory signaling, and fibrogenesis. Metabolic dysfunction induces hepatic lipid accumulation, oxidative stress, and endoplasmic reticulum stress, triggering inflammatory cascades that drive disease progression from simple steatosis to MASLD, metabolic dysfunction-associated steatohepatitis (MASH), and ultimately fibrosis. Emerging evidence indicates that CB2 activation exerts anti-steatotic, anti-inflammatory, and anti-fibrotic effects through cell-specific mechanisms in hepatocytes, Kupffer cells, and hepatic stellate cells. This review revisits CB2 as a central regulator of hepatic pathophysiology, integrating mechanistic insights with preclinical and clinical evidence. Collectively, targeting CB2 signaling presents a promising therapeutic strategy to mitigate steatosis, inflammatory cascades, and fibrotic progression in chronic liver diseases.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148519665","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}

引用次数: 0

A bovine in vitro platform improves species comparability of mitochondrial apoptosis drug-response readouts. 牛体外平台提高线粒体凋亡药物反应读数的物种可比性。

IF 10.9 2区医学

Archives of Toxicology Pub Date : 2026-07-14 DOI: 10.1007/s00204-026-04506-9

Frederike Werry, Axel Schöniger, Annett Honak, Janett Fischer, Paula Richter, Frank Edlich

{"title":"A bovine in vitro platform improves species comparability of mitochondrial apoptosis drug-response readouts.","authors":"Frederike Werry, Axel Schöniger, Annett Honak, Janett Fischer, Paula Richter, Frank Edlich","doi":"10.1007/s00204-026-04506-9","DOIUrl":"https://doi.org/10.1007/s00204-026-04506-9","url":null,"abstract":"Species differences in mitochondrial apoptosis control can bias cytotoxicity endpoints and hazard-relevant mechanistic inference in preclinical test systems that rely on intrinsic-apoptosis readouts. We benchmarked steady-state localization and outer mitochondrial membrane (OMM) assemblies of the BCL-2 effectors BAX and BAK across mammals and combined this with functional apoptosis assays in bovine hepatocytes. Across species, bovine cells most closely recapitulated the human baseline state, whereas murine systems displayed distinct BAX/BAK partitioning and reduced capture of mitochondrial BAX in high-molecular-weight OMM assemblies. Functionally, bovine BFH12 cells showed minimal apoptotic response to the BH3 mimetic ABT-737 as a single agent, while responding robustly to doxorubicin and actinomycin D, as assessed by cytochrome c release, caspase processing and activity, and Annexin V/PI cytometry. These findings identify species-dependent regulation of BAX/BAK retrotranslocation and OMM assembly states as a baseline variable that shapes intrinsic-apoptosis pharmacodynamics. Incorporating bovine systems as a complementary non-rodent in vitro platform may improve model selection and pharmacodynamic readouts for compounds expected to engage mitochondrial apoptosis, thereby reducing avoidable translational misclassification in apoptosis-focused pipelines.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434870","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}

引用次数: 0

Comparative in vitro study of structure related uptake of ten perfluoroalkyl substances by human and rat renal transporters. 人与大鼠肾转运体对十种全氟烷基物质结构摄取的体外比较研究。

IF 10.9 2区医学

Archives of Toxicology Pub Date : 2026-07-14 DOI: 10.1007/s00204-026-04508-7

Chloé M L Argoul, Pierre-Louis Toutain, Nicole Picard-Hagen, Anna Klukovits, Gábor Koncsos, Véronique Gayrard, Marlène Z Lacroix

{"title":"Comparative in vitro study of structure related uptake of ten perfluoroalkyl substances by human and rat renal transporters.","authors":"Chloé M L Argoul, Pierre-Louis Toutain, Nicole Picard-Hagen, Anna Klukovits, Gábor Koncsos, Véronique Gayrard, Marlène Z Lacroix","doi":"10.1007/s00204-026-04508-7","DOIUrl":"https://doi.org/10.1007/s00204-026-04508-7","url":null,"abstract":"Understanding the renal mechanisms underlying per- and polyfluoroalkyl substances (PFASs) elimination is critical to explain species- and structure-dependent toxicokinetic (TK) differences. This study investigated the in vitro uptake of ten PFASs, including perfluoroalkyl carboxylic acids (PFCAs) and sulfonic acids (PFSAs) with carbon chain lengths ranging from 4 to 10, as well as emerging PFASs (GenX, PFO2OA), by eight human and four rat homologous renal transporters using in vitro cell-based assays. Results showed that Organic Anion Transporter 1 (OAT1) specifically mediated PFHxA uptake and identified PFCAs up to nine carbons (PFHxA, PFOA, PFNA) and PFSAs up to six carbons (PFBS and PFHxS) as likely substrates of human OAT3 and OAT4. In rats, Oat1 and Oatp1a1 mediated the transport of these short- and medium-chain PFASs. In addition, the emerging PFASs, GenX and PFO2OA, were identified as likely substrates for human OAT3, rat Oat1, and rat Oatp1a1. In contrast, long-chain PFASs (PFDA, PFOS, PFDS) were not substrates for any tested transporter in either species. Uptake of short- and medium-chain PFASs by human OAT1, OAT3, and rat Oat1, located on the basolateral membrane, supports their roles in active secretion, whereas their interaction with human OAT4 and rat Oatp1a1, in the apical membranes of proximal tubular cells, indicates a potential contribution to tubular reabsorption. The comparable PFAS chain-length threshold for the uptake of PFASs by homologous human and rat renal transporters suggests that additional mechanisms may account for interspecies differences in PFAS renal clearance.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434898","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}

引用次数: 0