Archives of Toxicology最新文献

{"title":"NAD(P)⁺-dependent alcohol oxidoreductases oxidize 7-hydroxycannabidiol to a reactive formyl metabolite.","authors":"Qiangen Wu, Jia-Long Fang, Suresh K Nagumalli, Xiaoqing Guo, Frederick A Beland","doi":"10.1007/s00204-025-04140-x","DOIUrl":"https://doi.org/10.1007/s00204-025-04140-x","url":null,"abstract":"<p><p>Cannabidiol (CBD) undergoes oxidation to 7-hydroxy-CBD in the liver via cytochrome P450 enzymes. 7-Hydroxy-CBD can be further oxidized to 7-carboxy-CBD, the principal circulating metabolite in humans. An aldehyde intermediate, 7-formyl-CBD, is hypothesized to be the precursor of 7-carboxy-CBD; however, the formation of 7-formyl-CBD and the enzymes leading to its formation and metabolism have not been thoroughly investigated. Upon incubating 7-hydroxy-CBD with human liver S9 or microsomes, and using O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine (PFBHA) as a trapping agent, we demonstrated the formation of 7-formyl-CBD as its oxime derivative 7-pentafluorobenzyl oxime-CBD (7-PFBO-CBD). The transformation of 7-hydroxy-CBD to 7-formyl-CBD in S9 or microsomes required NAD⁺ or NADP⁺. Trapping 7-formyl-CBD with PFBHA decreased the formation of 7-carboxy-CBD, indicating that the formation of 7-carboxy-CBD depends on the availability of 7-formyl-CBD. The flavonoid kaempferol, which inhibits xanthine oxidoreductase and hydroxysteroid dehydrogenases, suppressed the formation of 7-PFBO-CBD and 7-carboxy-CBD in human liver S9 and microsomes incubated with 7-hydroxy-CBD. The xanthine oxidoreductase inhibitor allopurinol and its substrate xanthine did not affect the metabolism of 7-hydroxy-CBD. The hydroxysteroids estradiol and dehydroepiandrosterone reduced the formation of 7-carboxy-CBD in liver microsomes and S9. These results suggest that alcohol oxidoreductases associated with hydroxysteroid metabolism may play a role in the conversion of 7-hydroxy-CBD to 7-formyl-CBD. The irreversible aldehyde dehydrogenase inhibitors, disulfiram and WIN 18,446, inhibited the formation of 7-carboxy-CBD and led to a significant accumulation of 7-PFBO-CBD in the S9 and microsomal incubations. The accumulation of the aldehyde intermediate may play a role in the enhanced cytotoxicity of 7-hydroxy-CBD in HepG2 cells when co-treated with disulfiram. These findings indicate that NAD(P)⁺-dependent alcohol oxidoreductases may catalyze the conversion of 7-hydroxy-CBD to 7-formyl-CBD in human liver S9 and microsomes. The potentially toxic aldehyde intermediate is further oxidized by aldehyde dehydrogenase to 7-carboxy-CBD.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740984","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":"The important role of standards for the uptake of transcriptomics and metabolomics based in vitro methods in regulatory toxicology.","authors":"Julia M Malinowska, Maurice Whelan","doi":"10.1007/s00204-025-04119-8","DOIUrl":"https://doi.org/10.1007/s00204-025-04119-8","url":null,"abstract":"<p><p>Driven by increasing regulatory interest in applying omics-based methods and reducing animal testing, this study reviewed existing documentary standards for transcriptomics and metabolomics, focusing on those applicable to in vitro test systems. Investigation revealed the landscape to be heterogeneous: for transcriptomics (using RNA-seq), some documentary standards have been produced by formal standardisation bodies (e.g., International Organization for Standardization), whilst for metabolomics (using MS), these were primarily driven by the work of the scientific community developing best practices. The value of reference materials is also highlighted since they enable characterisation of both (analytical) intra-laboratory repeatability and reproducibility as well as inter-laboratory reproducibility. Leveraging standards within omics-based in vitro methods that enter the OECD Test Guideline Programme will ensure their reliability, accessibility across jurisdictions, and sustainability for their long-term use. These benefits are explained with practical examples and make the case for better use of existing standards and initiating targeted development of new standards for efficient and effective development of international Test Guidelines based on in vitro transcriptomics and metabolomics methods.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752155","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":"Functional crosstalk between the lung and eye: a new frontier in chronic lung diseases.","authors":"Hannah Taylor Lee, Hudson C Taylor-Blair, Dinesh Kumar Chellappan, Gabriele De Rubis, Keshav Raj Paudel, Brian G Oliver, Kamal Dua, Stewart Yeung","doi":"10.1007/s00204-025-04136-7","DOIUrl":"https://doi.org/10.1007/s00204-025-04136-7","url":null,"abstract":"<p><p>Respiratory diseases are among the main causes of morbidity and mortality worldwide, encompassing a wide array of illnesses. Among these diseases, including acute lung injury, chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, obstructive sleep apnoea (OSA), and pathogenic infections, the immune system plays a significant role in whole-body pathophysiology. These occurrences have been recognised to affect the ocular system, bringing about the novel idea of the lung-eye axis with emerging literature highlighting the fundamental connection of exacerbation between systems. Prior literature has recognised axial activity across systems, the gut and eye, where gut microbiota has an indicated correlation with the ocular environment. In addition, crosstalk has been hypothesized in a brain-lung axis via neurological anatomy, immune mechanisms and microbial pathways. Such cascades offer foundation for the lung-eye axis, supporting the potential for a correlative relationship between the ocular and respiratory system through anatomical, mucosal and inflammatory crosstalk. Although in its infancy, the interconnection between ocular and respiratory systems has been considered in the development of chronic diseases. Amid chronic diseases, COPD, OSA and glaucoma exhibit underlying mechanisms, incorporating hypoxia, oxidative stress and vascular dysfunction, postulating dual system pathophysiology. Finally, potential biomarkers are proposed following pathophysiological mechanism exploration, with an advocation for longitudinal studies in future. The current review proposes a novel axis in the field of lung diseases and aims to provide significant insights for respiratory and ocular clinicians, in addition to translational researchers, paving a new path for understanding systemic disease and treatment modality.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726955","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":"Dermal absorption, skin retention and urinary elimination of bisphenol S in rats: in vitro, in vivo and intravenous comparative analysis.","authors":"Fabrice Marquet, Matthieu Aubertin, Emmy Joubert, Claire Seiwert, Frédéric Cosnier","doi":"10.1007/s00204-025-04138-5","DOIUrl":"https://doi.org/10.1007/s00204-025-04138-5","url":null,"abstract":"<p><p>Bisphenol S (BPS) is widely used as a substitute for bisphenol A (BPA) in industrial applications, but concerns have been raised about its dermal absorption and potential systemic toxicity. Here, we investigated the toxicokinetics of BPS following dermal and intravenous (i.v.) exposure in rats, and performed complementary in vitro dermal absorption studies. A single dose of 20 µg/cm² [¹⁴C]-BPS was applied (50 µL/cm²) in vitro and in vivo to rat skin. Maximum systemic exposure was achieved by administering 0.05, 0.5, or 5 mg/kg i.v. In vitro percutaneous absorption depended on the solvent, with the highest uptake measured in artificial sebum (~ 5000 ng/cm² over 40 h). Most absorbed BPS remained unmetabolised (78-85%), with a significant skin reservoir (25-60% of the applied dose). In vivo dermal exposure resulted in low systemic absorption (~ 10%), with BPS persisting in the skin for more than 72 h. The primary excretion route was in urine (60-70%), mainly as BPS-glucuronide. Systemic i.v. exposure confirmed rapid metabolisation, with BPS-G dominating in the plasma and urinary profiles. Applying the Triple-Pack approach, by integrating in vitro and in vivo rat data with prior human in vitro findings, human in vivo dermal absorption was estimated at 1.4% of the applied dose. The results presented highlight prolonged skin retention and slow systemic release of BPS, raising concerns about chronic low-level exposure following dermal contact. Further studies are needed to refine risk assessments, particularly to enhance toxicokinetic modelling and forward dosimetry to improve exposure prediction and regulatory decision-making.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688726","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":"Response to letter titled \"Bats, bugs and babies-why stringent guidelines are needed for cause-and-effect interpretation in epidemiological studies\" by Philip Marx-Stoelting, Tewes Tralau, Veronika Städele, Stefanie Rotter, Vera Ritz, Jörg Rahnenführer, Jan G. Hengstler.","authors":"Eyal G Frank","doi":"10.1007/s00204-025-04128-7","DOIUrl":"https://doi.org/10.1007/s00204-025-04128-7","url":null,"abstract":"","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697465","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":"Integrated multi-omic profiling uncovers endocannabinoid system as a driver of nerve agent-induced cognitive dysfunction in guinea pigs.","authors":"Qian Jin, Yuxin Lin, Yue Wei, Zhanbiao Liu, Manzhu Cao, Xuejun Chen, Liqin Li","doi":"10.1007/s00204-025-04131-y","DOIUrl":"https://doi.org/10.1007/s00204-025-04131-y","url":null,"abstract":"<p><p>Soman, a highly lethal organophosphorus compound (OP), is notorious for its rapid induction of irreversible acetylcholinesterase binding through accelerated aging. Although subacute soman exposure has been specifically implicated in cognitive deficits, the molecular pathways driving these impairments remain poorly characterized, highlighting a significant research gap. This study aims to comprehensively elucidate the effects of soman exposure on cognitive impairment by analyzing proteome and lipidome alterations in the hippocampal tissue of guinea pigs administered a sublethal dose (11 µg/kg) of soman. A molecular network based on lipidomic and proteomics data was constructed to investigate the key molecules. The study demonstrates that subcutaneous exposure to low-dose soman for 14 consecutive days in guinea pigs impairs learning and memory. We further observed that soman exposure induces damage to both the hippocampal neurons and the mitochondrial ultrastructure in the brains of these animals. The study revealed that subacute soman exposure significantly altered the endocannabinoid system, characterized by disrupted biosynthesis and metabolism of 2-arachidonoylglycerol (2-AG), with a significant down-regulation of 2-AG lipid metabolism pathways, as well as a significant up-regulation of cannabinoid receptor 1 (CB1R) pathways. Notably, the disruption of 2-AG biosynthesis and metabolism is primarily attributed to the upregulation of the activities of three key enzymes, DAGLα, MAGL, and ABHD6. The activation of CB1R negatively feedback-regulate the cAMP/PKA pathway which further leads to dysregulation of mitochondrial homeostasis and reduced energy metabolism. Pharmacodynamic evaluations demonstrated that reversible MAGL inhibitor and ABHD6 inhibitor effectively elevate 2-AG levels in cerebral organoid models, subsequently restoring mitochondrial energy metabolism. This research expands the current understanding of soman's systemic neurotoxicity, particularly its capacity to modulate endocannabinoid-mediated cognitive processes. Our results provide mechanistic insights into soman-induced cognitive deficits and associated health risks. Importantly, elevating 2-AG levels may serve as an effective strategy for preventing and treating soman-induced memory impairment.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681910","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":"Evaluating CYP enzyme induction by cigarette smoking: a new in vitro approach using primary human hepatocytes.","authors":"Ann-Kathrin Lenich, Stephanie Ruez","doi":"10.1007/s00204-025-04135-8","DOIUrl":"https://doi.org/10.1007/s00204-025-04135-8","url":null,"abstract":"<p><p>Cigarette smoke contains compounds that significantly affect drug interactions in clinical settings, primarily through the induction of cytochrome P450 (CYP) enzymes. Given the complexity of cigarette smoke, use of cigarette smoke extract (CSE) in in vitro systems is essential for mimicking in vivo effects and analyzing CYP enzyme induction. Regulatory authorities recommend testing drug-drug interactions; however, there is currently no in vitro model to study smoke-drug interactions. This study developed a model using primary human hepatocytes (PHH) to analyze CYP enzyme induction by CSE inspired by the ICH M12 (2024) guideline. The robustness of the model was evaluated by analyzing the effects of CSE derived from three lots of research cigarettes on three PHH donors. The parameters of CSE production were optimized for a 2.5-min cigarette burning and a cell culture medium as CSE solvent. A reliable, concentration-dependent induction of CYP1A1 and CYP1A2 by CSE across different donors and cigarettes was verified based on an enzyme activity (LC-MS/MS) and mRNA expression levels (qRT-PCR). The strongest induction was observed for CYP1A1 mRNA with at least 15-fold, and CYP1A1 enzyme activity with at least 57-fold induction, across all donors. Protein levels of induced CYP1A1 in PHH were comparable to those of non-induced CYP1A2. Therefore, the data suggest a notable role of induced CYP1A1 in liver metabolism. Additionally, CSE induced the mRNA expression levels of CYP2B6, CYP2C8, and CYP3A4. This model has the potential to provide in vitro smoke-drug interaction results prior to clinical trials and can therefore assist in clinical study planning.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673810","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":"A hair-follicle reconstructed in vitro immunocompetent skin model for prediction of the sensitizing potential of chemicals.","authors":"Tarada Tripetchr, Marla Dubau, Sarah Hedtrich, Burkhard Kleuser","doi":"10.1007/s00204-025-04130-z","DOIUrl":"https://doi.org/10.1007/s00204-025-04130-z","url":null,"abstract":"<p><p>The development of immunocompetent skin models represents a significant advancement in in vitro methods for detecting skin sensitizers, adhering to the 3R principles aimed at reducing, refining and replacing animal testing. In the present study, an advanced skin model from hair follicle-derived cells was constructed and enriched with two key immune cell types, namely Langerhans cells and T-lymphocytes, named ImmuSkin-MT. The model features a physiologically relevant epidermis and dermis, integration of monocyte-derived Langerhans cells (MoLCs) beneath the dermal layer, and co-cultivation with CD4⁺-T cells in the lower chamber of a transwell system. This setup closely mimics the native interplay between skin-resident immune cells and T-cells, marking a significant advancement in in vitro toxicology. When exposed to known sensitizers of varying potency, the model demonstrated a robust ability to predict the sensitizing potential of chemicals. By addressing different key events in skin sensitization, a differentiation between extreme, moderate and even weak sensitizers was achieved. The results showed that the MoLCs migrated, and upregulated CD86 expression in response to contact sensitizers. Additionally, proliferation of CD4⁺ T-lymphocytes was increased in response to the treatment. These results highlight the potential of the ImmuSkin-MT construct to serve as a valuable tool for mechanistic studies and future regulatory applications in the assessment of skin sensitization.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666954","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":"Alignment between Duplex Sequencing and transgenic rodent mutation assay data in the assessment of in vivo NDMA-induced mutagenesis.","authors":"Anne L Ashford, Daniela Nachmanson, John W Wills, Jacob E Higgins, Thomas H Smith, Kevin C Vavra, Farah A Dahalan, Jonathan Howe, Joanne M Elloway, Jesse J Salk, Ann Doherty, Anthony M Lynch","doi":"10.1007/s00204-025-04121-0","DOIUrl":"https://doi.org/10.1007/s00204-025-04121-0","url":null,"abstract":"<p><p>The nitrosamine N-nitrosodimethylamine (NDMA) is a mutagen and rodent carcinogen that has been identified as a process impurity in some commercially available medicines, leading to market withdrawals and new impurity control measures. Error-corrected DNA sequencing techniques, such as Duplex Sequencing (DS), have error rates low enough to revolutionise genetic toxicology testing by directly measuring in vivo mutagenesis within days of exposure. Here, DS was performed on liver samples from an OECD-compliant, Transgenic Rodent Gene Mutation Assay (TGR) conducted under GLP standards. Muta™Mouse specimens were orally dosed with NDMA using either a repeat-dose 28-day regimen (0.02-4 mg/kg(bw)/day) or single bolus doses of either 5 or 10 mg/kg(bw) administered on day 1. Dose-dependent increases in mutation frequency were detected by DS in liver, enabling a No-Observed Genotoxic Effect Level (NOGEL) of 0.07 mg/kg(bw)/day to be determined, supported by mechanistic analyses of trinucleotide mutation spectra. Benchmark dose (BMD) modelling determined similar BMD₅₀ values for both DS or TGR, demonstrating concordance across the two techniques albeit with greater precision from DS due to smaller inter-animal variation. DS offers a fundamental change in mutagenicity assessments enabling more precise point-of-departure determinations with mechanistic clarity and 3Rs advantages compared to the standard TGR approach.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658238","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":"Tiny molecules, big concerns: ultrashort-chain PFAS on the regulatory radar.","authors":"Amy Maerten, Julen Sanz-Serrano, Lindsey Devisscher, Mathieu Vinken","doi":"10.1007/s00204-025-04126-9","DOIUrl":"https://doi.org/10.1007/s00204-025-04126-9","url":null,"abstract":"","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635984","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}