Archives of Toxicology最新文献

{"title":"Molecular dosimetry of estragole and 1'-hydroxyestragole-induced DNA adduct formation, clastogenicity and cytotoxicity in human liver cell models.","authors":"G Ackermann, M Peil, C Quarz, A Schmidt, M Halaczkiewicz, A D Thomas, S Stegmüller, E Richling, G Manolikakes, M Christmann, J H Küpper, D Schrenk, J Fahrer","doi":"10.1007/s00204-025-04084-2","DOIUrl":"https://doi.org/10.1007/s00204-025-04084-2","url":null,"abstract":"<p><p>The phenylpropene estragole (ES) is found in essential oils of herbs and spices, such as bitter fennel and basil. Humans are exposed to ES through the diet and phytomedicines. After its absorption, ES undergoes metabolic activation by CYP1A2 and SULT1A1 in the liver, which can give rise to DNA adducts and hepatocarcinogenesis. Until now, quantitative genotoxicity data for ES in human liver cells are scarce, correlating DNA adduct levels with critical effects such as clastogenicity. Here, we used human HepG2 and HepG2-CYP1A2 cells as well as primary human hepatocytes (PHH) to study the genotoxic, clastogenic and cytotoxic potential of ES and its crucial metabolite 1'-hydroxyestragole (1'OH-ES). In addition, primary rat hepatocytes (PRH) were used for selected endpoints. Treatment of HepG2-CYP1A2 cells with ES (0-2 mM) led to the concentration-dependent formation of E3'-N²-dG adducts. Apart from a moderate γH2AX induction, neither p53 accumulation nor cytotoxicity was observed. However, clastogenicity was demonstrated at ES concentrations ≥ 1 mM. Incubation of HepG2 cells with 1'OH-ES (0-35 µM) led to 10-50-fold higher E3'-N²-dG adduct levels compared to equimolar ES concentrations. Furthermore, 1'OH-ES caused γH2AX formation, p53 accumulation and cytotoxicity, which was confirmed in PHH. In agreement, 1'OH-ES induced clastogenicity at concentrations ≥ 25 µM. Molecular dosimetry revealed that a certain E3'-N²-dG adduct level is required to trigger clastogenicity and cytotoxicity. This was confirmed by Benchmark Concentration (BMC) modelling, showing that the BMC for clastogenicity is 12-17-fold higher than the respective BMC for DNA adduct formation. Our data indicate that a threshold level of DNA adducts is required, both in rat and human liver cells, to trigger markers of clastogenicity. These levels are unlikely to be reached in humans following chronic ES exposure through phytomedicines or the diet.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109686","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":"Bridging approaches to facilitate innovation: building an approach for heated tobacco products from case studies in the food and drug domains a comparative review.","authors":"Ruth Dempsey, Irfan Gunduz, Patrick Vanscheeuwijck","doi":"10.1007/s00204-025-04081-5","DOIUrl":"https://doi.org/10.1007/s00204-025-04081-5","url":null,"abstract":"<p><p>An increasing number of heated tobacco products (HTPs) have been commercialized in several countries over the last decade. To benefit public health, these products should have a lower health risk profile than cigarettes. This includes the need to be sufficiently acceptable to adults who smoke so that a reasonable proportion of those who do not want to quit smoking are persuaded to switch completely. Additionally, the product should not increase the likelihood of non-smokers starting to use tobacco or smokers increasing their total consumption of tobacco products. Part of this process involves iterative development of new product versions, leveraging lessons learned from consumer experiences with marketed products, and applying novel technologies to improve the consumer product offering. Risk assessment for these products may include pre-clinical quality, analytical and toxicity evaluations, pre-market clinical studies, and post-market surveillance studies. In recent years, approaches to bridge the assessment for modified or new products to data generated for reference products by comparing their equivalence were proposed. Here, we review the approaches taken for such bridging studies and relate them to product comparability and bridging approaches established in a diverse range of consumer and pharmaceutical products. This leads to a proposal for a logical, stepwise, and tiered bridging approach to effectively manage the introduction of new HTPs through scientific substantiation and have potential to increase the public health benefit by reducing risk and improving product acceptability for adult smokers without attracting non-smokers by new innovations.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118667","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 metabolism and excretion kinetics of Bronopol after oral administration.","authors":"Isabell Schönrath, Christoph Schmidtkunz, Katharina E Ebert, Katja Küpper, Thomas Brüning, Holger M Koch, Gabriele Leng","doi":"10.1007/s00204-025-04077-1","DOIUrl":"https://doi.org/10.1007/s00204-025-04077-1","url":null,"abstract":"<p><p>Bronopol is a preservative mainly used in various industrial applications, but also in cosmetics and pharmaceuticals. The aim of this study was to investigate the human toxicokinetics of Bronopol after oral administration. Five volunteers (two male and three female) were orally dosed with 9.715 mg Bronopol (0.100 to 0.154 mg/kg bw) and their urine was collected for 48 h. The samples were analyzed for the postulated metabolite 2-nitro-1,3-propanediol using an analytical human biomonitoring method. The maximum urinary concentrations of 1830-7666 µg/L (1981-5847 µg/g creatinine) were reached around 2.5 h (1.7-4.7 h) post dose. The excretion profile was monophasic with an average half life of 6.3 h (4.7-8.6 h). In total, 29.2% (19.5-35.9%) of the oral dose was excreted as 2-nitro-1,3-propanediol making it an amenable biomarker for the assessment of Bronopol exposure. The urinary excretion fraction can be used in population studies for the back-calculation of Bronopol intakes enabling an informed exposure and risk assessment of individual and population exposures.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109678","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":"Structure-metabolism relationships of 4-pentenyl synthetic cannabinoid receptor agonists using in vitro human hepatocyte incubations and high-resolution mass spectrometry.","authors":"Steven R Baginski, Karin Lindbom, Bryan Valencia Crespo, Ghidaa Bessa, Tobias Rautio, Xiongyu Wu, Johan Dahlén, Lorna A Nisbet, Craig McKenzie, Henrik Gréen","doi":"10.1007/s00204-025-04080-6","DOIUrl":"https://doi.org/10.1007/s00204-025-04080-6","url":null,"abstract":"<p><p>The rapid structural evolution and extensive metabolism of synthetic cannabinoid receptor agonists (SCRAs) following consumption makes their detection in biological samples challenging, especially in urine. In vitro metabolite identification studies are an essential tool for identifying analytical targets to confirm SCRA consumption in clinical and forensic toxicology casework. Systematic studies on structurally related SCRAs allow structure-metabolism relationships (SMRs) to be determined, helping to predict the metabolites of emerging and future compounds. In this study, a series of amino acid-derived 4-pentenyl SCRAs and the OXIZID 4-pentenyl SCRA BZO-4en-POXIZID were incubated at 5 µM with pooled human hepatocytes for up to 3 h. Metabolites were identified using liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) and SMRs investigated using the proportion that each type of biotransformation contributed to the total abundance of metabolites for each parent compound. Metabolites were mainly produced via terminal amide/ester hydrolysis, dihydrodiol formation on the tail, hydroxylation and N-dealkylation, but also by ketone formation, dehydrogenation, glucuronidation and combinations thereof. Methyl valinate (MMB) and ethyl valinate (EMB) SCRAs underwent extensive ester hydrolysis (90.9-96.0%), which was less dominant for methyl tert-leucinate (MDMB) SCRAs (47.6-60.7%), with dihydrodiol formation (24.3-27.7%) and hydroxylation (6.2-17.3%) becoming more prominent. For AB-4en-PICA and tert-leucinamide (ADB) SCRAs, hydroxylation was the major metabolic pathway (47.9-58.4%), while tail dihydrodiol formation was most prominent for BZO-4en-POXIZID (61.5%). Clear SMRs were identified for 4-pentenyl SCRAs and can be used to recommend biomarkers of consumption and aid prediction of metabolites of emerging and future SCRAs.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109696","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 CB₁ receptor activity of halogenated indazole synthetic cannabinoid receptor agonists.","authors":"Henrik Green, Craig McKenzie, Elias Hamra, Tobias Rautio, Xiongyu Wu, Emma Juneskog, Rebecka Sandblom, Manuela Carla Monti, Mattias Persson, Caitlyn Norman","doi":"10.1007/s00204-025-04082-4","DOIUrl":"https://doi.org/10.1007/s00204-025-04082-4","url":null,"abstract":"<p><p>Synthetic cannabinoid receptor agonists (SCRAs) are a group of new psychoactive substances (NPS) that bind to and activate the cannabinoid 1 and 2 (CB₁ and CB₂) receptors. Following the introduction of SCRA analog controls in China in July 2021, new SCRAs with a bromine at the 5 position on the indazole core emerged on the recreational drug market. In this study, the in vitro CB₁ receptor activity of 19 different SCRAs with a halogenated indazole core was systematically examined using a AequoScreen^® CB₁ assay alongside four available non-halogenated analogs, ADB-BUTINACA, MDMB-BUTINACA, MDMB-4en-PINACA, and MDMB-INACA, and the newly emerged MDMB-5'Me-INACA (MDMB-5-methyl-INACA). Of SCRAs with a substitution at the 5 position on the indazole core, analogs with a fluorine had the lowest EC₅₀ values. For SCRAs with a methyl ester head moiety (MMB or MDMB), chlorinated analogs had the next lowest EC₅₀ values followed by brominated analogs; however, the opposite relationship was observed for SCRAs with an amide head moiety (AB or ADB). All halogenated compounds had similar potency to their non-halogenated analog, except the brominated tert-leucine methyl ester SCRAs, which had significantly reduced potency. Of the different head moieties, tert-leucine methyl ester SCRAs were the most potent, followed by tert-leucinamide, valinamide, and valine methyl ester. The potencies of the SCRAs with pentyl (ADB-5'Br-PINACA/ADMB-5'Br-PINACA/ADB-P-5'Br-INACA), pent-4-enyl (ADB-4en-5'Br-PINACA/ADMB-4en-5'Br-PINACA/ADB-4en-P-5'Br-INACA and MDMB-4en-5'Br-PINACA/MDMB-4en-P-5'Br-INACA), and butyl tails (ADB-5'Br-BUTINACA/ADMB-5'Br-BUTINACA/ADB-B-5'Br-INACA) were not significantly different, whereas fluorobenzyl (ADB-5'Br-FUBINACA), tail-less (ADB-5'Br-INACA), and decyl tail (ADB-5'Br-DECINACA/ADMB-5'Br-DECINACA/ADB-D-5'Br-INACA) analogs were significantly less potent.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092723","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 carvedilol mediated by cytochrome P450s in vitro and in vivo.","authors":"Shibo Sun, Yang Wang, Yan Shen, Weiwei Li, Zixia Hu, Ying Peng, Jiang Zheng","doi":"10.1007/s00204-025-04054-8","DOIUrl":"https://doi.org/10.1007/s00204-025-04054-8","url":null,"abstract":"<p><p>Carvedilol (CAR) is commonly administered in the treatment of essential hypertension. Current reports suggest that CAR therapy may elevate the risk of hepatotoxicity, occasionally progressing to liver injury. However, the underlying mechanisms of the toxicity remain poor understood. This study investigated CAR-associated hepatotoxicity through reactive metabolites formation. In the microsomal incubation mixture containing CAR (50 μM), four phase I metabolites (M1-M4) were detected. Upon the addition of glutathione (GSH), N-acetylcysteine (NAC), or cysteine as trapping agents, four GSH conjugates (M5-M8), four NAC conjugates (M9-M12), and four cysteine conjugates (M13-M16) were also detected. Chemical synthesis of 8-hydroxy CAR identified M1 as the primary oxidative metabolite of CAR. Following the administration of CAR (25 mg/kg), we detected GSH conjugate (M5) in bile, NAC conjugate (M9) in urine, and cysteine adduct (M13) in proteolytic mixture of liver tissues of rat. Furthermore, it was found that CYP3A4 dominated the metabolic activation of CAR. Additionally, CAR exhibited time-course changes and dose-dependent (0, 25, 50, and 100 mg/kg) protein adduction in rat liver tissues, as well as time- and concentration-dependent (0, 10, 25, 50 and 100 μM) inhibition of hepatocyte viability. Ketoconazole (KTZ) significantly decreased the susceptibility of hepatocytes to CAR-induced cytotoxicity. Collectively, these findings offer new insight into the hepatotoxicity mechanism associated with the metabolic activation of CAR.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085695","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":"Discovering a predictive metabolic signature of drug-induced structural cardiotoxicity in cardiac microtissues.","authors":"Tara J Bowen, Andrew R Hall, Gavin R Lloyd, Matthew J Smith, Ralf J M Weber, Amanda Wilson, Amy Pointon, Mark R Viant","doi":"10.1007/s00204-025-04074-4","DOIUrl":"https://doi.org/10.1007/s00204-025-04074-4","url":null,"abstract":"<p><p>Improved prediction of drug-induced structural cardiotoxicity is required to reduce attrition driven by cardiac safety concerns in drug discovery. Omics measurements are well suited to this need, offering the potential to discover molecular signatures associated with toxicological endpoints. In addition, untargeted metabolomics can simultaneously measure xenobiotic fate within the test system. We present an extensive metabolomics study to discover a predictive metabolic signature of drug-induced structural cardiotoxicity. A human-relevant in vitro cardiac model, cardiac microtissues, were exposed to twelve xenobiotics (eight clinically labelled structural cardiotoxins and four non-cardiotoxic pharmaceuticals), each at two concentrations, for 6, 24, and 48 h. The measurements were made by direct-infusion and liquid-chromatography mass spectrometry from intracellular polar and lipid extracts, and spent culture medium, respectively. Data were used to quantify levels, and reveal the metabolic fate of the xenobiotics, and to simultaneously explore their effects on the cardiac microtissues. Xenobiotic quantification revealed free concentrations to be typically lower than nominal values, whilst discovery of xenobiotic-related features evidenced the biotransformation capacity of the microtissues. Both common and condition-specific effects of the xenobiotics on the intracellular metabolome, lipidome, and metabolic footprint were discovered. Moreover, metabolic signatures with capacity to predict structural cardiotoxicity were revealed. These included features representing several ceramides, energy metabolism intermediates, e.g. creatine, purine-related metabolites, and markers of oxidative stress, e.g. glutathione.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085681","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 risk assessment of di(2-ethylhexyl)phthalate (DEHP) using human population pharmacokinetic modeling of DEHP and its major in vivo metabolites.","authors":"Ji-Hun Jang, Seung-Hyun Jeong","doi":"10.1007/s00204-025-04083-3","DOIUrl":"https://doi.org/10.1007/s00204-025-04083-3","url":null,"abstract":"<p><p>Di(2-ethylhexyl)phthalate (DEHP) is widely used as a plasticizer and is associated with potential adverse health effects, including endocrine disruption and organ toxicity. Accurate assessment of DEHP exposure risks requires robust pharmacokinetic models capable of capturing inter-individual variability and integrating human biomonitoring data. This study aimed to develop and validate a population pharmacokinetic model for DEHP and its major metabolites, mono(2-ethylhexyl)phthalate (MEHP), 2-ethyl-5-hydroxy-hexylphthalate (5-OH MEHP), and 2-ethyl-5-oxo-hexylphthalate (5-Oxo MEHP), to quantitatively assess DEHP exposure risks in human populations. Clinical data from DEHP-d₄, a radiolabeled DEHP isotope, were used to construct a pharmacokinetic model using non-linear mixed effects modeling. The model incorporated plasma concentration and urinary excretion data for DEHP and its metabolites. Biomonitoring data were integrated using reverse dosimetry to estimate external exposure levels, and margins of safety were then calculated by comparing these estimates with established reference doses. The model demonstrated robust correlations (R² > 0.99) between external DEHP exposure and internal biomarker levels. Predicted external exposure levels ranged from 0.52 to 157.52 µg/kg/day, with margins of safety varying between 0.13 and 38.17. Despite substantial inter-individual variability, the model accurately captured population-level pharmacokinetic diversity and provided reliable risk assessments. The developed pharmacokinetic model offers a versatile tool for integrating biomonitoring data and conducting rapid, population-specific DEHP risk assessments. These findings underscore the importance of ongoing monitoring and stringent regulatory measures to mitigate DEHP-associated health risks.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075752","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":"How to organise a successful toxicology workshop? A participant perspective on the Collaboration to Harmonise the Assessment of Next Generation Evidence (CHANGE) workshop in Oslo, 18-20 June 2024.","authors":"Michael G Diemar, Arianna Giusti, Cécile Michel-Caillet, Daniela Morais Leme, Daniele Wikoff, Denise Bloch, Jennifer Sass, Karsten Beekmann, Kevin C Elliott, Robyn Tanguay, Tina Hofmaier, Weihsueh Chiu, Anne Kienhuis","doi":"10.1007/s00204-025-04064-6","DOIUrl":"https://doi.org/10.1007/s00204-025-04064-6","url":null,"abstract":"<p><p>To create a regulatory infrastructure for the effective use of NAMs, the CHANGE project aims to organise three workshops to Collaborate and Harmonise the Assessment of Next Generation Evidence. To better ensure the success of the CHANGE approach, project organisers invited a group of participants to provide feedback on the first workshop held in Oslo on 18-20 June 2024. This report represents the participants' perspective on the CHANGE working methodology and serves as a companion piece to the CHANGE organisers' publication \"Improving how we use workshops when solving complex research problems: Reflections from the CHANGE Project\", which provides a detailed description of the methodology, outputs, and conclusions from the workshop. The report includes feedback from most participants in response to the workshop evaluation as well as personal experiences from the authors. The workshop successfully facilitated stimulating engagement with a diversity of perspectives, though representation could be further broadened across sectors and geographies. Additionally, future workshops could refine the explanation of novel approaches to participants, as well as improve how information gathering is structured and formatted for feedback. Overall, participants were enthusiastic about CHANGE and believe the approach holds great promise in shaping future effective use of NAMs for chemical safety assessments. The report concludes with recommendations for follow-up workshops in 2025 and 2026, aiming to contribute to a regulatory infrastructure open to the acceptance and effective use of NAMs and to the use of similar workshops to address other emerging science policy issues.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075753","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":"TRPM7 underlies cadmium cytotoxicity in pulmonary cells.","authors":"Leonor Correia, Alexey Shalygin, Anna Erbacher, Joanna Zaisserer, Thomas Gudermann, Vladimir Chubanov","doi":"10.1007/s00204-025-04058-4","DOIUrl":"https://doi.org/10.1007/s00204-025-04058-4","url":null,"abstract":"<p><p>TRPM7 is a kinase-coupled ion channel that exhibits high activity in the immune and epithelial cells of different organs, including the lung. Electrophysiological studies have established that the TRPM7 channel displays high permeability to Mg²⁺, Zn²⁺, and Ca²⁺, as well as trace metal cations. While the critical role of TRPM7 in the cellular balance of Mg²⁺, Zn²⁺, and Ca²⁺ is well-documented, its contribution to the cellular uptake of trace metal cations, frequent respiratory pollutants, remains unclear. Here, we performed an electrophysiological assessment of pulmonary A549 cells revealing endogenous TRPM7 currents, which were eliminated by knockout (KO) of the TRPM7 gene using the CRISPR/Cas9 approach or by administration of NS8593 and VER155008, two structurally unrelated inhibitors of the TRPM7 channel. Unlike prior studies with various cell lines showing that TRPM7 KO mutation induces cell growth arrest, we observed that A549 cells maintained normal viability after genetic and pharmacological inactivation of TRPM7. Consequently, we used A549 cells to examine the impact of Cd²⁺ on cell viability and found that TRPM7 KO mutation and both pharmacological agents mitigated the Cd²⁺ cytotoxicity. Analogous to A549 cells, electrophysiological analysis of mouse primary alveolar type 2 (ATII) cells revealed endogenous TRPM7 currents and Cd²⁺ exposure reduced the cell viability of ATII cells in a TRPM7-dependent fashion. Hence, the TRPM7 channel contributes to Cd²⁺ cytotoxicity in pulmonary cells and can serve as a therapeutic target to alleviate the toxic effects of trace metal exposure.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075754","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}