Archives of Toxicology最新文献

{"title":"Challenges in laser tattoo removal: the impact of titanium dioxide on photodegradation of yellow inks","authors":"Batool A. Aljubran,&nbsp;Kirstin E. Ross,&nbsp;Ula Alexander,&nbsp;Claire E. Lenehan","doi":"10.1007/s00204-025-03989-2","DOIUrl":"10.1007/s00204-025-03989-2","url":null,"abstract":"<div><p>As tattoos have grown increasingly popular, there has been an increase in their removal. This is commonly achieved using laser treatments. However, certain tattoo inks are resistant to removal using laser methods because of their composition. This includes the removal of yellow pigments and tattoo inks containing titanium dioxide (TiO₂). This research examined a series of yellow pigments (PY14, PY74, PY65) and tattoo inks, pre- and post-irradiation, with a QS Nd:YAG laser irradiation at 532 nm. The pigments and products were analysed using a range of techniques, including EDX-SEM, DLS, XRD and GC–MS. Results of this study indicate that the presence of TiO₂ alters the laser degradation process of the pigments studied, with observable changes to particle morphologies, particle size, and evolved volatile products. In addition, some of the degradation products were identified to be potentially harmful to the human body.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 4","pages":"1371 - 1385"},"PeriodicalIF":4.8,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-025-03989-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565869","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":"The potent human CAR activator CITCO is a non-genotoxic hepatic tumour-promoting agent in humanised constitutive androstane receptor mice but not in wild-type animals.","authors":"C J Henderson, A W McLaren, A K MacLeod, D Lin, A R Cameron, L R Chatham, J Moggs, F Inesta-Vaquera, John P Thomson, Richard R Meehan, P Chakravarty, M Schwarz, C Roland Wolf","doi":"10.1007/s00204-025-03982-9","DOIUrl":"https://doi.org/10.1007/s00204-025-03982-9","url":null,"abstract":"<p><p>A large number of drugs and compounds produced by the chemical and agrochemical industry, often referred to as 'non-genotoxic carcinogens' (NGC), score as tumour promotors in rodent models. It is unclear whether these compounds act similarly in humans. The most extensively investigated compounds have been the anti-convulsive drugs, phenobarbital (PB), and phenytoin. Liver tumours induced by PB are dependent upon the activation of the constitutive androstane receptor (CAR). However, marked species differences in CAR activation by exogenous chemicals exist with some being much more potent activators of human CAR, e.g., 6-(4-chlorophenyl)imidazo[2,1-β][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime (CITCO). We have compared CITCO-induced tumour formation in the livers of mice in which murine CAR has been replaced with its human counterpart. Our findings reveal that CITCO-dependent liver tumours are only formed in mice-expressing human CAR and not in wild-type animals. In addition, contrary to one of the proposed mechanisms of NGC carcinogenicity, we show that CITCO did not induce a hyperplastic response in the liver of the humanised mice. These data raise some key questions about the mechanism of action of NGCs and identify the limitations of current rodent carcinogenicity test systems in relation to risk assessment.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565882","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":"Developments in tattoo and tattoo removal toxicology","authors":"Hermann M. Bolt,&nbsp;Jan G. Hengstler","doi":"10.1007/s00204-025-04007-1","DOIUrl":"10.1007/s00204-025-04007-1","url":null,"abstract":"","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 4","pages":"1253 - 1255"},"PeriodicalIF":4.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555724","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":"Comprehensive ubiquitome analysis reveals persistent mitochondrial remodeling disruptions from doxorubicin-induced cardiotoxicity in aged CD-1 male mice.","authors":"Sofia Reis Brandão, Elisa Lazzari, Rui Vitorino, Germana Meroni, Ana Reis-Mendes, Maria João Neuparth, Francisco Amado, Félix Carvalho, Rita Ferreira, Vera Marisa Costa","doi":"10.1007/s00204-025-04006-2","DOIUrl":"https://doi.org/10.1007/s00204-025-04006-2","url":null,"abstract":"<p><p>Doxorubicin (DOX)-associated cardiotoxicity is characterized by long-term manifestations, whose mechanisms remain incompletely understood, and is exacerbated by various risk factors, with age being a prominent contributor. The objective of this study was to assess the enduring cardiac molecular impacts of DOX in old CD-1 male mice, focusing on ubiquitinated proteins. At 19 months of age, DOX group received a cumulative dose of 9.0 mg/kg of DOX, while control animals got saline solution. Animals were sacrificed 2 months after the administration. DOX induced heart structural changes and increased proteolytic activity. Additionally, increased protein ubiquitination was observed in DOX group, despite the decreased content of the E3 ubiquitin-protein ligase Atrogin-1. A search of poly-ubiquitinated proteins, enriched by tandem ubiquitin-binding entities (TUBEs), showed increased poly-ubiquitination of proteins associated with sarcomere organization and mitochondrial metabolism processes by DOX. Increased mitochondrial density inferred by higher citrate synthase activity was found in DOX group. Moreover, decreased biogenesis and auto(mito)phagy occurred in DOX animals, proven by decreased peroxisome proliferator-activated receptor γ coactivator 1 α, Beclin1 and microtubule-associated protein light chain 3 content. These findings indicate a reduction in mitochondrial biogenesis and accumulation of dysfunctional mitochondria in the aged heart, along with elevated levels of poly-ubiquitinated proteins after DOX treatment. Thus, the disruption of mitochondrial remodeling and impaired protein ubiquitination emerge as enduring consequences of DOX-induced cardiotoxicity, persisting for even 2 months after DOX exposure. This underscores the long-lasting impact of DOX, with significant effects continuing beyond the period of administration, which advocates for longer clinical surveillance.</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":"143539922","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 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}