Archives of Toxicology最新文献

{"title":"Application of in silico methods to predict the acute toxicity of bicyclic organophosphorus compounds as potential chemical weapon.","authors":"Maciej Noga, Kamil Jurowski","doi":"10.1007/s00204-025-04000-8","DOIUrl":"https://doi.org/10.1007/s00204-025-04000-8","url":null,"abstract":"<p><p>Bicyclic organophosphorus compounds (BOPCs), including flame retardants and plasticisers, are widely used in industrial applications because of their thermal stability and resistance to degradation. However, their unique structural properties and mechanisms of toxicity raise concerns regarding their potential misuse. Unlike classical organophosphorus compounds that inhibit acetylcholinesterase, BOPCs exert toxicity by antagonising gamma-aminobutyric acid receptors, resulting in severe neurotoxic effects, including convulsions and seizures. This underscores the urgent need to prioritise predictive toxicity studies on these compounds as part of a national defence strategy. The present study represents the first extensive application of in silico toxicological approaches to investigate the acute toxicity of a BOPC dataset (n = 18) utilising advanced in silico tools, such as QSAR models and probabilistic software/platforms, to predict acute oral toxicity in rats. All the investigated BOPCs are highly acutely toxic, judging from LD₅₀ values ranging for humans between < 1 mg and > 1.000 mg/kg bw, depending on the applied model. Noticeable variation between model predictions reminds us that present in silico approaches have significant limitations, at least when addressing chemically complex compounds, such as the BOPC class. This calls for wet-laboratory experimentation. Major toxicophoric groups, such as phosphate and phosphorothione moieties, have been identified as significant contributors to their toxicity. This study considers the need for high-level computational tools, well-founded experimental validation, targeted antidotes, and regulatory measures to reduce the risks from BOPCs and improve public health protection and chemical safety.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143571593","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 hepatoprotective potential of ferulic acid against a spectrum of pharmaceuticals and toxic compounds.","authors":"Anandakumar Pandi, Balarko Chakraborty, Nabendu Sen, Vanitha Manickam Kalappan","doi":"10.1007/s00204-025-03996-3","DOIUrl":"https://doi.org/10.1007/s00204-025-03996-3","url":null,"abstract":"<p><p>Despite advancements in medicine, drug-induced liver injury continues to pose regulatory and clinical challenges. Ferulic acid, a naturally occurring polyphenol found in vegetables, fruits, and grains, has gained attention for its therapeutic properties. We report the hepatoprotective effects of ferulic acid against a range of pharmaceuticals and toxic compounds. Given the growing interest in natural hepatoprotective compounds, further research is essential to elucidate ferulic acid's role in liver protection.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565881","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":"Potential role of ochratoxin A in Parkinson's disease: a systematic review of current evidence.","authors":"M Serrano-Civantos, E Beraza, L Álvarez-Erviti, A López de Cerain, A Vettorazzi","doi":"10.1007/s00204-025-03994-5","DOIUrl":"https://doi.org/10.1007/s00204-025-03994-5","url":null,"abstract":"<p><p>Ochratoxin A (OTA) is a mycotoxin produced by Aspergillus and Penicillium species that contaminates various food and feed products, presenting potential risks to human health. While OTA is well-known for its nephrotoxic effects, emerging evidence highlights its neurotoxic potential. Parkinson's disease (PD) is a neurodegenerative disorder with both genetic and environmental aetiologies. Emerging lines of investigation have focused their research on the role of environmental toxins, including mycotoxins, in PD pathogenesis. However, the specific involvement of OTA in PD-related pathways still needs to be unravelled. This systematic review compiles and evaluates OTA neurotoxicity studies according to the adverse outcome pathway (AOP) for PD, established by the Organisation for Economic Cooperation and Development (OECD). The AOP framework outlines a series of key event (KEs) beginning with mitochondrial Complex I (CI) inhibition and progressing through mitochondrial dysfunction, impaired proteostasis, dopaminergic neuron degeneration, neuroinflammation, and resulting in parkinsonian motor deficits. In this systematic review, a comprehensive literature search was conducted in PubMed, to identify studies evaluating OTA neurotoxic effects. Using a search strategy of 19 terms and following a two-phased study selection, 30 relevant studies were retrieved, of which 16 dealt with in vitro adult neurotoxicity (ANT), 13 focused on in vivo ANT, and 1 gave both in vitro and in vivo approaches. Authors agree that in vitro and in vivo exposure to OTA causes mitochondrial dysfunction, impaired proteostasis, degeneration of dopaminergic (DA) neurons, and neuroinflammation. However, a notable absence of research remains on the molecular initiating event (MIE), binding to CI, and on KE1, inhibition of CI. This review identifies critical research gaps and highlights the need for further mechanistic studies on the impact of OTA on neurodegenerative pathways, particularly its binding and inhibition of CI, as well as mechanisms related to KE3: impaired proteostasis. Addressing these gaps may provide valuable insights into OTA neurotoxic potential and its relevance in PD-like neurodegeneration.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565877","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 approaches to investigate the effect of chemicals on antibody production: the case study of PFASs.","authors":"Martina Iulini, Valeria Bettinsoli, Ambra Maddalon, Valentina Galbiati, Aafke W F Janssen, Karsten Beekmann, Giulia Russo, Francesco Pappalardo, Styliani Fragki, Alicia Paini, Emanuela Corsini","doi":"10.1007/s00204-025-03993-6","DOIUrl":"https://doi.org/10.1007/s00204-025-03993-6","url":null,"abstract":"<p><p>The increasing variety and quantity of new chemical substances have raised concerns about their potential immunotoxic effects, making it essential to assess their impact on human health. One key concern is the reduction of antibody production, as seen with per- and poly-fluoroalkyl substances (PFASs), commonly known as \"forever chemicals.\" Both in vivo and epidemiological data show that PFASs have immunosuppressive effects, leading to reduced antibody responses, particularly following vaccination. In animal studies, the T cell-dependent (TD) antibody response is the gold standard for assessing chemical effects on immune function. This study utilized two in vitro approaches to investigate the effects of chemicals on antibody production using human peripheral blood mononuclear cells. Initial tests used unstimulated, negative (vehicle), and positive (rapamycin) controls to confirm the robustness of the models. Subsequently, four long-chain PFASs (PFOA, PFOS, PFNA, and PFHxS) were tested. Keyhole limpet hemocyanin (KLH) was used to mimic the TD response, while a TLR9 agonist and IL-2 activated B cells for T cell-independent (TI) immunoglobulin production. The results demonstrated the ability to reproduce TD and TI responses in vitro with robust, reproducible outcomes across a cohort of 20 human donors. The data, consistent with existing literature, showed a significant reduction in anti-KLH IgM production, especially for PFOA in male donors. Similar trends were observed for all PFASs in suppressing total TI IgG and IgM production. These methods closely replicated in vivo conditions, offering a potential alternative to animal models in immunotoxicity assessments.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565874","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":"Challenges in laser tattoo removal: the impact of titanium dioxide on photodegradation of yellow inks.","authors":"Batool A Aljubran, Kirstin E Ross, Ula Alexander, Claire E Lenehan","doi":"10.1007/s00204-025-03989-2","DOIUrl":"https://doi.org/10.1007/s00204-025-03989-2","url":null,"abstract":"<p><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>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the multifaceted impact of bisphosphonates on bone graft integration: transitioning from in vivo insights to clinical applications.","authors":"Ronnakrit Maethungkul, Apiruk Sangsin, Nipon Chattipakorn, Siriporn C Chattipakorn","doi":"10.1007/s00204-025-03991-8","DOIUrl":"https://doi.org/10.1007/s00204-025-03991-8","url":null,"abstract":"<p><p>Numerous researchers have explored the efficacy of the use of bisphosphonates, in particular alendronate and zoledronate, in bone graft integration. Mechanisms underlying the beneficial effects of bisphosphonates on bone graft integration have been previously investigated. Previous studies have demonstrated that both local and systemic applications of bisphosphonates in the integration of autogenous and allogenic bone grafts yield promising results in enhancing allograft and autograft outcomes. Several animal studies have revealed that low to moderate doses of local bisphosphonate optimize new bone formation with good mechanical properties. In addition, bisphosphonates in combination with certain growth factors, such as bone morphogenetic protein (BMP)-7, have synergistic effects on the integration of both autogenous and allogenic bone grafts. However, only some clinical parameters support these findings from in vivo studies, including increased bone volume and density in bone-grafted areas following the integration of bone grafts. Thus, the present review aims to summarize and discuss the effects of bisphosphonates and the mechanistic insights associated with the integration of autogenous and allogenic bone grafts. The contradictory findings between studies will also be presented and discussed in this review. While the promising benefits of bisphosphonates on bone grafts have been reported, further research is still needed to investigate optimal dosage. Larger clinical trials to assess the long-term outcomes of bisphosphonates are required before they can be widely adopted in orthopedic, dental, and maxillofacial bone grafting procedures.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565872","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 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, Jan G Hengstler","doi":"10.1007/s00204-025-04007-1","DOIUrl":"https://doi.org/10.1007/s00204-025-04007-1","url":null,"abstract":"","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":"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}