Toxicology in Vitro最新文献_第6页

Testing chemicals for CYP19 inhibition: Comparison of a modified H295R steroidogenesis assay to a commercial fluorometric enzyme inhibition kit 检测CYP19抑制的化学物质：改良的H295R甾体生成试验与商业荧光酶抑制试剂盒的比较。

IF 2.6 3区医学

Toxicology in Vitro Pub Date : 2025-12-01 Epub Date: 2025-07-13 DOI: 10.1016/j.tiv.2025.106108

Caroline Despicht, Kieu-Mi Tran, Terje Svingen, Anna Kjerstine Rosenmai

{"title":"Testing chemicals for CYP19 inhibition: Comparison of a modified H295R steroidogenesis assay to a commercial fluorometric enzyme inhibition kit","authors":"Caroline Despicht, Kieu-Mi Tran, Terje Svingen, Anna Kjerstine Rosenmai","doi":"10.1016/j.tiv.2025.106108","DOIUrl":"10.1016/j.tiv.2025.106108","url":null,"abstract":"<div><div>Aromatase (CYP19A1) is a key enzyme that converts androgens to estrogens. Given its central role in estrogen biosynthesis, aromatase is a target of endocrine disruption. Aromatase disruption can be measured in vitro with cell-free enzyme assays or using cells expressing CYP19A1. Results may vary between models, as cell-based models can have adaptive responses not present in enzyme assays. Here, we have compared 21 chemicals for their ability to affect aromatase by direct and indirect disruption using an aromatase commercial kit and a modified H295R steroidogenesis assay. New data was generated for eighteen test compounds in either one or both of the models. Chemicals eliciting a response could be divided into five categories: 1) substances that decreased the response in both models, 2) substances that directly inhibited aromatase, but increased 17β-estradiol (E2) levels in H295R assay, 3) substances that directly inhibited aromatase, but did not affect E2 levels in H295R assay, 4) substances that did not inhibit aromatase activity, but increased E2 levels in the H295R model, and 5) substances that did not alter responses in either of the assays. These results illustrate that both assays are useful for assessing the potential of chemicals to affect E2 levels either through direct aromatase inhibition or other indirect mechanisms.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"109 ","pages":"Article 106108"},"PeriodicalIF":2.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144644153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Isolation and characterization of bovine Limbal mesenchymal stromal cells for application in ocular toxicity studies 牛角膜缘间充质间质细胞的分离与鉴定及其在眼毒性研究中的应用

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2025-12-01 Epub Date: 2025-07-30 DOI: 10.1016/j.tiv.2025.106125

Martina Daniela Benedetti , Mariela Lenze , Mora Renée García , Sofía Fátima Magaña Guerrero , Silvia Wikinski , Yonathan Garfias , María Laura Gutiérrez

{"title":"Isolation and characterization of bovine Limbal mesenchymal stromal cells for application in ocular toxicity studies","authors":"Martina Daniela Benedetti , Mariela Lenze , Mora Renée García , Sofía Fátima Magaña Guerrero , Silvia Wikinski , Yonathan Garfias , María Laura Gutiérrez","doi":"10.1016/j.tiv.2025.106125","DOIUrl":"10.1016/j.tiv.2025.106125","url":null,"abstract":"<div><div>Ocular toxicity assessment is essential to ensure the safety of chemicals and human-use products. Although the Draize test in rabbits has historically been the regulatory standard, it presents significant ethical and scientific limitations. While validated <em>in vitro</em> methods are currently available, most of them do not allow the evaluation of damage reversibility—a key parameter for hazard classification under the United Nations Globally Harmonized System (UN GHS).</div><div>This study evaluates the utility of an <em>in vitro</em> model based on limbal mesenchymal stromal cells (LMSC) for ocular toxicity testing and the prediction of corneal damage reversibility. LMSC were obtained from slaughterhouse-derived residual tissue, cultured under specific conditions, and briefly exposed to substances classified according to UN GHS. Cell migration was then assessed as an indicator of tissue recovery.</div><div>This preliminary report presents, to our knowledge, the first application of short-term (5-min) exposure in a scratch assay to evaluate its effect on migration capacity. Unlike previous studies relying on prolonged exposure to inhibitory compounds, this approach better simulates accidental ocular exposure scenarios. While migration was not significantly disrupted under the tested conditions, these results offer valuable insight into the relationship between viability and wound healing and highlight the importance of exposure time and concentration in <em>in vitro</em> ocular toxicity models. Overall, this work establishes a promising foundation for future refinement of alternative methods that aim to predict damage persistence and reversibility more accurately.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"109 ","pages":"Article 106125"},"PeriodicalIF":2.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144750760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Employing histopathology to enhance the BCOP test: The emerging role of stromal thickness as a quantitative endpoint 利用组织病理学加强BCOP测试：间质厚度作为定量终点的新作用

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2025-12-01 Epub Date: 2025-07-29 DOI: 10.1016/j.tiv.2025.106123

Martín Nicolás Rivero , Mariela Lenze , Martina Daniela Benedetti , Mora Renée García , Romina Martínez , Silvia Wikinski , María Laura Gutiérrez

{"title":"Employing histopathology to enhance the BCOP test: The emerging role of stromal thickness as a quantitative endpoint","authors":"Martín Nicolás Rivero , Mariela Lenze , Martina Daniela Benedetti , Mora Renée García , Romina Martínez , Silvia Wikinski , María Laura Gutiérrez","doi":"10.1016/j.tiv.2025.106123","DOIUrl":"10.1016/j.tiv.2025.106123","url":null,"abstract":"<div><div>The Bovine Corneal Opacity and Permeability (BCOP) assay is a validated <em>ex vivo</em> method widely used to assess the ocular irritation potential of chemical substances. It is useful for identifying both chemicals that cause serious eye damage and those that are not classified for eye irritation. This study incorporated histopathological parameters into the BCOP assay to enhance the characterization of corneal damage. Fifteen reference chemicals were tested, and IVIS scores were obtained from corneal opacity and permeability measurements. Fixed corneal tissues were then analyzed histologically. Three complementary models were applied: Depth of Injury (DOI), Stromal Thickness (ST), and Total Histopathological Damage (THD). The DOI model helped categorize damage by affected corneal layers and provided relevant information about the depth of the lesions. ST showed a strong correlation with IVIS scores and emerged as a robust indicator of edema. In contrast, the more complex THD model did not improve the classification. Overall, integrating ST and DOI into the BCOP framework provides complementary and informative endpoints that enhance the interpretation of ocular irritation potential. In particular, we highlight ST as a quantitative, and easy-to-measure endpoint that does not rely on expert interpretation.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"109 ","pages":"Article 106123"},"PeriodicalIF":2.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144750715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inter-laboratory validation study of an in vitro glucocorticoid receptor transactivation assay for testing potential endocrine disrupting chemicals 用于检测潜在内分泌干扰物的体外糖皮质激素受体反激活试验的实验室间验证研究。

IF 2.6 3区医学

Toxicology in Vitro Pub Date : 2025-12-01 Epub Date: 2025-07-17 DOI: 10.1016/j.tiv.2025.106109

Andrea Rivero-Arze , Marina Grimaldi , Géraldine Maillet , Cindie Gesbert , Erwan Michelin , Clémentine Garoche , Emmanuelle Maillot-Maréchal , Olivier Palluel , François Sermier , Sebastian Hoffmann , Jérôme Couteau , Philippe Hubert , Elise Grignard , Selim Aït-Aïssa , Patrick Balaguer , Torben Österlund

{"title":"Inter-laboratory validation study of an in vitro glucocorticoid receptor transactivation assay for testing potential endocrine disrupting chemicals","authors":"Andrea Rivero-Arze , Marina Grimaldi , Géraldine Maillet , Cindie Gesbert , Erwan Michelin , Clémentine Garoche , Emmanuelle Maillot-Maréchal , Olivier Palluel , François Sermier , Sebastian Hoffmann , Jérôme Couteau , Philippe Hubert , Elise Grignard , Selim Aït-Aïssa , Patrick Balaguer , Torben Österlund","doi":"10.1016/j.tiv.2025.106109","DOIUrl":"10.1016/j.tiv.2025.106109","url":null,"abstract":"<div><div>The glucocorticoid receptor (GR) belongs to the family of steroid receptors (SRs). These receptors regulate a vast selection of cell-, tissue-, and organism biology, and are also targets of endocrine disrupting chemicals warranting design and validation of <em>in vitro</em> assays. Here we report a “blinded” ring trial of an <em>in vitro</em> cell-based GR transactivation assay with four involved laboratories. The laboratories set up the assay and tested 34 selected chemicals with remarkably good concordance. There was agreement between all laboratories for the classification of activity in 97 % of the cases, and three or more laboratories were always in agreement. The within laboratory concordance was very high (99.6 %) with only one of all 272 triplicates deviating. The assay was, thus, deemed easily transferable and reproducible within and between laboratories, since they would arrive at the same qualitative results. Furthermore, for the chemicals with solid data regarding GR activation or inhibition, the laboratories arrived at the expected conclusion in all cases. Overall, the transfer and validation were successful, and the method is under evaluation to become an OECD test guideline. The method is expected to become valuable in tiered approaches for assessing chemicals or environmental samples together with other similar methods.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"109 ","pages":"Article 106109"},"PeriodicalIF":2.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Comparison of the behavior of human lung epithelial cell lines cultured at the air-liquid interface and assessment of their responses after benzo(a)pyrene exposure 在气液界面培养的人肺上皮细胞系的行为比较及其暴露于苯并(a)芘后的反应评估

IF 2.6 3区医学

Toxicology in Vitro Pub Date : 2025-12-01 Epub Date: 2025-07-23 DOI: 10.1016/j.tiv.2025.106122

Suen Boulé, Louise Verhaeghe, Dominique Courcot, Yann Landkocz

{"title":"Comparison of the behavior of human lung epithelial cell lines cultured at the air-liquid interface and assessment of their responses after benzo(a)pyrene exposure","authors":"Suen Boulé, Louise Verhaeghe, Dominique Courcot, Yann Landkocz","doi":"10.1016/j.tiv.2025.106122","DOIUrl":"10.1016/j.tiv.2025.106122","url":null,"abstract":"<div><div>The biological effects of air pollution are still not well known, due to its complex mixture of particulate and gaseous compounds. <em>In vitro</em> cell culture models exposed at the air-liquid interface (ALI) represent a potential alternative to <em>in vivo</em> experiments to assess the effects of outdoor air pollution. This study compares two bronchial cell lines, Calu-3 and BEAS-2B, and two alveolar cell lines, hAELVi and A549, regarding their capacity to form a tight epithelial cell barrier for a 2-week culture period and metabolize xenobiotics actively. Culture at the air-liquid interface permits the Calu-3 and hAELVi cells to form and maintain a tight epithelial cell barrier with lower permeability to lucifer yellow, greater trans-epithelial electrical resistance, and the presence of <em>Zonula Occludens 1</em> (ZO-1) protein at the membrane, than the BEAS-2B and A549 cells. Exposure to benzo(<em>a</em>)pyrene (B<em>a</em>P) induces the up-regulation of CYP1A1 and CYP1B1 genes, proteins, and functional activity at the air-liquid interface in all cell lines. So, these results demonstrate that the Calu-3 and the hAELVi cells are the more relevant models to assess the effects of ambient air pollution at the air-liquid interface, forming a tight epithelial cell barrier and being metabolically active.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"109 ","pages":"Article 106122"},"PeriodicalIF":2.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144704469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cytotoxic and immunotoxic profile of HgCl2 involves alterations in purinergic signaling through the P2X7/NLRP3/CASP-1/IL-1β pathway: An in vitro study using human blood immune cells HgCl2的细胞毒性和免疫毒性谱涉及通过P2X7/NLRP3/CASP-1/IL-1β途径改变嘌呤能信号：一项使用人血液免疫细胞的体外研究

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2025-12-01 Epub Date: 2025-08-19 DOI: 10.1016/j.tiv.2025.106131

Mairin Schott , Charles Elias Assmann , Bianca Vedoin Copês Rambo , Marcylene Vieira da Silveira , Milagros Fanny Vera Castro , Vitor Bastianello Mostardeiro , Adriel Antônio Schirmann , Robson Lourenço da Silva Santos , Pâmela de Almeida Milioni , Ana Barbosa Viana , Valderi Luiz Dressler , Daniel Lázaro Gallindo Borges , Nilda Berenice de Vargas Barbosa , Vera Maria Melchiors Morsch , Michael Aschner , João Batista Teixeira da Rocha , Maria Rosa Chitolina Schetinger

{"title":"Cytotoxic and immunotoxic profile of HgCl2 involves alterations in purinergic signaling through the P2X7/NLRP3/CASP-1/IL-1β pathway: An in vitro study using human blood immune cells","authors":"Mairin Schott , Charles Elias Assmann , Bianca Vedoin Copês Rambo , Marcylene Vieira da Silveira , Milagros Fanny Vera Castro , Vitor Bastianello Mostardeiro , Adriel Antônio Schirmann , Robson Lourenço da Silva Santos , Pâmela de Almeida Milioni , Ana Barbosa Viana , Valderi Luiz Dressler , Daniel Lázaro Gallindo Borges , Nilda Berenice de Vargas Barbosa , Vera Maria Melchiors Morsch , Michael Aschner , João Batista Teixeira da Rocha , Maria Rosa Chitolina Schetinger","doi":"10.1016/j.tiv.2025.106131","DOIUrl":"10.1016/j.tiv.2025.106131","url":null,"abstract":"<div><div>An in vitro model using human peripheral blood mononuclear cells (PBMCs) was established to investigate the cytotoxic, oxidative and inflammatory effects and changes in purinergic system parameters caused by mercuric chloride (HgCl<sub>2</sub>). Cells were exposed to concentrations of HgCl<sub>2</sub> (0.05, 0.5, 5, and 50 μM) for 24, 48 and 72 h. Cell viability was measured by trypan blue and MTT assays, and IC<sub>50</sub>; apoptosis and cell death were assessed by flow cytometry. Oxidative stress was evaluated by reactive species (RS) generation, determination of Mercury (ICP-MS), Nitric Oxide (NO), and lipid peroxidation. Increased levels of HgCl₂ induced RS generation, NO, lipid peroxidation, apoptosis, and altered the cell cycle, reducing DNA synthesis and cell division of PBMCs. Flow cytometry confirmed decreased viability and increased late apoptosis. HgCl₂ accumulation in PBMCs was confirmed by ICP-MS. HgCl₂ altered purinergic system components, inhibiting NTPDase and increasing ADA activity. At 5 μM, it increased gene expression of purinergic receptors and both anti-inflammatory (IL-10) and pro-inflammatory markers (IL-1β, IL-6, TNF-α, NLRP3, CASP-1, NF-κB). Overexpression of the P2X7/NLRP3/CASP-1/IL-1β axis triggered cell death by pyroptosis. These findings provide compelling evidence HgCl<sub>2</sub> induces cytotoxic and inflammatory effects in PBMCs.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"109 ","pages":"Article 106131"},"PeriodicalIF":2.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144890368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Computational and spectrofluorimetric validation on glyphosate interactions with zebrafish (Danio rerio) acetylcholinesterase: Mechanistic and ecotoxicological implications 计算和荧光法验证草甘膦与斑马鱼乙酰胆碱酯酶的相互作用：机制和生态毒理学意义。

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2025-12-01 Epub Date: 2025-08-14 DOI: 10.1016/j.tiv.2025.106130

Andressa Rubim Lopes , Michael González-Durruthy , Maria Natália D.S. Cordeiro , Ana S. Moura , Ramón Rial , Juan M. Ruso , Juliana Zomer Sandrini , Carlos Eduardo da Rosa , Camila de Martinez Gaspar Martins

{"title":"Computational and spectrofluorimetric validation on glyphosate interactions with zebrafish (Danio rerio) acetylcholinesterase: Mechanistic and ecotoxicological implications","authors":"Andressa Rubim Lopes , Michael González-Durruthy , Maria Natália D.S. Cordeiro , Ana S. Moura , Ramón Rial , Juan M. Ruso , Juliana Zomer Sandrini , Carlos Eduardo da Rosa , Camila de Martinez Gaspar Martins","doi":"10.1016/j.tiv.2025.106130","DOIUrl":"10.1016/j.tiv.2025.106130","url":null,"abstract":"<div><div>This study explores the toxicodynamics of glyphosate in zebrafish (<em>Danio rerio</em>) acetylcholinesterase (zf-AChE) using a combined computational and experimental approach to reveal its potential cholinergic neurotoxic effects. Computational modeling suggested that glyphosate could block critical amino acid residues in the zf-AChE binding site, disrupting acetylcholine positioning and potentially leading to its pathological accumulation in cholinergic synapses. Additionally, glyphosate may adversely impact zf-AChE's flexibility, inducing conformational rigidity <em>via</em> hydrophobic van der Waals and hydrogen-bond interactions. These effects mirrored the binding behavior of physostigmine, a known specific zf-AChE inhibitor. Interestingly, the structural similarity between zf-AChE and human AChE (hs-AChE) suggests potential neurotoxicity in humans. Spectrofluorimetry confirmed binding between glyphosate and hs-AChE, resembling physostigmine binding. To sum up, our findings provide insights into glyphosate-induced cholinergic neurotoxicity in zebrafish, supporting extrapolations to humans and contributing valuable insights for ecotoxicology, new approach methodologies, and environmental risk assessment.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"109 ","pages":"Article 106130"},"PeriodicalIF":2.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The neuroprotective role of chlorogenic acid and Fisetin in differentiated neuronal cell line-SHSY5Y against amyloid-β-induced neurotoxicity 绿原酸和非西汀对分化神经细胞系shsy5y抗淀粉样蛋白β诱导的神经毒性的保护作用。

IF 2.6 3区医学

Toxicology in Vitro Pub Date : 2025-12-01 Epub Date: 2025-07-20 DOI: 10.1016/j.tiv.2025.106110

Apoorv Sharma , Puneet Kumar , Asimul Islam , Monika Bhardwaj , Vijay Kumar , Hridayesh Prakash

{"title":"The neuroprotective role of chlorogenic acid and Fisetin in differentiated neuronal cell line-SHSY5Y against amyloid-β-induced neurotoxicity","authors":"Apoorv Sharma , Puneet Kumar , Asimul Islam , Monika Bhardwaj , Vijay Kumar , Hridayesh Prakash","doi":"10.1016/j.tiv.2025.106110","DOIUrl":"10.1016/j.tiv.2025.106110","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a neurodegenerative disorder and characterized by amyloid-beta (Aβ) accumulation, synaptic dysfunction, oxidative stress, and lacks effective therapies. Fisetin and chlorogenic acid (CGA) are natural polyphenols have shown potential in mitigating several age-related diseases. Therefore this study investigates their neuroprotective effects against Aβ1–42-induced toxicity in differentiated SHSY5Y cells. Both Fisetin and CGA reversed the deleterious effects of Aβ1–42 by restoring redox balance, suppressing reactive oxygen species, and upregulating mRNA expression of critical antioxidant enzymes like <em>SOD1, GSR,</em> and <em>CAT</em>. These compounds also attenuated Aβ1–42-induced mitophagy via reduced <em>PINK1</em> expression and restored mitochondrial fusion by upregulating <em>MFN2</em>. Autophagy-related pathways were significantly modulated which was evidenced by increased <em>PRKAA1</em> (AMPK) and decreased <em>MTOR</em> mRNA levels, alongside elevated expression of <em>ATG101, ATG13, ULK1, SQSTM1</em> (p62) and reduced <em>ATG5</em> levels. Fisetin and CGA improved synaptic integrity by upregulating <em>DLG4</em> (PSD95) and <em>SYP</em> (synaptophysin) and reducing <em>ACHE</em> (acetylcholinesterase) expression. These findings highlight their potential in ameliorating Aβ1–42-induced neuronal toxicity through autophagy activation, synaptic preservation, and mitochondrial function enhancement. Furthermore, our docking studies also revealed good Fisetin and CGA binding affinity within AMPK and mTOR's binding pocket (FKBP12-FRB). Although the neuroprotective effects of CGA and Fisetin are underscored by transcriptional and docking studies, further translational and biophysical validation is required to demonstrate their therapeutic efficacy against AD-related neurodegeneration.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"109 ","pages":"Article 106110"},"PeriodicalIF":2.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Transcriptomic points of departure for 6PPD-Quinone derived from human Caco-2 and HepG2 cells 来自人Caco-2和HepG2细胞的6ppd -醌的转录组学起点。

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2025-12-01 Epub Date: 2025-08-14 DOI: 10.1016/j.tiv.2025.106129

Ke Xu, Krittika Mittal, Niladri Basu

{"title":"Transcriptomic points of departure for 6PPD-Quinone derived from human Caco-2 and HepG2 cells","authors":"Ke Xu, Krittika Mittal, Niladri Basu","doi":"10.1016/j.tiv.2025.106129","DOIUrl":"10.1016/j.tiv.2025.106129","url":null,"abstract":"<div><div>N-(1,3-Dimethyl butyl)-<em>N</em>′-phenyl-phenylenediamine-quinone (6ppd-quinone) is of emerging concern due to its widespread presence and toxicity to aquatic species. The chemical has been detected in human biofluids though little is known about its effects on human tissues. The objective of this study was to increase understanding of 6ppd-quinone's potential human health effects by deriving transcriptomic points of departure (tPOD) values in two human cell lines using the TPD-seq workflow. An EC20 for cytotoxicity was calculated for Caco-2 (104 μg/L) but not for HepG2 cells. Even in the absence of cytotoxicity, tPOD values (20th gene, 10th percentile, mode) were calculated in Caco-2 (6.5-25 μg/L) and HepG2 (0.36-35 μg/L) cells. These ranges capture values from 16 statistical and bioinformatic tests that examined mapping methods (CLC and Deplexer), algorithms (Limma and DESeq2), and filters (log2FC and BMR). The most common and sensitive genes with calculable benchmark doses (BMDs) in Caco-2 (DPF2, CD44, PGAP1, GDF15, H4C16) and HepG2 (SLC5A3, DKK1, ARG2, PHLDA1, TM4SF1) cells are listed. Pathway BMDs were also calculated for Caco-2 (systemic lupus erythematosus, 9.7-18 μg/L; alcoholism, 9.7-20 μg/L; viral carcinogenesis, 9.3–18.1 μg/L), and HepG2 (metabolic pathways, 50-60 μg/L) cells. These findings highlight TPD-seq as an efficient workflow to yield quantitative and mechanistic data relevant for human health risk assessment.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"109 ","pages":"Article 106129"},"PeriodicalIF":2.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evaluating cannabidiol-induced liver injury with and without valproate using a three-dimensional human hepatocyte spheroid model. 使用三维人肝细胞球体模型评估大麻二酚诱导的有丙戊酸和无丙戊酸肝损伤。

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2025-12-01 Epub Date: 2025-08-05 DOI: 10.1016/j.tiv.2025.106126

Jessica L Beers, Shalon L Harvey, Raeanne M Lanphier, Blake R Rushing, Susan L McRitchie, Susan J Sumner, Klarissa D Jackson

{"title":"Evaluating cannabidiol-induced liver injury with and without valproate using a three-dimensional human hepatocyte spheroid model.","authors":"Jessica L Beers, Shalon L Harvey, Raeanne M Lanphier, Blake R Rushing, Susan L McRitchie, Susan J Sumner, Klarissa D Jackson","doi":"10.1016/j.tiv.2025.106126","DOIUrl":"10.1016/j.tiv.2025.106126","url":null,"abstract":"<p><p>Cannabidiol (CBD) and valproate (VPA) are anti-epileptic medications commonly co-prescribed to treat seizures due to Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex in children. Clinical trial data have demonstrated that CBD carries a risk for severe hepatotoxicity that is greatly increased when prescribed with VPA through an unknown mechanism. The aim of this study was to investigate CBD-induced liver injury in combination with VPA using an in vitro liver model. Three-dimensional human hepatocyte spheroids are an emerging in vitro system that allows investigation of long-term toxicity. Spheroids derived from primary human hepatocytes were treated with vehicle control, 2-200 μM CBD, 0.5-20 mM VPA, CBD + VPA, and 0.1-10 mM acetaminophen (positive control). After 24 h, 8 days, and 15 days of exposure, spheroids were analyzed for ATP depletion, urea production, and CBD and VPA metabolite generation. Untargeted metabolomic analysis was also conducted. A delayed-onset, dose-dependent hepatotoxicity was observed in spheroids exposed to each drug treatment compared to vehicle control. This study is the first to recapitulate the hepatotoxic drug interaction of CBD and VPA in vitro and demonstrates the utility of human hepatocyte spheroids for toxicity studies. Future work is needed to examine mechanisms of CBD-induced hepatotoxicity with VPA.</p>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":" ","pages":"106126"},"PeriodicalIF":2.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12412670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144800952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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