Toxicology in Vitro最新文献_第3页

Corrigendum to ‘Particulate matter exposure-induced holesterol metabolism dysregulation in lung epithelial cells’ [Toxicology in Vitro 111 (2026) 106164] “颗粒物质暴露诱导肺上皮细胞胆固醇代谢失调”的更正[Toxicology in Vitro 111(2026) 106164]。

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2026-03-01 Epub Date: 2025-11-29 DOI: 10.1016/j.tiv.2025.106179

Huanxiang Li, Yimin Li , Xiaozhen Wang

引用次数: 0

Thymoquinone attenuates poly(I:C)-induced cellular stress via PKR/ATF4/CHOP signaling and autophagy modulation in human alveolar epithelial cells 百里醌通过PKR/ATF4/CHOP信号传导和自噬调节，减弱人肺泡上皮细胞poly（I:C）诱导的细胞应激。

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2026-03-01 Epub Date: 2025-10-12 DOI: 10.1016/j.tiv.2025.106165

Umut Kerem Kolac , Bakiye Goker Bagca , Gizem Donmez Yalcin , Mina Ilayda Taskiran , Soner Sertan Kara

{"title":"Thymoquinone attenuates poly(I:C)-induced cellular stress via PKR/ATF4/CHOP signaling and autophagy modulation in human alveolar epithelial cells","authors":"Umut Kerem Kolac , Bakiye Goker Bagca , Gizem Donmez Yalcin , Mina Ilayda Taskiran , Soner Sertan Kara","doi":"10.1016/j.tiv.2025.106165","DOIUrl":"10.1016/j.tiv.2025.106165","url":null,"abstract":"<div><div>Alveolar type II (ATII) epithelial cells are essential for maintaining pulmonary homeostasis and defending against viral pathogens. Polyinosinic:polycytidylic acid [Poly(I:C)], a synthetic analog of viral double-stranded RNA, activates protein kinase R (PKR)-mediated stress responses in these cells. Thymoquinone, the principal bioactive compound of <em>Nigella sativa</em>, exhibits antioxidant and immunomodulatory properties; however, its regulatory effects on viral mimic-induced stress pathways in alveolar epithelium are not well defined. In this study, primary human ATII cells were treated with Poly(I:C), thymoquinone, or their combination for 24 h. Activation of the PKR/eIF2α/ATF4/CHOP integrated stress response axis and apoptotic gene expression was evaluated. Autophagic activity was assessed by monitoring LC3-II/I, p62, and BECLIN1 expression levels, supported by fluorescence microscopy and flow cytometry. Intracellular reactive oxygen species (ROS) levels were quantified using a probe-based flow cytometric assay. Poly(I:C) activated the PKR/eIF2α/ATF4/CHOP pathway and increased the <em>BAX/BCL2</em> ratio, indicating enhanced cellular stress and apoptosis. Thymoquinone co-treatment attenuated these effects. While Poly(I:C) enhanced autophagic flux, evidenced by increased LC3-II/LC3-I ratio and BECLIN1 expression with decreased p62, thymoquinone reversed these alterations, suggesting suppressed autophagy. Imaging and flow cytometry confirmed that thymoquinone led to autophagosome accumulation, implying impaired autophagic clearance. Additionally, thymoquinone significantly reduced Poly(I:C)-induced intracellular ROS production. These findings demonstrate the cytoprotective potential of thymoquinone via modulation of stress signaling, autophagy, and oxidative stress in alveolar epithelial cells.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"111 ","pages":"Article 106165"},"PeriodicalIF":2.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145294373","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 Nrf2 activator tBHQ inhibits dendritic cell maturation and activation in response to bacterial and viral stimuli Nrf2激活因子thbhq抑制树突状细胞在细菌和病毒刺激下的成熟和激活。

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2026-03-01 Epub Date: 2025-10-15 DOI: 10.1016/j.tiv.2025.106169

Saamera Awali , Yining Jin , David M. Duriancik , Cheryl E. Rockwell

{"title":"The Nrf2 activator tBHQ inhibits dendritic cell maturation and activation in response to bacterial and viral stimuli","authors":"Saamera Awali , Yining Jin , David M. Duriancik , Cheryl E. Rockwell","doi":"10.1016/j.tiv.2025.106169","DOIUrl":"10.1016/j.tiv.2025.106169","url":null,"abstract":"<div><div>Dendritic cells (DCs) are professional antigen presenting cells that promote both innate and adaptive immune responses. Pertinent to adaptive immunity, DCs activate naïve T cells by presenting peptides on MHC class II molecules. Tert-butylhydroquinone (tBHQ) is a widely used food additive and a potent activator of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). Studies from our lab demonstrated that tBHQ impedes CD4 and CD8 T cell activation and effector function, but the effects of tBHQ on dendritic cell function remain unclear. To address this, splenic DCs were collected from wildtype C57BL/6 mice and treated with tBHQ (0.5 or 1 μM) for 30 mins prior to activation with either LPS or influenza A virus for 24 h. tBHQ treatment led to a significant decrease in the expression of the MHC class II receptor, CD80 and CD86, suggesting tBHQ may negatively impact DC maturation and activation. In addition, tBHQ inhibited secretion of IL-6, and to a lesser extent, TNFα, by LPS and IAV-activated DCs. Overall, our data suggest that tBHQ inhibits the expression of proteins important for DC function, which could ultimately have a negative impact on T cell response to pathogen.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"111 ","pages":"Article 106169"},"PeriodicalIF":2.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145314139","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

Development of an in vitro acute respiratory toxicity test using the SoluAirway™, 3D human airway model 使用3D人体气道模型SoluAirway™开发体外急性呼吸道毒性试验。

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2026-03-01 Epub Date: 2025-11-17 DOI: 10.1016/j.tiv.2025.106175

Ji-Woo Choe , Geon-Hee Lee , Su-Hyun Lee , Ga-Eun Kim , Ha-Ryong Kim , Kyung-Min Lim

{"title":"Development of an in vitro acute respiratory toxicity test using the SoluAirway™, 3D human airway model","authors":"Ji-Woo Choe , Geon-Hee Lee , Su-Hyun Lee , Ga-Eun Kim , Ha-Ryong Kim , Kyung-Min Lim","doi":"10.1016/j.tiv.2025.106175","DOIUrl":"10.1016/j.tiv.2025.106175","url":null,"abstract":"<div><div>This study presents a novel in vitro method for acute respiratory toxicity testing using the SoluAirway™ model (SoluAirway™ ARTT). SoluAirway™ is a 3D human airway tissue model constructed from primary human nasal epithelial cells, recapitulating the structural and molecular characteristics of the human bronchial epithelium. Tissues were exposed to four concentrations of test chemicals using two application methods—vapor-cap and direct application—for 4 h, followed by a 20 h post-incubation. Tissue viability was assessed using the MTT assay. Following established classification approaches, EC₅₀ and EC₂₅ values were determined and used to assign GHS acute inhalation toxicity categories: EC₂₅/₅₀ ≤ 5 mg/tissue: GHS Category 1 or 2, 5 < EC₂₅/₅₀ ≤ 25 mg/tissue: GHS Category 3 or 4 and EC₂₅/₅₀ > 25 mg/tissue: No Category. The direct application method showed an excellent predictive accuracy of 76.92 % (10/13). When 20 additional reference chemicals (33 total) were tested, the EC₅₀-based classification achieved a predictive accuracy of 75.76 % (25/33). Notably, applying a fixed-dose viability threshold (≤50 % viability at 5 mg/tissue for GHS 1/2; >50 % at 5 and ≤ 50 % at 25 mg/tissue for GHS 3/4; others as No Category) yielded comparable predictive performance. Collectively, these results suggest that SoluAirway™ ARTT is a promising, cost-effective alternative method for assessing acute inhalation toxicity.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"111 ","pages":"Article 106175"},"PeriodicalIF":2.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145558319","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

Commercial glyphosate formulations exceed active ingredient toxicity via mitochondrial ROS and transcriptomic disruption 商业草甘膦配方通过线粒体ROS和转录组破坏超过活性成分毒性。

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2026-03-01 Epub Date: 2025-11-20 DOI: 10.1016/j.tiv.2025.106178

Jakeline Liara Teleken , Leticia Prates Roma , Rosane Aparecida Ribeiro , Alex Rafacho , Maria Lúcia Bonfleur

{"title":"Commercial glyphosate formulations exceed active ingredient toxicity via mitochondrial ROS and transcriptomic disruption","authors":"Jakeline Liara Teleken , Leticia Prates Roma , Rosane Aparecida Ribeiro , Alex Rafacho , Maria Lúcia Bonfleur","doi":"10.1016/j.tiv.2025.106178","DOIUrl":"10.1016/j.tiv.2025.106178","url":null,"abstract":"<div><div>Glyphosate (GLY) is among the most widely used pesticides globally. Emerging evidence suggests that GLY-based herbicides (GBHs) are more toxic than GLY alone. In this study, we used HepG2 cells expressing mitochondrial-targeted Hyper7 to monitor H₂O₂ production and performed RNA sequencing to compare transcriptomic responses to GLY and a commercial GBH formulation. GBH exposure significantly elevated mitochondrial H₂O₂ levels compared to control and GLY-treated cells. Transcriptomic analysis revealed upregulation of gene ontology (GO) terms associated with oxidative stress and response to hydrogen peroxide, alongside downregulation of antioxidant enzyme genes and reduced PRDX3 protein, indicating impaired redox homeostasis in GBH-exposed cells. GBH also induced ER stress, marked by increased expression of stress-related genes (Ern1, Ddit3) and enrichment of GO terms for the unfolded protein response. GBH treatment upregulated genes involved in autophagy and apoptosis (Sqstm1, Bbc3, Map1lc3b), suggesting progressive stress response. Additionally, in GBH-treated cells metabolic pathways were altered, with higher expression of Atf3 and Ppargc1a, and enrichment of GO terms including response to glucose and lipid metabolism regulation These results indicate that GBH triggers complex stress and metabolic changes distinct from GLY alone, highlighting the importance of assessing full formulations to better evaluate potential health risks.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"111 ","pages":"Article 106178"},"PeriodicalIF":2.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582816","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

Neuromodulatory efficacy of Bacopa monniera extract against streptozotocin-induced neuronal dysfunction in SH-SY5Y cells: Implications for diabetic neuropathy 假马齿苋提取物对链脲佐菌素诱导的SH-SY5Y细胞神经功能障碍的神经调节作用：对糖尿病神经病变的影响。

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2026-03-01 Epub Date: 2025-10-13 DOI: 10.1016/j.tiv.2025.106166

H.S. Bhumika , M.D. Pandareesh

{"title":"Neuromodulatory efficacy of Bacopa monniera extract against streptozotocin-induced neuronal dysfunction in SH-SY5Y cells: Implications for diabetic neuropathy","authors":"H.S. Bhumika , M.D. Pandareesh","doi":"10.1016/j.tiv.2025.106166","DOIUrl":"10.1016/j.tiv.2025.106166","url":null,"abstract":"<div><div>Diabetic neuropathy (DN), a major complication of diabetes mellitus, is characterized by progressive neuronal damage driven by hyperglycemia-induced oxidative stress, mitochondrial dysfunction, and advanced glycation end product (AGE) accumulation. <em>Bacopa monniera</em> (Scrophulariaceae), enriched with the neuroactive saponin Bacoside A (BA), has demonstrated neuroprotective potential. This study explored the molecular mechanisms underlying the neuroprotective effects of <em>B. monniera</em> extract (BME) against streptozotocin (STZ)-induced toxicity in SH-SY5Y neuroblastoma cells. <em>In silico</em> ADMET analysis revealed that BA and its sapogenins possess favorable pharmacokinetic profiles, including enhanced absorption, reduced toxicity, and improved clearance, supporting their bioactive role in BME. Pretreatment with BME (25 μg/mL) significantly (<em>p</em> < 0.01) reduced STZ-induced mitochondrial (51.24 %) and membrane (41.69 %) damage, as shown by MTT and LDH assays. BME markedly reduced intracellular ROS, protein carbonylation, and lipid peroxidation (<em>p</em> < 0.001), while restoring mitochondrial membrane potential, ATP levels, enzymatic antioxidant levels, and glutathione content. Furthermore, BME upregulated brain-derived neurotrophic factor (BDNF) expression and inhibited AGE formation. Collectively, these findings highlight the antioxidant, antiglycation, and neurotrophic actions of BME, underscoring its promise as a multi-targeted phytotherapeutic candidate for DN management.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"111 ","pages":"Article 106166"},"PeriodicalIF":2.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145304576","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

Particulate matter exposure-induced cholesterol metabolism dysregulation in lung epithelial cells 颗粒物暴露诱导的肺上皮细胞胆固醇代谢失调。

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2026-03-01 Epub Date: 2025-10-14 DOI: 10.1016/j.tiv.2025.106164

Huanxiang Li , Yimin Li , Xiaozhen Wang , Zhiqian Zhong , Yadang Kuang , Jiaxuan Huang

{"title":"Particulate matter exposure-induced cholesterol metabolism dysregulation in lung epithelial cells","authors":"Huanxiang Li , Yimin Li , Xiaozhen Wang , Zhiqian Zhong , Yadang Kuang , Jiaxuan Huang","doi":"10.1016/j.tiv.2025.106164","DOIUrl":"10.1016/j.tiv.2025.106164","url":null,"abstract":"<div><div>Particulate matter (PM) poses a significant threat to human health, yet its systemic impact on molecular networks and cellular toxicity remains poorly understood. RNA sequencing was employed to explore the molecular mechanisms of micrometer-sized PMs obtained from air near the Yellow River on mink lung epithelial cells. PM particles were first characterized using scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and infrared spectra (IR) to examine morphology and elemental components. Then, the cellular toxicity of PM was examined using the CCK8 method. Results of gene ontology (GO) analysis and gene set enrichment analysis (GSEA) were confirmed using qRT-PCR of cholesterol homeostasis-related genes and free cholesterol measurements. PM exhibited dose-dependent inhibition of proliferation. Bioinformatics analysis indicated that 190 downregulated and 56 upregulated genes were identified after high-dose exposure to PM particles. The cholesterol metabolism pathway was substantially downregulated. The intrinsic mechanism driving the dysfunction of cholesterol metabolism was identified as oxidative stress, confirmed by measurements of reactive oxygen species (ROS), mitochondrial membrane potential, and the characterization of GSSG/GSH and NADP/NADPH ratios. The study highlights the link between PM-induced oxidative stress, impaired cholesterol homeostasis, and potential respiratory diseases, offering new insights into PM's physiological impact on lung cells.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"111 ","pages":"Article 106164"},"PeriodicalIF":2.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145309844","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

Advances in thyroid hormone system disruption testing – In vitro method for monitoring disrupted thyrotropin signaling through the human TSH receptor (hTSHR) 甲状腺激素系统干扰试验的进展-通过人TSH受体（hTSHR）监测促甲状腺激素信号干扰的体外方法

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2026-03-01 Epub Date: 2025-10-31 DOI: 10.1016/j.tiv.2025.106171

Markéta Dvořáková, Kristina Kejlová, Gabriela Goffová, Eliška Pácalová, Lada Svobodová, Dagmar Jírová

{"title":"Advances in thyroid hormone system disruption testing – In vitro method for monitoring disrupted thyrotropin signaling through the human TSH receptor (hTSHR)","authors":"Markéta Dvořáková, Kristina Kejlová, Gabriela Goffová, Eliška Pácalová, Lada Svobodová, Dagmar Jírová","doi":"10.1016/j.tiv.2025.106171","DOIUrl":"10.1016/j.tiv.2025.106171","url":null,"abstract":"<div><div>In recent years, increasing attention has been directed toward development of <em>in vitro</em> methods to assess thyroid hormone system disrupting chemicals suitable for regulatory applications. As a part of this effort, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) coordinated an international validation project through the European Union Network of Laboratories for the Validation of Alternative Methods (EU-NETVAL). This initiative involved the validation of 18 test methods, all aimed at contributing to a comprehensive testing battery for thyroid disruption. This work presents our contribution to the project, specifically focusing on the further development of a method designed to screen for disruption of the human thyrotropin receptor (hTSHR). Our objective is to provide an update on recent advancements in creating a reliable <em>in vitro</em> assay for toxicological assessment of chemicals that mimic or inhibit thyroid-stimulating hormone (TSH) function. We present and discuss pilot data generated using the developed standard operating procedure, including results from the initial testing of coded chemicals. The work highlights key challenges encountered during the method development and offers recommendations for future research and improvement. Our aim is to encourage more research teams to build upon this foundation, contributing to the refinement of a robust and reliable method. Ultimately, this approach could support the development of a comprehensive test battery for detecting disruptions in thyroid hormone signaling.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"111 ","pages":"Article 106171"},"PeriodicalIF":2.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145432968","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

Evaluation of metal removal from skin exposed to stainless steel and cement particles: Insights from an in vitro permeation study 金属从暴露于不锈钢和水泥颗粒的皮肤去除的评估：来自体外渗透研究的见解。

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2026-03-01 Epub Date: 2025-11-07 DOI: 10.1016/j.tiv.2025.106173

Greta Camilla Magnano , Veronique Malard , Matteo Crosera , Giovanna Marussi , Olivier Debellemanière , Marcella Mauro , Francesca Larese Filon

{"title":"Evaluation of metal removal from skin exposed to stainless steel and cement particles: Insights from an in vitro permeation study","authors":"Greta Camilla Magnano , Veronique Malard , Matteo Crosera , Giovanna Marussi , Olivier Debellemanière , Marcella Mauro , Francesca Larese Filon","doi":"10.1016/j.tiv.2025.106173","DOIUrl":"10.1016/j.tiv.2025.106173","url":null,"abstract":"<div><div>Occupational exposure to metal-containing particles can pose significant risks to skin health, particularly in environments where materials such as stainless steel and cement are handled. This study evaluates the effectiveness of simple aqueous cleansing methods—water and soapy water—for removing metals from the skin after exposure to stainless steel particles (SSP) and cement dust, with the aim of informing dermal decontamination practices. Using an in vitro skin permeation model with Franz diffusion cells, we assessed the extent of metal absorption following exposure, with decontamination applied 15 min post-contact. Quantification of permeated metals was performed via ICP-MS. Notably, soapy water significantly reduced dermal retention of lead (Pb) from cement dust, from 305 ± 111 ng/cm<sup>2</sup> (untreated) to 7.74 ± 0.7 ng/cm<sup>2</sup> (<em>p</em> < 0.05). Conversely, the same procedure increased skin retention of nickel (Ni) and chromium (Cr), suggesting a wash-in effect. For SSP exposure, soapy water was effective in reducing permeation of all tested metals. These findings emphasize the need for tailored skin cleansing strategies and contribute to the development of protective and cleansing formulations aimed at mitigating metal-induced skin toxicity.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"111 ","pages":"Article 106173"},"PeriodicalIF":2.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145483968","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

Quantitative in vitro to in vivo extrapolation (QIVIVE) of atrazine's effects on phosphodiesterase and aromatase mRNA expression in vitro to the rat in vivo based on pharmacokinetic 基于药代动力学的阿特拉津体外对大鼠体内磷酸二酯酶和芳香化酶mRNA表达影响的体外体外外推法（QIVIVE）

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2026-03-01 Epub Date: 2025-11-21 DOI: 10.1016/j.tiv.2025.106177

James W. Simpkins, Ralph L. Cooper, Charles Breckenridge

{"title":"Quantitative in vitro to in vivo extrapolation (QIVIVE) of atrazine's effects on phosphodiesterase and aromatase mRNA expression in vitro to the rat in vivo based on pharmacokinetic","authors":"James W. Simpkins, Ralph L. Cooper, Charles Breckenridge","doi":"10.1016/j.tiv.2025.106177","DOIUrl":"10.1016/j.tiv.2025.106177","url":null,"abstract":"<div><div>This study investigated the effects of atrazine (ATZ) and its metabolites on phosphodiesterase (PDE) activity <em>ex vivo</em> and aromatase mRNA expression in two steroidogenic cell lines (H295R and JEG-3). The pharmacokinetics of ATZ and its chlorometabolites were characterized for intact female Sprague-Dawley (SD) rats. A “Quantitative <em>In Vitro</em> to <em>In Vivo</em> Extrapolation” (QIVIVE) method was developed and used to calculate the margins of exposure to chlorotriazines in humans. Atrazine, and to a much lesser extent, its metabolites, resulted in PDE inhibition <em>ex vivo</em>. The IC<sub>50</sub> for atrazine was 39.52 μM. Neither H295R nor JEG-3 cells metabolize atrazine <em>in vitro</em>. 10 μM atrazine induced a 2- to 3-fold increase in aromatase mRNA expression in H295R cells. JEG3 cells gave similar results.</div><div>Pharmacokinetic parameters for the chlorotriazines in female SD rats indicated that atrazine is rapidly absorbed and cleared from plasma after a bolus dose. QIVIVE analyses revealed the AUC at the No Observed Effect Concentration (NOEC) for atrazine inhibition of PDE <em>ex vivo</em> following 1 h of exposure was 350- to 1013-fold greater than the AUC plasma concentration following gavage or dietary dosing <em>in vivo</em> at the lowest NOEL currently used as a point of departure (POD) in human risk assessment. These results indicate that atrazine-induced PDE inhibition <em>in vitro</em> would not have a functional effect <em>in vivo</em> at the POD from animal studies or in humans exposed to atrazine <em>via</em> diet, drinking water or occupationally.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"111 ","pages":"Article 106177"},"PeriodicalIF":2.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145589828","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