Toxicology最新文献_第6页

Impact of fluoride on antioxidant activity and mitochondrial homeostasis in fetal rat kidney 氟对胎鼠肾脏抗氧化活性和线粒体稳态的影响。

IF 4.6 3区医学

Toxicology Pub Date : 2026-02-01 Epub Date: 2025-11-19 DOI: 10.1016/j.tox.2025.154342

Sabino Hazael Avila-Rojas , Esaú Montañez-Rodriguez , Ana Karen Pantaleón-Gómez , Iliana Angélica Tostado-Fernández , José Pedraza-Chaverri , Casimiro Gerarduzzi , Omar Noel Medina-Campos , Brenda Marquina-Castillo , Juan Carlos León-Contreras , Rogelio Hernández-Pando , Olivier Christophe Barbier

{"title":"Impact of fluoride on antioxidant activity and mitochondrial homeostasis in fetal rat kidney","authors":"Sabino Hazael Avila-Rojas , Esaú Montañez-Rodriguez , Ana Karen Pantaleón-Gómez , Iliana Angélica Tostado-Fernández , José Pedraza-Chaverri , Casimiro Gerarduzzi , Omar Noel Medina-Campos , Brenda Marquina-Castillo , Juan Carlos León-Contreras , Rogelio Hernández-Pando , Olivier Christophe Barbier","doi":"10.1016/j.tox.2025.154342","DOIUrl":"10.1016/j.tox.2025.154342","url":null,"abstract":"<div><div>Fluoride exposure harms human health. Additionally, recent attention has focused on understanding the impact of an adverse in utero environment on the programming of chronic kidney disease in adult offspring. A previous study has described that fluoride alters kidney development, inducing oligonephronia and promoting the premature maturation of remnant nephrons. Therefore, it is essential to continue researching the potential mechanisms involved in fluoride-induced alterations. Female Wistar rats were administered two doses of fluoride (2.5 or 5.0 mg/kg body weight/day) for 20 days before and after mating. The results showed that fluoride diminished catalase and superoxide dismutase activities while increasing the markers of nuclear factor erythroid 2-related factor 2 (Nrf2) activation, mitochondrial dynamics, autophagy, and biogenesis. Morphometric analysis revealed an increase in mitochondrial size and content. Although the levels of Bcl-2-associated X protein (Bax) and B-cell lymphoma 2 (Bcl-2) increased, the activity of caspase-3 and the immunodetection in the TUNEL assay decreased. Several of these changes were mainly observed with the high fluoride dose. In conclusion, the results suggest that fluoride alters the redox status and mitochondrial homeostasis while decreasing apoptosis. It is essential to recognize that, under normal conditions, apoptosis plays a crucial role in proper kidney development, and its occurrence decreases as the structures mature. Therefore, collectively, these alterations could lead to undesirable effects on postnatal life.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154342"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145574652","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

Retraction notice to “2,3,7,8-Tetrachlorodibenzo-p-dioxin induced autophagy in a bovine kidney cell line” [Toxicology 290 (2011) 258–270] 撤回“2,3,7,8-四氯二苯并-对二恶英诱导牛肾细胞系自噬”的通知[毒理学290(2011)258-270]。

IF 4.6 3区医学

Toxicology Pub Date : 2026-02-01 Epub Date: 2025-11-20 DOI: 10.1016/j.tox.2025.154330

Filomena Fiorito , Roberto Ciarcia , Giovanna Elvira Granato , Gabriella Marfe , Valentina Iovane , Salvatore Florio , Luisa De Martino , Ugo Pagnini

引用次数: 0

Linking AhR and Nrf2 activation to neurotoxicity through adverse outcome pathway-based machine learning 通过基于不良结果通路的机器学习将AhR和Nrf2激活与神经毒性联系起来。

IF 4.6 3区医学

Toxicology Pub Date : 2026-02-01 Epub Date: 2025-12-09 DOI: 10.1016/j.tox.2025.154366

Jiajia Yang , Kai Yan , Xiaofang Li , Wenjing Deng , Meian He , Hao Zhu , Xiliang Yan , Bing Yan

{"title":"Linking AhR and Nrf2 activation to neurotoxicity through adverse outcome pathway-based machine learning","authors":"Jiajia Yang , Kai Yan , Xiaofang Li , Wenjing Deng , Meian He , Hao Zhu , Xiliang Yan , Bing Yan","doi":"10.1016/j.tox.2025.154366","DOIUrl":"10.1016/j.tox.2025.154366","url":null,"abstract":"<div><div>Chemical-induced neurotoxicity poses a challenge for safety assessment due to the complexity of central nervous system responses and the limitations of conventional assays. We developed an adverse outcome pathway (AOP)-guided machine-learning framework that links molecular initiating events, using the activation of the aryl hydrocarbon receptor (AhR) and Nrf2-mediated oxidative stress responses as examples, to neurotoxicity. A curated dataset was assembled from public sources and the literature, key molecular features such as nitrogen-containing groups were identified as structural alerts associated with neurotoxicity. Within this framework, AhR and Nrf2 activity information (measured or predicted) was integrated with structural fingerprints to enhance biological interpretability while maintaining robust predictive performance (e.g., AUC value > 0.80) in both cross-validation and external validation. The AOP-based model was further applied to virtual screening of 7576 compounds, with blood–brain barrier (BBB) permeability and applicability domain (AD) constraints ensuring reliable predictions. Molecular docking of 12 prioritized persistent organic pollutants (POPs) further supported these predictions, revealing strong binding affinities with AhR (up to –10.2 kcal/mol) and Nrf2 (up to –7.9 kcal/mol) through interactions such as hydrogen bonding and π–π stacking. Overall, this strategy highlights AOP-based machine learning as a powerful approach to connect structure, mechanism, and outcomes, thereby improving chemical risk assessment and prioritization.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154366"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145726133","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

A meta-analysis-based adverse outcome pathway for the reproductive toxicity induced by per- and poly-fluoroalkyl substances in animals 基于荟萃分析的全氟烷基和多氟烷基物质对动物生殖毒性的不良后果途径。

IF 4.6 3区医学

Toxicology Pub Date : 2026-02-01 Epub Date: 2025-11-23 DOI: 10.1016/j.tox.2025.154352

Ying Zhu , Chao Zhao , Hong Guo , Qingtong Shi , Ruijun Dong , Qianqian Wang , Yong Wu , Hu Zhang

{"title":"A meta-analysis-based adverse outcome pathway for the reproductive toxicity induced by per- and poly-fluoroalkyl substances in animals","authors":"Ying Zhu , Chao Zhao , Hong Guo , Qingtong Shi , Ruijun Dong , Qianqian Wang , Yong Wu , Hu Zhang","doi":"10.1016/j.tox.2025.154352","DOIUrl":"10.1016/j.tox.2025.154352","url":null,"abstract":"<div><div>Per- and poly-fluoroalkyl substances (PFAS) were highly toxic to reproductive systems due to the widespread environmental distribution and persistence. However, the underlying mechanisms were not well understood. This study systematically evaluated the association between existing adverse outcome pathways (AOPs) and PFAS-induced reproductive toxicity using the AOP conceptual framework. A meta-analysis of 28 studies quantified the effect sizes, providing a comprehensive assessment of PFAS-induced reproductive toxicity in animals. Within the AOP framework, the molecular initiating event (MIE) was increased reactive oxygen species (ROS), which triggered several key events (KEs) at different levels. At the cellular level, the KEs included oxidative stress, mitochondrial dysfunction, DNA damage, endoplasmic reticulum stress, reduced steroidogenic protein expression, decreased thyroid hormone synthesis, epigenetic modification process, lipid metabolism disorders, decreased androgen and estrogen receptors. These KEs led to decreased testosterone and elevated estrogen levels, alongside disruptions in spermatogenesis, oocyte maturation, and ovulation. Consequently, this resulted in lower sperm count, impaired sperm quality, and decline in oocyte quantity. Meta-analysis results showed that PFAS exposure significantly decreased juvenile survival rates (Standardized Mean Difference (SMD): −3.10, 95 % Confidence Interval (CI): −4.01, −2.18), reduced male testosterone (SMD: −4.17, 95 % CI: −6.00, −2.33) and female estradiol levels (SMD: −1.98, 95 % CI: −3.15, −0.81) in animals. Our findings systematically summarized the reproductive toxicity mechanisms of PFAS and alternatives, providing scientific basis for assessing the environmental impact.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154352"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145605978","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

Prenatal diesel exhaust exposure enhances neonatal hyperoxia-induced kidney injury via oxidative stress and lipid disruption 产前柴油机废气暴露通过氧化应激和脂质破坏增强新生儿高氧诱导的肾损伤。

IF 4.6 3区医学

Toxicology Pub Date : 2026-02-01 Epub Date: 2025-12-13 DOI: 10.1016/j.tox.2025.154373

Sheng-Yuan Ho , Yu-Shan Chang , Hsiu-Chu Chou , Chung-Ming Chen

{"title":"Prenatal diesel exhaust exposure enhances neonatal hyperoxia-induced kidney injury via oxidative stress and lipid disruption","authors":"Sheng-Yuan Ho , Yu-Shan Chang , Hsiu-Chu Chou , Chung-Ming Chen","doi":"10.1016/j.tox.2025.154373","DOIUrl":"10.1016/j.tox.2025.154373","url":null,"abstract":"<div><div>Prenatal exposure to diesel exhaust particles (DEP) and postnatal oxygen therapy are both clinically relevant perinatal stressors, but their combined effects on kidney development are not well characterized. Using a rat model (Sprague Dawley, n = 10/group), pregnant dams received DEP via intranasal instillation (500 μg/day in PBS, gestational day 16–21; NIST SRM 2975), and offspring were maintained in either room air or 85 % oxygen chambers from birth through postnatal day 14. At postnatal day 14, kidneys were analyzed by histology, Western blot, ELISA, and LC-MS metabolomics. Offspring that received both prenatal DEP and postnatal oxygen showed more severe tubular injury across sexes, and higher kidney-to-body weight ratios that were driven primarily by significant increases in male offspring, whereas changes in females did not reach statistical significance. Kidney injury molecule-1 (KIM-1) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels were increased, and 8-OHdG showed a significant interaction between DEP and oxygen exposure. Interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-α) were elevated by both DEP and oxygen, indicating additive effects. Serum cystatin C, a marker of renal dysfunction, was also increased in all exposed groups and was highest in the dual-exposure group. Cystatin C levels showed strong positive correlations with renal levels of IL-1, IL-6, and TNF-α. Untargeted metabolomics revealed changes in glycerophospholipid metabolism that were specific to the group exposed to both DEP and oxygen. These results suggest that prenatal DEP exposure may increase renal sensitivity to postnatal oxidative stress, pointing to a time-sensitive window of vulnerability during early kidney development.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154373"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145763870","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

Notch1-dependent hippocampal apoptosis is associated with monocrotaline-induced anxiety-like behavior notch1依赖性海马细胞凋亡与单可可碱诱导的焦虑样行为有关。

IF 4.6 3区医学

Toxicology Pub Date : 2026-02-01 Epub Date: 2025-11-26 DOI: 10.1016/j.tox.2025.154357

Lai Baochang , Li Fan , Wang Fei , Yan Xianchun , Wang Zichen , Han Mengzhuan , Zhang Yiman , Kang Mengyang , Liu Bing , Wang Ying , Ma Qiang , Jia Pu , Zheng Xiaohui , Hu Hao , Tian Hongyan , Yin Qian

{"title":"Notch1-dependent hippocampal apoptosis is associated with monocrotaline-induced anxiety-like behavior","authors":"Lai Baochang , Li Fan , Wang Fei , Yan Xianchun , Wang Zichen , Han Mengzhuan , Zhang Yiman , Kang Mengyang , Liu Bing , Wang Ying , Ma Qiang , Jia Pu , Zheng Xiaohui , Hu Hao , Tian Hongyan , Yin Qian","doi":"10.1016/j.tox.2025.154357","DOIUrl":"10.1016/j.tox.2025.154357","url":null,"abstract":"<div><div>Monocrotaline (MCT), an alkaloid from the genus <em>Crotalaria</em>, is widely used to establish an animal model of pulmonary hypertension. The toxicity of MCT extends not only to peripheral organs but also to the nervous system. However, the molecular mechanism responsible for the development of anxiety disorders after MCT poisoning remains unclear. MCT (60 mg/kg) administration for 4 weeks was used to induce a rat model of anxiety-like behavior with pulmonary hypertension. Open field and elevated plus maze tests showed MCT increased anxiety-like behavior in rats with pulmonary hypertension. Hematoxylin and eosin staining of the hippocampus and annexin V-FITC/PI staining of the mouse hippocampal cell line HT22 with MCT infusion showed that MCT promoted apoptosis in hippocampal neurons. The western blot showed MCT increased the apoptosis effector caspase-3 expression and activation in vivo and in vitro. Simultaneously, Notch1 and its downstream gene expression were also increased in vivo and in vitro. Furthermore, Notch1 deletion with siRNA can eliminate MCT-induced apoptosis and caspase-3 expression and activation. The Notch1 inhibitor DAPT has the same effect <em>in vitro</em>. In addition, DAPT alleviated MCT-induced anxiety-related behavior and attenuated hippocampal apoptosis <em>in vivo</em>. The present study reveals that the mechanism of MCT-induced neurotoxic effects in hippocampal neurons is mediated by the Notch1/caspase-3 pathway.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154357"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145639272","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

Corrigendum to “Loss of c-Met signaling sensitizes hepatocytes to lipotoxicity and induces cholestatic liver damage by aggravating oxidative stress” [Toxicology 361–362 (2016) 39–48] “c-Met信号的缺失使肝细胞对脂肪毒性敏感，并通过加重氧化应激诱导胆汁淤积性肝损伤”的更正[毒理学361-362(2016)39-48]。

IF 4.6 3区医学

Toxicology Pub Date : 2026-02-01 Epub Date: 2025-11-25 DOI: 10.1016/j.tox.2025.154340

Luis E. Gomez-Quiroz , Daekwan Seo , Yun-Han Lee , Mitsuteru Kitade , Timo Gaiser , Matthew Gillen , Seung-Bum Lee , Ma Concepcion Gutierrez-Ruiz , Elizabeth A. Conner , Valentina M. Factor , Snorri S. Thorgeirsson , Jens U. Marquardt

引用次数: 0

AhR/ROS-mediated endoplasmic reticulum stress contributes to PFOSA-induced cardiac defects AhR/ ros介导的内质网应激有助于pfosa诱导的心脏缺陷。

IF 4.6 3区医学

Toxicology Pub Date : 2026-02-01 Epub Date: 2025-12-02 DOI: 10.1016/j.tox.2025.154363

Kang Wang , Huixian Chen , Pinyi Chen , Lei Wu , Yan Jiang , Tao Chen

{"title":"AhR/ROS-mediated endoplasmic reticulum stress contributes to PFOSA-induced cardiac defects","authors":"Kang Wang , Huixian Chen , Pinyi Chen , Lei Wu , Yan Jiang , Tao Chen","doi":"10.1016/j.tox.2025.154363","DOIUrl":"10.1016/j.tox.2025.154363","url":null,"abstract":"<div><div>Perfluorooctane sulfonamide (PFOSA), an immediate precursor of perfluorooctane sulfonate (PFOS), is widely detected in the environment. Recent studies have indicated that the aryl hydrocarbon receptor (AhR) mediates PFOSA-induced cardiac defects; however, the precise mechanisms remain unclear. Given that genes involved in endoplasmic reticulum stress (ERS) are enriched in zebrafish larvae following PFOSA exposure, we hypothesized that AhR mediates PFOSA-induced cardiac defects through ERS. In this study, we observed a dose-dependent increase in the ERS markers Grp78 and Chop in the hearts of zebrafish larvae exposed to PFOSA. Furthermore, PFOSA-induced ERS activated the PERK branch of the unfolded protein response (UPR), while inhibition of either AhR or reactive oxygen species (ROS) significantly attenuated PFOSA-triggered ERS and PERK branch activation. The results further demonstrated that PFOSA-induced ERS and PERK activation led to 1) mitochondrial calcium overload through the Ip3r/Grp75/Vdac1 complex, and 2) downregulation of PGC-1α resulting from CHOP overexpression. Collectively, these events resulted in apoptosis in the zebrafish embryonic heart. AhR/ROS-dependent ERS, PERK branch activation, and mitochondrial damage were also observed in rat embryonic cardiomyocytes exposed to PFOSA. In conclusion, our findings indicate that PFOSA induces ERS and activates the PERK branch through the AhR/ROS axis, leading to mitochondrial damage via calcium overload and PGC-1α suppression, ultimately resulting in apoptosis and cardiac defects. Overall, these results highlight the fundamental role of ERS in the cardiac developmental toxicity of PFOSA.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154363"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145669377","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

Palmitic acid induced the onset of lipotoxicity in a HepaSH-on-chip model with raised of H2O2 and IL-6, and altered p38/MAPK & JAK/STAT pathways 棕榈酸诱导hepsh芯片模型的脂毒性发作，H2O2和IL-6升高，p38/MAPK和JAK/STAT通路改变。

IF 4.6 3区医学

Toxicology Pub Date : 2026-02-01 Epub Date: 2025-11-22 DOI: 10.1016/j.tox.2025.154345

Hanyuan Wang , Stéphane Poulain , Wenxin Cao , Hiroshi Arakawa , Soo Hyeon Kim , Yukio Kato , Masaki Nishikawa , Yasuyuki Sakai , Eric Leclerc

{"title":"Palmitic acid induced the onset of lipotoxicity in a HepaSH-on-chip model with raised of H2O2 and IL-6, and altered p38/MAPK & JAK/STAT pathways","authors":"Hanyuan Wang , Stéphane Poulain , Wenxin Cao , Hiroshi Arakawa , Soo Hyeon Kim , Yukio Kato , Masaki Nishikawa , Yasuyuki Sakai , Eric Leclerc","doi":"10.1016/j.tox.2025.154345","DOIUrl":"10.1016/j.tox.2025.154345","url":null,"abstract":"<div><div>Hepatic inflammation induced by lipotoxicity is a key event in the progression of liver steatosis to non-alcoholic steatohepatitis (NASH). To characterize this process, we investigated the response of HepaSH cells—a novel mature human hepatocyte derived from chimeric mice—to a weak but chronic palmitic acid (PA) exposure, a prevalent dietary fatty acid. To mimic the hepatic microphysiological environment, cells were cultured using organ-on-chip technology and exposed to PA for two weeks. Functional assays revealed no changes in glucose or lactate metabolism. Likewise, PA exposure did not alter albumin secretion, TGF-β1 or TNF-α production, bile acid synthesis, or CYP450 biotransformation activity. Furthermore, there was no lipid accumulation or change in triglyceride production. However, PA-treated cells cleared the palmitic acid and increased the levels of reactive oxygen species (H₂O₂) and interleukin-6 (IL-6) compared to controls. mRNA analysis concurrently revealed perturbations in transcriptional regulators and genes associated with lipid metabolism, NF-<sub>K</sub>B, inflammation, and mitochondrial functions. Addtional RT-qPCR confirmed the activation of the JNK1/MAPK8 gene in p38/MAPK and JAK2 in the JAK/STAT/IL-6 pathways in response to PA. We believed that our findings using an advanced mature human hepatic on-chip model would help to provide insight of the early stages of PA-induced lipotoxicity in hepatocytes.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154345"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145597668","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

Acetyl tributyl citrate induces intestinal toxicity by regulating the IDH2/NF-κB pathway and lipid peroxidation 乙酰柠檬酸三丁酯通过调节IDH2/NF-κB通路和脂质过氧化作用诱导肠道毒性。

IF 4.6 3区医学

Toxicology Pub Date : 2026-02-01 Epub Date: 2025-11-27 DOI: 10.1016/j.tox.2025.154360

Kai Kang, Ying Huang

{"title":"Acetyl tributyl citrate induces intestinal toxicity by regulating the IDH2/NF-κB pathway and lipid peroxidation","authors":"Kai Kang, Ying Huang","doi":"10.1016/j.tox.2025.154360","DOIUrl":"10.1016/j.tox.2025.154360","url":null,"abstract":"<div><div>In recent years, the increasing prevalence of environmental pollutants has raised concerns about their potential role in intestinal-related diseases. Previous studies have shown that various chemicals, including plasticizers like acetyl tributyl citrate (ATBC), may adversely affect intestinal health, but the specific mechanisms remain unclear. Herein, we aimed to elucidate the potential molecular mechanisms underlying ATBC-induced intestinal toxicity. We systematically screened professional databases, including ChEMBL, STITCH, and GSE16879, and identified 29 potential targets associated with ATBC-related intestinal toxicity. Through rigorous filtering using the STRING platform and Cytoscape software, 15 hub genes were ultimately selected, and four core targets—ATM, FYN, IDH2, and TOP1—were identified using two machine-learning methods. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that these core targets were primarily enriched in NF-κb pathways. Molecular docking simulations using the AutoDock software further confirmed strong binding interactions between ATBC and the core targets, and IDH2 was selected for the following analyses. <em>In vitro</em> experiments demonstrated that ATBC treatment decreases IDH2 expression in NCM460 and HCT116 cells and activates the NF-κB pathway. Given the pivotal role of the IDH2 gene in cellular energy metabolism, we systematically evaluated reactive oxygen species (ROS) levels and performed JC-1 staining assays. Our findings demonstrate that ATBC significantly promotes intracellular ROS accumulation, induces mitochondrial membrane-potential depolarization, and concurrently triggers cellular lipid peroxidation damage. Overall, our findings confirm that ATBC induces intestinal damage by regulating the IDH2/NF-κB pathway and lipid peroxidation, and lay the foundation for the development of preventive and therapeutic strategies against intestinal damage caused by exposure to ATBC-containing plastics.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154360"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145640217","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