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DockTox: Targeting molecular initiating events in organ toxicity through molecular docking DockTox:通过分子对接靶向器官毒性的分子起始事件
IF 4.8 3区 医学
Toxicology Pub Date : 2025-04-17 DOI: 10.1016/j.tox.2025.154155
Rita Ortega-Vallbona , David Talavera-Cortés , Laureano E. Carpio , Jessica Coto Palacio , Alessandra Roncaglioni , Marina Garcia De Lomana , Domenico Gadaleta , Emilio Benfenati , Rafael Gozalbes , Eva Serrano-Candelas
{"title":"DockTox: Targeting molecular initiating events in organ toxicity through molecular docking","authors":"Rita Ortega-Vallbona ,&nbsp;David Talavera-Cortés ,&nbsp;Laureano E. Carpio ,&nbsp;Jessica Coto Palacio ,&nbsp;Alessandra Roncaglioni ,&nbsp;Marina Garcia De Lomana ,&nbsp;Domenico Gadaleta ,&nbsp;Emilio Benfenati ,&nbsp;Rafael Gozalbes ,&nbsp;Eva Serrano-Candelas","doi":"10.1016/j.tox.2025.154155","DOIUrl":"10.1016/j.tox.2025.154155","url":null,"abstract":"<div><div>Adverse Outcome Pathways (AOPs) in toxicology describe the sequence of key events from chemical exposure to adverse outcomes, facilitating the development of predictive models. The EU ONTOX project uses this framework to predict liver, developmental brain, and kidney toxicity without animal testing. Focusing on Molecular Initiating Events (MIEs), more concretely on the interaction of chemicals with key proteins, we have developed an automated workflow for docking small molecules onto over 20 pre-processed protein structures, implemented in the online tool DockTox. This tool generates conformers of small molecules, performs docking on MIE-associated proteins, and provides binding energy, interacting residues, and interaction maps. Additionally, it compares the interactions to a reference list of known ligands, producing an interaction fraction as an additional similarity measure. Evaluation of the docking workflow’s predictive performance on Peroxisome Proliferator-Activated Receptor α (PPARα) showed that interaction fraction values are more informative than binding energy alone for distinguishing binders from non-binders. This unique feature enhances the understanding of target protein interactions. DockTox supports the virtual screening of small molecules targeting MIE-associated proteins, offering insights into binding energies and interaction profiles. It is a valuable tool for anticipating adverse outcomes from chemical exposure in a tiered risk assessment approach.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154155"},"PeriodicalIF":4.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143870287","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
An In Vitro test battery using human whole blood for immunotoxicity hazard identification: Proof of concept studies with dexamethasone and benzo(a)pyrene 使用人全血进行免疫毒性危险鉴定的体外试验电池:地塞米松和苯并(a)芘的概念验证研究
IF 4.8 3区 医学
Toxicology Pub Date : 2025-04-14 DOI: 10.1016/j.tox.2025.154153
Victor J. Johnson , Michael I. Luster , Amber Edwards , Michael Kashon , Gary R. Burleson , Florence G. Burleson , Dori R. Germolec
{"title":"An In Vitro test battery using human whole blood for immunotoxicity hazard identification: Proof of concept studies with dexamethasone and benzo(a)pyrene","authors":"Victor J. Johnson ,&nbsp;Michael I. Luster ,&nbsp;Amber Edwards ,&nbsp;Michael Kashon ,&nbsp;Gary R. Burleson ,&nbsp;Florence G. Burleson ,&nbsp;Dori R. Germolec","doi":"10.1016/j.tox.2025.154153","DOIUrl":"10.1016/j.tox.2025.154153","url":null,"abstract":"<div><div>Immunotoxicity assessment is nearing a crossroads predicated on mounting pressure for reduction/replacement of animals in toxicology. This has fueled the development of alternative New Approach Methodologies (NAMs) for hazard identification. This work details a comprehensive human whole blood NAM battery for immunotoxicity testing. The test system is a closed tube culture containing whole blood diluted 1:3 in culture media with or without an immune stimulant, anti-CD3/CD28 or viral peptide pool. Model immunotoxicants dexamethasone (DEX; 0 – 1.94 μM) and benzo(<em>a</em>)pyrene [B(<em>a</em>)P; 0–6.3 μM], were added to the test system for 24 hours. Immune cells were identified and counted by flow cytometric immunophenotyping and assessed for natural killer (NK) cell activity and T cell activation. Supernatants were interrogated for proinflammatory cytokine concentrations. <em>In vitro</em> treatment with DEX resulted in concentration-dependent suppression of cytokine production, NK cell activity, and T cell activation induced by anti-CD3/CD28, as well as viral-induced cytokine production. B(<em>a</em>)P caused suppression of cytokine production and a nonsignificant reduction in T cell activation but did not impact NK cell activity, however, immunosuppression by B(<em>a</em>)P only occurred following metabolic activation by S9 fraction enzymes. Advantages of this NAM battery include assessment of adaptive immunity and direct translation of immunotoxicity to viral host resistance. These results provide evidence of <em>in vitro</em> immunotoxicity that reflect known outcomes from <em>in vivo</em> studies. This multi-endpoint human whole blood NAM battery should be useful for screening compounds for immunotoxicity hazard identification without reliance on animal systems for increased translatability to humans.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154153"},"PeriodicalIF":4.8,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143870286","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
Glutathione attenuates diesel exhaust-induced lung epithelial injury via NF-κB/Nrf2/GPX4-mediated ferroptosis 谷胱甘肽通过 NF-κB/Nrf2/GPX4 介导的铁氧化作用减轻柴油废气诱导的肺上皮损伤
IF 4.8 3区 医学
Toxicology Pub Date : 2025-04-14 DOI: 10.1016/j.tox.2025.154154
Ekta Nagar , Naresh Singh , Neeru Saini , Naveen Arora
{"title":"Glutathione attenuates diesel exhaust-induced lung epithelial injury via NF-κB/Nrf2/GPX4-mediated ferroptosis","authors":"Ekta Nagar ,&nbsp;Naresh Singh ,&nbsp;Neeru Saini ,&nbsp;Naveen Arora","doi":"10.1016/j.tox.2025.154154","DOIUrl":"10.1016/j.tox.2025.154154","url":null,"abstract":"<div><div>Diesel exhaust (DE) emissions pose a significant threat to public health. This study linked DE-mediated reactive oxygen species (ROS) and ferroptosis with lung epithelial disruption, also the protective potential of exogenous glutathione (GSH) administration was investigated. C57BL/6 mice were divided into three groups: filtered air (control), DE exposed, and DE+GSH (administered intranasally on alternate days). Airway hyperresponsiveness (AHR), lung tissues, and bronchoalveolar lavage fluid (BALF) were used for analysis. DE exposure significantly impaired lung function parameters as shown by AHR. Elevated ROS depleted the GSH/GSSG ratio and suppressed Nrf2 activity, disrupting antioxidant defense mechanisms, which were restored by GSH administration. DE-induced ROS acted as a key driver of ferroptosis, characterized by suppressed SLC7411 expression thereby decreased GSH synthesis and GPX-4 activity, inducing lipid peroxidation. Ferroptosis was significantly mitigated by increased GSH pool, which restored GPX-4 levels and reduced lipid peroxidation. Concurrently, DE induced ROS promoted DNA damage and apoptosis in lung epithelial cells wherein GSH treatment preserved cell survival in DE exposed mice. The heightened DE-associated ROS further amplified inflammation, as shown by increased cytokines (TNF-α, IL-6, TSLP, IL-33) and P-NF-κB activation. Activated inflammatory cascade disrupted tight junction proteins (claudins, occludin), resulted in weakened epithelial barrier and increased permeability. Lung barrier disruption was evidenced by transmission electron microscopy and immunohistochemistry, corroborated with elevated albumin levels. GSH effectively restored tight junction integrity and preserved barrier function in DE+GSH mice lungs. In conclusion, DE-induced oxidative stress and ferroptosis-triggered inflammation compromised epithelial barrier promoting lung injury. Exogenous GSH administration showed potential in restoring DE-associated lung damage.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154154"},"PeriodicalIF":4.8,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874558","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
Effects of co-exposure to microplastics and perfluorooctanoic acid on the Caco-2 cells 微塑料和全氟辛酸共同暴露对Caco-2细胞的影响
IF 4.8 3区 医学
Toxicology Pub Date : 2025-04-11 DOI: 10.1016/j.tox.2025.154152
Xingyu Zou , Mengjun Pan , Yue Liu , Shuai Wang , Hongye Xu , Xiaoqin Chu
{"title":"Effects of co-exposure to microplastics and perfluorooctanoic acid on the Caco-2 cells","authors":"Xingyu Zou ,&nbsp;Mengjun Pan ,&nbsp;Yue Liu ,&nbsp;Shuai Wang ,&nbsp;Hongye Xu ,&nbsp;Xiaoqin Chu","doi":"10.1016/j.tox.2025.154152","DOIUrl":"10.1016/j.tox.2025.154152","url":null,"abstract":"<div><div>As plastics are produced and used, humans are inevitably exposed to microplastics (MPs) on a daily basis. The pollution of MPs has aroused widespread human concern. Perfluorooctanoic acid (PFOA), a persistent organic pollutant (POP), can be adsorbed by microplastics and may exacerbate human health hazards. In this study, we investigated the effects of co-exposure of PET MPs and PFOA on the human intestinal tract in terms of both cytotoxicity and intestinal barrier through in vitro experiments. The results showed that PFOA induced cellular oxidative stress, mitochondrial dysfunction exerted cytotoxic effects, and inhibited tight junction (TJ) protein expression causing intestinal barrier damage. PET MPs can synergize with PFOA to exacerbate the deleterious effects on the intestinal tract by decreasing cell membrane permeability to increase PFOA accumulation in the cell and enhancing the ability of PFOA to inhibit zonula occludens-1 (ZO-1) proteins.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154152"},"PeriodicalIF":4.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143821450","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
Exposure to submicroplastics promotes the progression of nonalcoholic fatty liver disease in ApoE-deficient mice 暴露于亚微塑料促进apoe缺陷小鼠非酒精性脂肪肝疾病的进展
IF 4.8 3区 医学
Toxicology Pub Date : 2025-04-11 DOI: 10.1016/j.tox.2025.154137
Qingwen Li , Xuan Niu , Yuli Cai , Lili Li , Zhongyuan Xia
{"title":"Exposure to submicroplastics promotes the progression of nonalcoholic fatty liver disease in ApoE-deficient mice","authors":"Qingwen Li ,&nbsp;Xuan Niu ,&nbsp;Yuli Cai ,&nbsp;Lili Li ,&nbsp;Zhongyuan Xia","doi":"10.1016/j.tox.2025.154137","DOIUrl":"10.1016/j.tox.2025.154137","url":null,"abstract":"<div><div>Microplastics (MPs) pose emerging threats to human health, with growing concerns about liver toxicity and other harmful effects from plastic particles. While aquatic species exhibit hepatic vulnerability to micro/nanoplastics, the role of submicroplastics (100 nm-1 μm) in mammalian non-alcoholic fatty liver disease (NAFLD) progression remains unclear. We investigated the effects of a 12-week exposure to 0.5 μm polystyrene MPs (submicroplastics) in drinking water, administering this to ApoE-deficient mice fed either a chow diet (CD) or a Western diet (WD). Submicroplastics accumulated predominantly in the liver and were excreted in the feces. Histologically, submicroplastics significantly increased NAFLD activity scores, hepatic steatosis (Oil Red O-positive area), and fibrosis (Masson-positive area), with maximal severity in the WD+MPs group. Also, the MPs exposure group had increases in positive areas for F4/80 and inflammatory markers TNF-α, IL-1β and IL-6 expression under both diets. Concurrently, submicroplastics inhibited antioxidant defenses by lowering levels of superoxide dismutase and glutathione, while also increasing the lipid peroxidation marker malondialdehyde. WD-fed mice exhibited pronounced MPs-induced lipid dysregulation, including elevated hepatic triglycerides, total cholesterol, and free fatty acids (FAs). Mechanistically, submicroplastics upregulated FA synthesis regulators (ACC, FASN, SREBP1) while downregulating FA oxidation mediators (CPT1A, ACOX1, PPARα) in the livers under a WD. Our findings demonstrate that chronic submicroplastics-exposure exacerbates the progression of NAFLD in ApoE-deficient mice by disturbing lipid metabolism, enhancing oxidative stress, and amplifying inflammatory responses. This study provides experimental evidence linking environmental plastic pollution to accelerated metabolic liver disease, thereby highlighting the urgent need for plastic exposure control strategies.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154137"},"PeriodicalIF":4.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143848465","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
High-content screening morphological analysis to evaluate hepatic apoptosis induced by plant alkaloids in a Chang cell model 植物生物碱诱导肝细胞凋亡的高含量筛选形态学分析
IF 4.8 3区 医学
Toxicology Pub Date : 2025-04-11 DOI: 10.1016/j.tox.2025.154140
Su Been Park, Hwa Young Choi, Young Eun Park, Sihyeon Jang, Hyang Sook Chun
{"title":"High-content screening morphological analysis to evaluate hepatic apoptosis induced by plant alkaloids in a Chang cell model","authors":"Su Been Park,&nbsp;Hwa Young Choi,&nbsp;Young Eun Park,&nbsp;Sihyeon Jang,&nbsp;Hyang Sook Chun","doi":"10.1016/j.tox.2025.154140","DOIUrl":"10.1016/j.tox.2025.154140","url":null,"abstract":"<div><div>As interest in plant-derived compounds and their application in the pharmaceutical and functional food industries has increased, the rapid detection of chemical toxicity has become increasingly important for developing safe products. High-content screening (HCS) can quantify cellular and organelle morphological changes through image analysis; however, most HCS studies on apoptosis, a key toxicological event, have focused on the expression of apoptosis-related genes or proteins. In this study, we aimed to verify whether apoptosis can be detected solely based on cellular morphological changes. Chang cells were treated with staurosporine (STS), a well-known apoptosis inducer, and the morphological changes in the cells were quantified using HCS assays. The correlation between these HCS morphological descriptors and apoptosis rates measured using flow cytometry was determined. Chang cells were also treated with several plant-derived alkaloids known to induce apoptosis, and the same process was performed. The correlation coefficients, which were used to evaluate the correlation between HCS descriptors and apoptosis rates after STS treatment, ranged from 0.64 to 0.98, with 13 descriptors showing significant correlations. In contrast, the highest correlation coefficients between HCS descriptors and apoptosis rates after treatment with 1 of the 12 alkaloids investigated were determined to be 0.75 (at 10 μg/ml) and 0.49 (at 100 μg/ml). The apoptosis-related morphological changes induced by STS and alkaloids were observed using confocal microscopy. The present study demonstrates that HCS assays can detect apoptosis solely based on cellular morphological changes, providing a potential tool for rapid toxicity screening in early product development.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154140"},"PeriodicalIF":4.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143829465","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 “Bioinformatics identification of shared signaling pathways and core targets linking Benzo[a]pyrene exposure to HCC progression” [Toxicology 514 (2025) 154129] “连接苯并[a]芘暴露与HCC进展的共享信号通路和核心靶点的生物信息学鉴定”[毒理学514(2025)154129]的勘误表
IF 4.8 3区 医学
Toxicology Pub Date : 2025-04-10 DOI: 10.1016/j.tox.2025.154149
Yong-Le Li , Rong He , Meng Tang , Jing-Yi Lan , Guo-Yang Liu , Li-He Jiang
{"title":"Corrigendum to “Bioinformatics identification of shared signaling pathways and core targets linking Benzo[a]pyrene exposure to HCC progression” [Toxicology 514 (2025) 154129]","authors":"Yong-Le Li ,&nbsp;Rong He ,&nbsp;Meng Tang ,&nbsp;Jing-Yi Lan ,&nbsp;Guo-Yang Liu ,&nbsp;Li-He Jiang","doi":"10.1016/j.tox.2025.154149","DOIUrl":"10.1016/j.tox.2025.154149","url":null,"abstract":"","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154149"},"PeriodicalIF":4.8,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143937187","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 “Chronic oral depleted uranium leads to reproductive damage in male rats through the ROS-hnRNP A2/B1-COX-2 signaling pathway” [Toxicology 449 (2021) 152666] “慢性口服贫铀通过ROS-hnRNP A2/B1-COX-2信号通路导致雄性大鼠生殖损伤”[毒理学449(2021)152666]的勘误。
IF 4.8 3区 医学
Toxicology Pub Date : 2025-04-10 DOI: 10.1016/j.tox.2025.154133
Binghui Lu , Yonghong Ran , Shuang Wang, Juan Li, Yazhen Zhao, Xinze Ran, Rong Li, Yuhui Hao
{"title":"Corrigendum to “Chronic oral depleted uranium leads to reproductive damage in male rats through the ROS-hnRNP A2/B1-COX-2 signaling pathway” [Toxicology 449 (2021) 152666]","authors":"Binghui Lu ,&nbsp;Yonghong Ran ,&nbsp;Shuang Wang,&nbsp;Juan Li,&nbsp;Yazhen Zhao,&nbsp;Xinze Ran,&nbsp;Rong Li,&nbsp;Yuhui Hao","doi":"10.1016/j.tox.2025.154133","DOIUrl":"10.1016/j.tox.2025.154133","url":null,"abstract":"","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154133"},"PeriodicalIF":4.8,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143937188","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 2.5 stimulates pyroptosis and necroptosis via the p38 MAPK/Akt/NF-κB signaling pathway in human corneal epithelial cells 颗粒物质2.5通过p38 MAPK/Akt/NF-κB信号通路刺激人角膜上皮细胞焦亡和坏死
IF 4.8 3区 医学
Toxicology Pub Date : 2025-04-06 DOI: 10.1016/j.tox.2025.154138
Da Hye Kim , Hyesook Lee , Min Yeong Kim , Hyun Hwangbo , Seon Yeong Ji , EunJin Bang , Su Hyun Hong , Gi Young Kim , Sun-Hee Leem , Dongryeol Ryu , JaeHun Cheong , Yung Hyun Choi
{"title":"Particulate matter 2.5 stimulates pyroptosis and necroptosis via the p38 MAPK/Akt/NF-κB signaling pathway in human corneal epithelial cells","authors":"Da Hye Kim ,&nbsp;Hyesook Lee ,&nbsp;Min Yeong Kim ,&nbsp;Hyun Hwangbo ,&nbsp;Seon Yeong Ji ,&nbsp;EunJin Bang ,&nbsp;Su Hyun Hong ,&nbsp;Gi Young Kim ,&nbsp;Sun-Hee Leem ,&nbsp;Dongryeol Ryu ,&nbsp;JaeHun Cheong ,&nbsp;Yung Hyun Choi","doi":"10.1016/j.tox.2025.154138","DOIUrl":"10.1016/j.tox.2025.154138","url":null,"abstract":"<div><div>Particulate matter 2.5 (PM<sub>2.5</sub>) exposure poses significant health risks, particularly to the eyes. This study aimed to investigate the cytotoxic effects of PM<sub>2.5</sub> on human corneal epithelial cells (HCECs) and to elucidate the mechanisms involved in pyroptosis and necroptosis. HCECs were exposed to PM<sub>2.5</sub>, and cytotoxicity, reactive oxygen species (ROS) levels, and the expression of pyroptosis- and necroptosis-related proteins were assessed. The roles of nuclear factor-kappa B (NF-κB) and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome signaling pathways were also investigated. Exposure to PM<sub>2.5</sub> caused a dose-dependent decrease in cell viability, accompanied by significant NLRP3 inflammasome activation, leading to pyroptosis and the release of pro-inflammatory cytokines. Enhanced ROS generation and mitochondrial dysfunction have also been observed, along with indicators of necroptosis, such as increased levels of mixed-lineage kinase domain-like proteins. Importantly, activation of the NF-κB signaling pathway was crucial for these responses. The suppression of p38 mitogen-activated protein kinase (MAPK) and activation of protein kinase B (Akt) using pharmacological modulators SB203580 and SC79, respectively, significantly reduced PM<sub>2.5</sub>-mediated cellular damage. These findings indicate that p38 MAPK inhibition and Akt activation are key regulatory mechanisms that help attenuate the deleterious effects of PM<sub>2.5</sub> on HCECs. In conclusion, our findings offer new insights into the mechanisms by which PM<sub>2.5</sub> induces pyroptosis and necroptosis in HCECs, especially by activating the NLRP3 inflammasome and NF-κB signaling pathways. The critical regulatory roles of p38 MAPK and Akt underscore their potential as therapeutic targets to alleviate PM-induced ocular damage.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154138"},"PeriodicalIF":4.8,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143800343","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
Atrazine exposure induces TDP-43 protein translocation: A potential mechanism for prefrontal cortical neurodegeneration induced by environmental pollutants 阿特拉津暴露诱导TDP-43蛋白易位:环境污染物诱导前额皮质神经退行性变的潜在机制
IF 4.8 3区 医学
Toxicology Pub Date : 2025-04-05 DOI: 10.1016/j.tox.2025.154128
Yuan Ma , Kaidong Wang , Yuxuan Jiao , Yujing Li , Rong Hu , Yang Li , Ge Shi , Min Huang
{"title":"Atrazine exposure induces TDP-43 protein translocation: A potential mechanism for prefrontal cortical neurodegeneration induced by environmental pollutants","authors":"Yuan Ma ,&nbsp;Kaidong Wang ,&nbsp;Yuxuan Jiao ,&nbsp;Yujing Li ,&nbsp;Rong Hu ,&nbsp;Yang Li ,&nbsp;Ge Shi ,&nbsp;Min Huang","doi":"10.1016/j.tox.2025.154128","DOIUrl":"10.1016/j.tox.2025.154128","url":null,"abstract":"<div><div>Atrazine (ATR) is a widely utilized herbicide that has been demonstrated to exert a multitude of deleterious effects on the environment, particularly with regard to water and soil contamination. Moreover, its disruption of endocrine function and implications for antibiotic resistance underscore the urgent need to prioritize alternative solutions for both ecosystems and human health. Therefore, the objective of this study was to investigate a range of neurotoxic effects associated with atrazine-induced damage in the prefrontal lobe of mice. The results of this study indicate that treatment with ATR in C57BL/6 J mice resulted in cognitive-related behavioral deficits, including anxiety and depression, as well as motor impairments. In vivo analyses demonstrated that ATR exposure resulted in a reduction in neuronal synapse density at the microstructural level, while also compromising prefrontal morphological integrity, nociceptor count, and overall neuronal health within the brain. These findings collectively suggest that synaptic deficits are implicated in ATR-induced behavioral abnormalities observed in these mice. Furthermore, our findings revealed that ATR exposure resulted in elevated TDP-43 expression levels that were ectopically localized within the cytoplasm. This alteration led to impaired functionality of mRNP granules and contributed to the development of abnormal synaptic defects. Conversely, TDP-43 has the potential to localize ectopically to mitochondria, where it activates the mitochondrial unfolded protein response (UPRmt), which ultimately results in mitochondrial dysfunction. These findings collectively indicate a strong correlation between TDP-43 dysregulation and the progression of neurodegenerative diseases. Further investigation into the potential neurotoxicity of atrazine may foster heightened awareness, leading to more stringent regulatory measures, research into safer alternatives, and the adoption of sustainable practices, which are essential for safeguarding environmental integrity alongside human health.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154128"},"PeriodicalIF":4.8,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804248","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
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