Toxicology最新文献

{"title":"Emerging roles of histone modifications in environmental toxicants-induced neurotoxicity","authors":"Ishita Mehta ,&nbsp;Manika Verma ,&nbsp;Mohammed Nazish Quasmi,&nbsp;Dinesh Kumar,&nbsp;Ashok Jangra","doi":"10.1016/j.tox.2025.154164","DOIUrl":"10.1016/j.tox.2025.154164","url":null,"abstract":"<div><div>Epigenetics describes itself as heritable modifications in gene function that eventually alter gene and protein expression levels without any alterations in the genome sequence. Epigenetic alterations are closely association with several neurological diseases and neurodevelopmental disorders. In recent years, growing shreds of evidences suggested the crucial role of epigenetic modifications especially histone modifications in environmental toxicants-induced neurotoxicity. This review will give an overview of the state of knowledge on histone alterations and the ways in which environmental pollutants bisphenol-A, heavy metals, pesticides, and phthalates affects post-translational modifications to alter gene transcription and cause neurological abnormalities. We provide a brief summary of the results of recent research on the effects of environmental toxins on each of the prior identified processes of histone modifications, including the neurological consequences and changes in histones. There is also discussion of the limitations of current research findings. Furthermore, this review aims to provide viewers a comprehensive knowledge regarding the role of histone modifications in various environmental toxicants-induced neurological diseases and offers insights for future research.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154164"},"PeriodicalIF":4.8,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874555","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}

{"title":"Increased TSLP and oxidative stress reflect airway epithelium injury upon cigarette smoke exposure. Is there a role for carbocysteine?","authors":"Paola Pinto ,&nbsp;Daniele Donzì ,&nbsp;Serena Di Vincenzo ,&nbsp;Maria Ferraro ,&nbsp;Valentina Lazzara ,&nbsp;Maria Giuseppina Bruno ,&nbsp;Nadia Moukri ,&nbsp;Bernardo Patella ,&nbsp;Rosalinda Inguanta ,&nbsp;Elisabetta Pace","doi":"10.1016/j.tox.2025.154160","DOIUrl":"10.1016/j.tox.2025.154160","url":null,"abstract":"<div><div>Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory degenerative disease. Disease exacerbations accelerate lung function deterioration. Airway epithelium has a central role in COPD pathophysiology. Airway epithelium releases alarmins including the thymic stromal lymphopoietin (TSLP) in response to exogenous stressors. Notch-1 in the nucleus acts as inhibitor of TSLP gene expression. Here, we investigated, in human bronchial epithelial cells, the effects of cigarette smoke extract (CSE) in TSLP production exploring the relationship with oxidative stress events and with Notch-1 signaling. In CSE exposed 16HBE, the effects of carbocysteine were assessed on: intracellular and extracellular oxidative stress; nuclear Notch-1 expression; TSLP gene expression. The TSLP levels in sera from non-smokers, smokers and exacerbated COPD patients (before and after therapy with carbocysteine) were also explored. CSE induced TSLP gene expression and oxidative stress and reduced nuclear expression of Notch-1 in 16HBE. The use of an electrochemical sensor allowed a reliable tool to assess oxidative stress. TSLP concentrations were higher in sera from smokers and exacerbated COPD than in sera from non-smokers. Carbocysteine was able to counteract the effects of CSE in oxidative stress and in TSLP gene expression in 16HBE and to reduce TSLP in exacerbated COPD. In conclusion, increased oxidative stress induced by smoke exposure in airway epithelium leads to increased TSLP production and carbocysteine <em>in vitro</em> and <em>in vivo</em> mitigates the induced TSLP production. Oxidative stress detection by electrochemical sensors can open new avenues for evaluating epithelial damage and for identifying patients eligible to alarmin targeted biologics.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154160"},"PeriodicalIF":4.8,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143870285","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}

{"title":"An adverse outcome pathway for DNA adduct formation leading to kidney failure","authors":"D.A. Barnes ,&nbsp;M.J. Janssen ,&nbsp;Huan Yang ,&nbsp;F.A. Redegeld ,&nbsp;R. Masereeuw","doi":"10.1016/j.tox.2025.154162","DOIUrl":"10.1016/j.tox.2025.154162","url":null,"abstract":"<div><div>An Adverse Outcome Pathway (AOP) is a conceptual framework in toxicology and risk assessment that outlines the series of events from a chemical's molecular interaction to the resulting adverse health effect. This framework offers a structured approach to organizing biological knowledge, making it especially useful for understanding the mechanisms through which chemicals cause harm. Following a comprehensive analysis of the literature, an AOP was elucidated for key events linking DNA adduct formation, caused by compounds such as platinum anticancer drugs, to tubular necrosis, resulting in kidney failure. Currently, cisplatin, carboplatin and oxaliplatin are the three most utilised Pt-based drugs used globally for the treatment of cancer. The hydrolysis of platinum anticancer agents post-cellular uptake yields electrophilic intermediates that covalently bind to nucleophilic sites on DNA to form adducts that represent the molecular initiating event. When DNA repair mechanisms become unbalanced, the nephrotoxic response following the formation of DNA adducts leads to DNA damage and mitochondrial dysfunction. These events promote the generation and release of reaction oxygen species (ROS) to induce oxidative stress, causing cell death and inflammation. Upon detachment from the basement membrane, these compromised cells are subsequently deposited in the tubular lumen. Tubular obstruction and inflammatory responses to proximal tubule insult can lead to secondary toxicity and tubular necrosis, further exacerbating kidney injury and precipitating a progressive decline of renal function, finally resulting in kidney failure.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154162"},"PeriodicalIF":4.8,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143870283","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}

{"title":"Embryonic exposure to GenX causes reproductive toxicity by disrupting the formation of the blood-testis barrier in mouse offspring","authors":"Zhencheng Fan ,&nbsp;Runyang Hong ,&nbsp;Shuhao Li ,&nbsp;Liang Kong ,&nbsp;Qiyue Zhou ,&nbsp;Tan Ma ,&nbsp;Hao Chen ,&nbsp;Chun Pan","doi":"10.1016/j.tox.2025.154161","DOIUrl":"10.1016/j.tox.2025.154161","url":null,"abstract":"<div><div>As a replacement for perfluorooctanoic acid, hexafluoropropylene oxide dimer acid, commercially referred to as “GenX”, has attracted significant attention. However, a comprehensive understanding of the reproductive systems of male offspring exposed to GenX is lacking. This study aimed to investigate how embryonic exposure to GenX affects the reproductive development of male offspring and the underlying mechanisms. We administered GenX daily via gavage (2 mg/kg body weight/day) to the mice from day 12.5 of pregnancy until delivery. Our results suggested that embryonic exposure to GenX led to delayed onset of puberty in male offspring, with destruction of the testicular structure, disruption of the blood-testis barrier, decreased serum testosterone levels, decreased sperm count, impaired sperm motility, and increased rates of sperm abnormalities. We investigated the mechanism of blood-testis barrier breakdown <em>in vitro</em> by treating Sertoli cells (TM4) with GenX. GenX exposure caused the accumulation of senescent TM4 cells, decreased their glutathione (GSH) levels, and increased their oxidized glutathione levels. GenX inhibited glutaminase activity in TM4 cells, leading to decreased GSH synthesis, increased intracellular oxidative stress, and subsequent TM4 cell senescence, ultimately compromising the blood-testis barrier. Our findings indicated that embryonic exposure to GenX may cause Sertoli cell senescence by altering glutamine metabolism, disrupting the blood-testis barrier, and resulting in abnormal reproductive development in male offspring.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154161"},"PeriodicalIF":4.8,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143864734","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}

{"title":"Interpretation of thyroid-relevant bioactivity data for comparison to in vivo exposures: A prioritization approach for putative chemical inhibitors of in vitro deiodinase activity","authors":"K.T. Truong ,&nbsp;J.F. Wambaugh ,&nbsp;D.F. Kapraun ,&nbsp;SE Davidson-Fritz ,&nbsp;S. Eytcheson ,&nbsp;R.S. Judson ,&nbsp;K. Paul Friedman","doi":"10.1016/j.tox.2025.154157","DOIUrl":"10.1016/j.tox.2025.154157","url":null,"abstract":"<div><div>Many ToxCast assay endpoints can be mapped to molecular initiating events (MIEs) within the thyroid adverse outcome pathway (AOP) network. Herein, we provide a framework for interpretation of thyroid-relevant bioactivity data across MIEs. As a proof-of-concept, we used ToxCast data on the inhibition of deiodinase (DIO) enzymes, which convert thyroid hormones between active and inactive forms, and identified substances most likely to inhibit DIO enzymes. Data from 4 relevant cell-free <em>in vitro</em> assays are available for &gt; 2000 chemicals in single concentration screening and 327 chemicals in multi-concentration screening. We filtered to identify chemicals that demonstrated inhibition for each DIO enzyme less likely to be confounded by assay interference, refining the list of putatively active chemicals from 523 to 135. <em>In vitro</em> bioactivity data were then used to estimate administered equivalent doses (AEDs) using a novel high-throughput toxicokinetic (HTTK) model for <em>in vitro</em> to <em>in vivo</em> extrapolation (IVIVE) of dose. To consider potential thyroid-disrupting activity in an appropriate life-stage and dose context, we extended an existing human maternal-fetal HTTK model to allow for simulations involving the first trimester of pregnancy. For many chemicals, using modeled fetal tissue concentrations produced lower AED estimates than using modeled maternal plasma concentrations alone, at least partially due to conservative assumptions in our HTTK model of complete gestation. This extensible approach for MIE groups of thyroid-related bioactivity data from ToxCast may inform further screening or analyses for potential adverse outcomes during pregnancy and development.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154157"},"PeriodicalIF":4.8,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143864736","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}

{"title":"Hypoxia-inducible factor 1α modulates acrolein-induced cellular damage in bronchial epithelial cells","authors":"Asha Ashraf ,&nbsp;Bernd Zechmann ,&nbsp;Erica D. Bruce","doi":"10.1016/j.tox.2025.154158","DOIUrl":"10.1016/j.tox.2025.154158","url":null,"abstract":"<div><div>Acrolein, a highly reactive α,β-unsaturated aldehyde, is a widespread environmental pollutant. It is generated during the incomplete combustion of materials such as tobacco smoke, petrol, coal, forest fires, and plastics, as well as from the overheating of frying oils. Acrolein is known to induce cellular damage and oxidative stress. This study investigates the critical role of hypoxia-inducible factor 1α (HIF-1α), which is a transcription factor required to regulate cell survival and angiogenesis, in protecting bronchial epithelial cells from acrolein-induced cytotoxicity and DNA damage under normoxic and hypoxic conditions. To our knowledge, no prior study has comprehensively evaluated the effects of HIF-1α on cellular responses to acrolein under normoxic and hypoxic conditions in vitro. Therefore, the goal of this study was to explore how silencing HIF-1α influences cellular responses to acrolein, and our study focused on changes in cytotoxicity, metabolic activity, DNA damage, and oxidative stress using the BEAS-2B cell line. We observed enhanced cell damage and reduced viability in cells exposed to acrolein when silenced with HIF-1α, particularly in hypoxic environments. While results indicate that silencing HIF-1α significantly increases cytotoxicity and DNA damage under hypoxia compared to normoxic conditions, oxidative stress indicator levels did not rise noticeably under hypoxia following HIF-1α silencing. This research warrants further investigation to indicate the importance of HIF-1α in adapting to environmental and hypoxic stressors, which are commonly found in chronic lung diseases and ischemic conditions.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154158"},"PeriodicalIF":4.8,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143848589","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}

{"title":"Translational insights into statin-induced myotoxicity: Differential impact of lipophilic and hydrophilic statins on iPSC-derived skeletal muscle cells from patients with familial hypercholesterolemia","authors":"Raul Hernandes Bortolin ,&nbsp;Felipe de Souza Leite ,&nbsp;Andre Ducati Luchessi ,&nbsp;Joyce Esposito ,&nbsp;Igor Neves Barbosa ,&nbsp;Renata Caroline Costa de Freitas ,&nbsp;Abhijeet Rajendra Sonawane ,&nbsp;Sasha Anna Singh ,&nbsp;Elena Aikawa ,&nbsp;Kayque Alves Telles-Silva ,&nbsp;Thiago Dominguez Crespo Hirata ,&nbsp;Antonia Pereira Rosa Neta ,&nbsp;Ernesto Goulart ,&nbsp;Luiz Carlos Caires-Júnior ,&nbsp;Thais Maria da Mata Martins ,&nbsp;Patrícia Semedo ,&nbsp;Danielle de Paula Moreira ,&nbsp;Michel Naslavsky ,&nbsp;Andre Arpad Faludi ,&nbsp;Rodrigo Marques Gonçalves ,&nbsp;Mario Hiroyuki Hirata","doi":"10.1016/j.tox.2025.154159","DOIUrl":"10.1016/j.tox.2025.154159","url":null,"abstract":"<div><div>Statins are highly effective cholesterol-lowering drugs that can reduce the risk of cardiovascular events. Statins are well tolerated but some patients experience statin-associated muscle symptoms (SAM) that can reduce adherence to therapy. We investigated molecular mechanisms statin-induced myotoxicity using induced pluripotent stem cells (iPSC)-derived skeletal muscle (SKgM) cells. iPSC-SKgM cells were obtained from patients with familial hypercholesterolemia (FH) experiencing SAM (n = 3) or not (nonSAM, n = 3). iPSC-SkgM cells were treated with atorvastatin and rosuvastatin (1 to 100 µM). Statin cytotoxicity was assessed by functional assays (cell death, mitochondrial damage, caspase 3/7 activity). iPSC-SkgM cells from SAM patients were more sensitive to atorvastatin toxicity than nonSAM cells (p &lt; 0.05), recapitulating the phenotype of SAM patients. Rosuvastatin was less cytotoxic than atorvastatin in iPSC-SkgM (p &lt; 0.05) from both SAM and nonSAM patients. Transcriptomic analysis revealed stronger effects on gene expression in SAM-derived iPSC-SKgM cells treated with atorvastatin (106 genes) than rosuvastatin (33 genes) compared to nonSAM cells. Enrichment analyses predicted associations of these genes with cell growth, muscle function, pro-inflammatory processes, and apoptosis. Proteomic analysis also showed more proteins differentially abundant in atorvastatin (61 proteins) than in rosuvastatin (26 proteins) treated cells. These proteins were related to cell biosynthetic process, signaling and communication, nucleic acid metabolism, and protein processing. In conclusion, atorvastatin has greater toxicity than rosuvastatin to iPSC-SKgM cells, an outcome exacerbated in FH patients who experienced SAM. Atorvastatin has stronger effects on expression of molecules involved in several signaling pathways suggesting novel molecular mechanisms of statin-induced myotoxicity.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"515 ","pages":"Article 154159"},"PeriodicalIF":4.8,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143870284","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}

{"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}

{"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}

{"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}