Toxicological Sciences最新文献

{"title":"Nonclinical Investigation of the Potential of MHAA4549A, an Anti-Influenza A Therapeutic Antibody, to Mediate Antibody-Dependent Enhancement.","authors":"Gautham K Rao, Min Xu, Rodney A Prell, Man-Wah Tan, Lee R Swem, Jenny Jiang, Olga Li, Summer Park, Donghong Yan, Daniel Sheinson, Lynn Kamen, Wendy G Halpern, Jacqueline M McBride","doi":"10.1093/toxsci/kfag109","DOIUrl":"https://doi.org/10.1093/toxsci/kfag109","url":null,"abstract":"<p><p>Antibody-dependent enhancement (ADE) of infection and disease is a theoretical safety risk for antiviral antibodies against seasonal viruses with antigenic drift such as influenza. ADE of infection may occur if virus-specific antibodies at sub-therapeutic, non-neutralizing concentrations facilitate virus uptake, thus potentially enhancing virus replication. In contrast, ADE of disease reflects exacerbation of viral disease severity through viral replication dependent or independent mechanisms. Because of the theoretical concern of ADE, nonclinical safety assessment of therapeutic anti-influenza antibodies includes a thorough evaluation of ADE potential. The current set of studies were conducted to investigate the potential of MHAA4549A - a broadly specific, neutralizing, therapeutic anti-influenza A antibody-to elicit ADE of infection and disease of influenza H3N2 A/Aichi/2/68 (X31) across a broad dose range. Assessment of ADE was based on totality of results from both in vitro and mouse influenza studies with integration across study endpoints. In vitro studies demonstrated that MHAA4549A can mediate increased X31 entry into human and murine monocytic cells, but increased uptake did not result in enhanced viral replication or release under physiologic conditions. In a mouse model of X31 infection, intravenous administration of MHAA4549A resulted in delayed body weight recovery, but no exacerbation in orthogonal endpoints including mortality, lung viral titers or genomes, lung weights, or severity of influenza pneumonia. Overall, the totality of nonclinical data did not demonstrate any clear indication of ADE of infection at non-neutralizing concentrations, suggesting a low risk for MHAA4549A to cause enhanced influenza A-mediated disease at sub-therapeutic doses.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798228","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":"Acute Exposure to Perfluorooctanoic Acid (PFOA) During Cardiomyogenesis disrupts Transcriptional and Electrophysiological Profiles in Differentiated Myocytes.","authors":"Tomoko Ishikawa, Christopher W Clark, Anagha Tapaswi, Kimberley E Sala-Hamrick, Todd J Herron, Eric N Jimenez Vazquez, Abhilasha Jain, David K Jones, Justin A Colacino, Andre Monteiro Da Rocha, Laurie K Svoboda","doi":"10.1093/toxsci/kfag107","DOIUrl":"10.1093/toxsci/kfag107","url":null,"abstract":"<p><p>Exposure to per and polyfluoroalkyl substances (PFAS) are linked to various cardiovascular diseases (CVDs), but effects of developmental PFAS exposures on the human heart remain unclear. Using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), the objective of this study was to investigate the effects of PFAS exposure during cardiac differentiation on gene expression and function of cardiomyocytes. We exposed two hiPSC lines (one male and one female donor) to perfluorooctanoic acid (PFOA), a common and ubiquitous PFAS (0.05, 0.5, 5, 50, 100, 150, 200 μM), followed by assessment of cellular number and pluripotency marker expression. PFOA exposure for 72 hours had no significant effects on hiPSC pluripotency, and modest inhibition of proliferation was observed only at the highest concentration. hiPSCs were then differentiated into ventricular cardiomyocytes in the continued presence or absence of PFOA using an established protocol. Optical mapping studies revealed dose and cell line-specific effects of PFOA on cardiomyocyte voltage and calcium dynamics that were still present 10 days after cessation of exposure. Patch clamping studies demonstrated small but significant reductions in repolarizing IKr currents with 5µM PFOA exposure in cardiomyocytes from both donors. Using RNA-seq, we found that exposure to PFOA led to significant changes in transcriptional pathways related to lipids and lipoproteins in the female hiPSC-CM, and developmental pathways and calcium homeostasis in the male hiPSC-CM. These findings provide direct experimental evidence that transient developmental exposure to PFOA can durably reprogram human cardiomyocyte gene expression and function, supporting a developmental origin of PFAS-associated cardiovascular disease risk.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798033","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":"Advancing genotoxicity assessment with transcriptomic biomarkers: From 2D to 3D HepaRG spheroid models.","authors":"Mariam Saleh, Kevin Hogeveen, Anouck Thienpont, Emmanuel Demuynck, Valérie Fessard, Birgit Mertens, Ludovic Le Hégarat","doi":"10.1093/toxsci/kfag095","DOIUrl":"https://doi.org/10.1093/toxsci/kfag095","url":null,"abstract":"<p><p>The development of New Approach Methodologies (NAMs) for genotoxicity testing is needed to support the transition towards animal-free human-relevant chemical genotoxicity assessment. In this context, we investigated the predictive power of two transcriptomic biomarkers developed in 2D cell systems (GENOMARK and TGx-DDI) in metabolically active 3D HepaRG spheroids to classify chemicals as genotoxic (GTx) or non-genotoxic (NGTx). Human-hepatic HepaRG spheroids were treated for 72h with three different groups of chemicals: A) five genotoxic chemicals: lasiocarpine, cyclophosphamide, ethyl methanesulfonate, aflatoxin B1, benzo[a]pyrene; B) five non-genotoxic non-carcinogens: aflatoxin B2, 2-deoxy-D-glucose, D-mannitol, caffeine, ampicillin trihydrate; and C) five non-genotoxic carcinogens: perfluorooctanoic acid, diethanolamine, thioacetamide, phorbol-12-myristate-13-acetate, di(2-ethylhexyl) phthalate. Gene expression data from the treated HepaRG spheroids were collected using the high-throughput TempO-SeqTM technology and analysed with the transcriptomic biomarkers GENOMARK and TGx-DDI. Results with both biomarkers generally aligned with existing knowledge for all three groups of tested chemicals, effectively distinguishing genotoxic from non-genotoxic chemicals. The results of this study indicate that combining the 3D HepaRG spheroid model with transcriptomic biomarkers offers a promising, human-relevant approach to complement traditional in vitro genotoxicity tests.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798051","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":"In Vitro Approaches to Assess Respiratory Toxicity from Volatile Organic Compounds: An In-Depth Review.","authors":"Olivia C G Lampe, Eva C M Vitucci, Carolyn L Cannon, Kyle Holland, Margaret J Foster, Natalie M Johnson","doi":"10.1093/toxsci/kfag110","DOIUrl":"https://doi.org/10.1093/toxsci/kfag110","url":null,"abstract":"<p><p>Volatile organic compounds (VOCs) are ubiquitous inhaled pollutants. This review showcases current literature utilizing in vitro models of the human respiratory system to characterize the toxicity of VOCs. To map the existing evidence base, we conducted a scoping review following systematic search and screening procedures. Comprehensive searches of MEDLINE, Embase, Web of Science, CINAHL, PubMed, and CENTRAL identified 3,052 records. After screening, 144 original studies evaluating VOC exposures in human lung epithelial models met inclusion criteria. Overall, the current literature reflects substantial heterogeneity in cell models, exposure systems, and endpoints. Among 105 unique VOCs evaluated, acrolein, formaldehyde, toluene diisocyanate, and benzene were most frequently studied. Most investigations used submerged culture systems with liquid-phase VOC application, while fewer employed air-liquid interface (ALI) exposures that better mimic inhalation. Cytotoxicity, oxidative stress, pro-inflammatory signaling, and apoptosis were the most commonly measured endpoints, with oxidative stress frequently identified as an upstream driver of inflammatory and cytotoxic responses. However, mechanistic depth varied, and studies examining metabolism, barrier function, morphology, or transcriptomic regulation were relatively uncommon. Notably, chronic or repeated exposures were rarely conducted. Overall, this review highlights the variety of VOC exposure methods and commonly assessed biological endpoints, as well as the critical lack of more detailed mechanistic studies and somewhat limited VOC/mixture evaluation. The field is expansive but methodologically fragmented, underscoring the need for broader use of human respiratory cell models, more physiologically relevant exposure systems, improved dose characterization, and greater mechanistic resolution to advance understanding and throughput for VOC-induced pulmonary toxicity studies.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798175","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":"Effects of phthalates on mammalian adipose tissue.","authors":"Flávia C F Dos Santos, Kerrington R Eskridge, Mary J Laws, Jodi A Flaws, Jones B Graceli","doi":"10.1093/toxsci/kfag111","DOIUrl":"https://doi.org/10.1093/toxsci/kfag111","url":null,"abstract":"<p><p>Adipose tissue plays a critical role in metabolic and endocrine function because it is essential for maintaining systemic energy homeostasis and other related physiological functions. Mammals have four types of adipose tissue: white adipose tissue (WAT), brown adipose tissue (BAT), beige or brite adipose tissue (BeAT), and pink adipose tissue (PAT). These adipose tissues release endocrine factors that modulate diverse processes such as energy storage and expenditure, appetite control, glucose homeostasis, insulin sensitivity, inflammation, lipid metabolism, tissue repair, thermogenesis, and milk production. Proper adipose tissue function relies on hormone receptors and signaling pathways that make the adipose tissues susceptible to disruption by endocrine-disrupting chemicals such as phthalates. Here, we review relevant research on the associations between phthalate exposures and abnormalities in WAT and BAT functions, including phthalate-induced changes in morphology, physiology, and gene expression effects. This review covers in vitro studies, in vivo studies in mammals, and studies in humans. We also discuss important gaps in the literature. Overall, the evidence indicates that phthalates adversely affect WAT and BAT functions. Further studies are needed to better elucidate the mechanisms through which phthalates act in the adipose tissues and to determine the effects of phthalates on human adipose tissues.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798171","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":"Prolonged Zero-Nicotine E-Cigarette Exposure Disrupts Blood-Brain Barrier Integrity and Promotes Neuroinflammation: Evidence from In-Vitro and In-Vivo Models.","authors":"David Mara, Khondker Ayesha Akter, Sejal Rajesh Jadhav, Thomas J Abbruscato","doi":"10.1093/toxsci/kfag105","DOIUrl":"https://doi.org/10.1093/toxsci/kfag105","url":null,"abstract":"<p><p>Electronic cigarettes (e-cigarettes), particularly nicotine-free (0%) formulations, are often perceived as safer alternatives to nicotine-containing products. However, the progressive and mechanistic basis of blood-brain barrier (BBB) injury following acute and sub-chronic 0% exposure remains poorly researched. In this study, we investigated whether short-term and prolonged 0% e-cigarette exposure alters BBB integrity using complementary in-vitro and in-vivo models. Using a well-established astrocyte-bEnd.3 co-culture BBB model, 24-hour exposure significantly reduced transendothelial electrical resistance (TEER) without increasing sodium fluorescein (NaF) permeability. Following prolonged 5-day exposure, TEER remained significantly reduced and was accompanied by increased NaF permeability. In contrast, permeability to 4 kDa and 70 kDa FITC-dextran tracers remained unchanged. Immunocytochemistry (ICC) demonstrated reduced claudin-5 mean fluorescence intensity (MFI) after 24 hours, along with reduced ZO-1 and claudin-5 MFI and disrupted junctional morphology following 5-day exposure. Western blot (WB) analysis additionally demonstrated a significant reduction in claudin-5 expression after 5 days. To assess translational relevance, male and female CD-1 mice were exposed to 0% aerosols for 7 or 14 days, with 7-day exposures producing no significant changes in BBB tight junction (TJ) proteins, inflammatory cytokines, or plasma cardiac troponin-l levels. 14-day exposures reduced ZO-1 expression in both sexes, occludin expression in males, and elevated pro-inflammatory cytokines IL-17A, GM-CSF, MCP-1, TNF-α, and IL-1α without affecting plasma troponin-1. Collectively, these findings demonstrate that repeated 0% e-cigarette exposure promotes progressive BBB dysfunction and a neuroinflammatory environment, highlighting the need to consider BBB vulnerability as a critical endpoint in 0% e-cigarette exposure toxicology.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798146","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":"Friend and Foe?: Metals as Facilitators and Disruptors of Steroid Nuclear Receptor Signaling.","authors":"Kyle R Siegel, Christopher D Kassotis","doi":"10.1093/toxsci/kfag106","DOIUrl":"https://doi.org/10.1093/toxsci/kfag106","url":null,"abstract":"<p><p>Steroid hormone signaling, transduced by nuclear receptors (NRs), is essential for mammalian physiology. Like other transcription factors, NRs are structurally and functionally influenced by essential and non-essential metal ions. Here, we provide a scoping review of the role metal ions play in NR signal transduction, focusing on class I steroid hormone receptors (androgen, estrogen, glucocorticoid, mineralocorticoid, and progesterone). Biochemical assessments, prior to and concomitant with the advent of NR cloning, suggest metal-mediated modification of NR ligand binding domains, cytosolic chaperone complexes, and zinc finger DNA binding domains as crucial mechanisms of metal-by-NR interactions. Subsequent molecular studies indicate that metals differentially affect NRs, largely driven by a metals' valence state (divalent, trivalent, etc). Some toxic metals can directly activate NRs. Despite six decades of work, crucial gaps in our knowledge of metal-by-NR effects remain, including in vitro to in vivo extrapolations, incorporation of mixture effects, and further delineation of direct and indirect receptor activation. This review concatenates how trace elements affect steroid hormone NR activity and identifies future areas of research that could mitigate metal-induced endocrine disruption.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798189","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":"Review of in vitro approaches for assessing the toxicity of chemical stressors across diverse physiological systems.","authors":"Chathuri Mudalige, Ranjini Mukherjee, Ayesha Hammad Khan, Maria Fernanda Gonzalez-Acosta, Min Seo Hong, Jean-Pierre Desforges","doi":"10.1093/toxsci/kfag097","DOIUrl":"https://doi.org/10.1093/toxsci/kfag097","url":null,"abstract":"<p><p>The widespread presence of chemicals in the environment poses significant health risks to humans and wildlife. Existing traditional in-vivo approaches, while informative, are limited by considerable ethical, economic, and logistical challenges that prevent timely and effective chemical testing and management strategies. To overcome these challenges, new approach methodologies (NAMs) offer promising alternatives for high-throughput, mechanistic, and ethically conscious chemical toxicity testing. Key to testing chemicals for potential adverse effects is selection of appropriate bioassays that cover the range of biological or physiological pathways likely targeted by the contaminant of interest. In other words, chemical testing strategies need to cover a broad range of physiological systems to account for mechanistic specificity of contaminants. Researchers and regulators thus face the challenge of navigating this interdisciplinary and rapidly growing space. This in-depth review attempts to address this important challenge by identifying and describing existing in vitro bioassays that can be used to assess functional impacts of chemical contaminants across vital physiological systems: endocrine, immune, cardiovascular, neurological, and hepatic. By summarizing the current tools and methodologies, this paper provides a comprehensive guide for researchers and regulators to help identify relevant NAMs for use in modern chemical toxicity testing strategies.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148685985","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":"Building structure activity relationships to avoid toxicity due to unwanted central nervous system ion channel activity.","authors":"Louisa A K Zolkiewski, Kimberly L Rockley, Ruth A Roberts, Hannah G Jennings, Magali-Anne Maizières, Karen Jones, James L McDonagh, Katie Newman, Ed J Griffen, Jessica E Stacey, Michael J Morton","doi":"10.1093/toxsci/kfag094","DOIUrl":"10.1093/toxsci/kfag094","url":null,"abstract":"<p><p>We previously described an integrated in vitro liability assay for seizure, a new approach methodology (NAM) to reduce toxicity due to central nervous system (CNS) liability in drug discovery and development. Here we report the development of structure activity relationships (SAR) to guide drug design away from this liability. SAR test compounds were selected from the Enamine REadily AccesibLe (REAL) database using pharmacophore features and similarity to previous test compounds (amoxapine, diphenhydramine, quetiapine, 4-AP, linopirdine) or to ion channel positive reference compounds (bepridil, NS1619, quinidine, verapamil, XE991). These 88 compounds (10 parent compounds and 78 structurally related derivatives) were screened by automated electrophysiology in cell lines expressing human KV2.1, NaV1.2, the α1β2γ2 GABAA or α4β2 nicotinic receptors to generate IC50 values. Across all 4 ion channels, the derivative compounds exhibited increased, equivalent or reduced potency compared with the parent compounds, providing a complex and rich dataset for SAR. Regarding individual pharmacophoric features, statistical analysis identified 12 features significantly associated with activity at the α4β2 nicotinic receptor; 4 of these were also significantly associated with activity at KV2.1. Selected parent compounds (amoxapine, diphenhydramine, quetiapine) and structural analogues were screened for seizure-like activity in human induced pluripotent stem cell neurons using microelectrode array. The seizure-like phenotype was altered with the derivatives, as expected from the respective ion channel IC50 values. These data provide insight into specific substructures associated with seizure-like drug toxicity, offering the opportunity to avoid CNS liability in the development of novel compounds, saving time, money, and resources.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13493187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial dysfunction, cerebral metabolic crisis, and exploratory bioenergetic biomarkers in a translational swine model of acute carbon monoxide poisoning.","authors":"Abigail Insana, Alistair Lewis, John C Greenwood, Matthew Kelly, Frances S Shofer, Shih-Han Kao, McKenna Mason, Stephen Baak, Jonathan Starr, Jarelis Cabrera, Johannes K Ehinger, Todd J Kilbaugh, Tiffany Ko, Angela N Viaene, Wesley B Baker, David H Jang","doi":"10.1093/toxsci/kfag093","DOIUrl":"10.1093/toxsci/kfag093","url":null,"abstract":"<p><p>Carbon monoxide (CO) poisoning remains a major cause of toxicologic morbidity and mortality and is a leading cause of acute neurologic injury among poisoned patients, yet the mechanisms underlying cerebral bioenergetic dysfunction remain incompletely understood. In addition to impaired oxygen delivery through carboxyhemoglobin (COHb) formation, CO poisoning is associated with mitochondrial respiratory dysfunction and cerebral metabolic injury. We characterized systemic physiology, cerebral metabolism, mitochondrial bioenergetics, and exploratory translational biomarkers in a swine model of acute CO poisoning. Yorkshire swine underwent sham exposure or inhalational CO exposure at 1,000 or 2,000 ppm with serial physiologic monitoring, arterial blood gas analysis, cerebral microdialysis, high-resolution mitochondrial respirometry, ATP quantification, western blotting, and histologic/immunohistochemical analyses. Peripheral blood mononuclear cell (PBMC) mitochondrial respiration was explored as a systemic correlate of cerebral mitochondrial function. CO exposure produced dose-dependent elevations in COHb and lactate with associated metabolic acidosis and hemodynamic impairment. Cerebral microdialysis demonstrated variable lactate-to-pyruvate ratios, whereas extracellular glycerol was significantly elevated during late exposure/recovery following severe CO exposure, consistent with membrane injury and metabolic dysfunction. Mitochondrial respiration was impaired in both cortical and hippocampal tissue, with Complex IV-linked respiration among the most consistently affected respiratory states. Cortical ATP content was significantly reduced in severely exposed animals, supporting cerebral bioenergetic failure. Western blot analysis demonstrated increased HO-1 expression without significant reductions in citrate synthase or Complex IV protein abundance, suggesting functional respiratory inhibition rather than loss of mitochondrial content. Collectively, these findings demonstrate that acute CO poisoning produces early cerebral bioenergetic dysfunction characterized by impaired mitochondrial respiration, ATP depletion, and metabolic alterations, while supporting the exploratory potential of PBMC mitochondrial respiration as a translational biomarker of cerebral mitochondrial dysfunction.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13503005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}