Toxicological Sciences最新文献

{"title":"Beyond respiratory depression: acute and delayed pulmonary responses following aerosolized fentanyl exposure.","authors":"Yesenia Lopez Hernandez, Tanima Chatterjee, Christine M Gross, Lilly Underwood, Kayla F Goliwas, Juan Xavier Masjoan Juncos, Adriana Yndart Arias, Satyanarayana Achanta, Jessy Deshane, Saurabh Aggarwal","doi":"10.1093/toxsci/kfag081","DOIUrl":"10.1093/toxsci/kfag081","url":null,"abstract":"<p><p>Fentanyl is a highly potent synthetic opioid and a major contributor to opioid-related mortality due to central respiratory depression. Inhalational exposure occurs during recreational misuse, polysubstance abuse, occupational handling, and potential chemical threat scenarios. However, whether inhaled fentanyl is associated with pulmonary toxicity independent of central effects remains unclear. Adult male C57BL/6 mice were exposed to aerosolized fentanyl (0.1, 1, or 5 mg/kg; nebulized dose, 5 min) or saline and evaluated 1- and 14 d postexposure. Within 24 h, fentanyl exposure was associated with acute lung injury characterized by alveolar hemorrhage, increased bronchoalveolar lavage protein and inflammatory cells, high lactate dehydrogenase levels, elevated lung wet-to-dry ratio, and reduced arterial oxygenation. Systemic hyperglycemia and increased plasma IL-1β and IL-12p70 were observed, with significant upregulation of caspase-1 activity and IL-1β in lung tissue. Similar IL-1β induction occurred in ex vivo human lung tissue and in vitro human macrophages. At 14 d, delayed dose-dependent remodeling was evident. Low-dose exposure (0.1 mg/kg) produced emphysematous changes, airspace enlargement, and increased mean linear intercept, consistent with emphysema-like changes. Higher doses (1 and 5 mg/kg) were associated with fibrotic remodeling, increased collagen deposition, and fibrotic remodeling. High-dose exposure (5 mg/kg) reduced 14-d survival to 65%. In conclusion, these findings demonstrate that aerosolized fentanyl exposure is associated with acute lung injury and subsequent delayed structural remodeling, accompanied by IL-1β-associated inflammatory signaling. These findings highlight potential pulmonary risks of inhaled fentanyl relevant to substance abuse, occupational safety, emergency response preparedness, and regulatory toxicology risk assessment.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13387602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148391669","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":"Correction to: E-cigarette exposure during pregnancy impairs uterine artery blood flow and feto-placental function.","authors":"","doi":"10.1093/toxsci/kfag082","DOIUrl":"https://doi.org/10.1093/toxsci/kfag082","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":"209 7","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148472841","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":"Aryl hydrocarbon receptor nuclear translocator 2: a forgotten per-ARNT-Sim transcription factor.","authors":"Israt Jahan, Yadeliz A Serrano Matos, Arul Jayaraman, Aditya D Joshi","doi":"10.1093/toxsci/kfag078","DOIUrl":"10.1093/toxsci/kfag078","url":null,"abstract":"<p><p>Aryl hydrocarbon receptor nuclear translocator 2 is a member of the basic helix-loop-helix/Per-ARNT-Sim family of transcription factors involved in responding to various environmental, metabolic, and chemical signals. Initially known for its involvement in neurodevelopment, ARNT2 is now recognized as an essential binding partner for other transcription factors, including single-minded homologs 1 and 2, neuronal PAS domain protein 4, hypoxia-inducible factor 1, and plausibly Aryl hydrocarbon receptor to regulate stress adaptation, synaptic plasticity, immune signaling, and energy balance pathways. The role of ARNT2 has also been implicated in a plethora of pathologies, including inflammation, cardiovascular diseases, neurological disorders, metabolic diseases, and cancers. This review summarizes the current knowledge of ARNT2's structure, regulation, interacting partners, and its toxicopathological significance. A better understanding of ARNT2 biology may open new avenues for its characterization as a molecular target and designing novel therapeutic strategies across multiple diseases.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13371768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148353699","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":"Environmental benzene exposure induces a conserved neutrophil degranulation program across species.","authors":"Jonathan J Panzer, Mackenzie L Connell, Aditi Singh, Anthony Maxwell, Paul M Stemmer, Emily Leydet, Camille Akemann, Homegnon Antonin Ferreol Bah, Mei Lu, Andrea E Cassidy-Bushrow, Jiahui Ding, Jennifer K Straughen, Tracie R Baker, Albert M Levin, Gil Mor","doi":"10.1093/toxsci/kfag085","DOIUrl":"10.1093/toxsci/kfag085","url":null,"abstract":"<p><p>Immune systems have evolved under constant pressure from pathogens and environmental challenges, leading to the emergence of conserved defense mechanisms across diverse organisms. Evidence indicates that environmental exposures perturb immune regulatory networks, particularly during development, when transcriptional programs governing hematopoiesis, immune cell differentiation, and inflammatory signaling are highly dynamic and sensitive to external stressors. Volatile organic compounds represent an important but incompletely understood source of immunological perturbation. Among these, benzene is a ubiquitous environmental contaminant associated with hematotoxicity and immune dysregulation; however, transcriptional responses to environmentally relevant low-level exposures during development remain poorly characterized. To determine whether benzene exposure engages conserved cross-species immune regulatory pathways, we performed a comparative transcriptomic analysis integrating developmental tissues from 3 vertebrate systems: human placenta, murine placenta, and zebrafish larvae. Bulk RNA sequencing datasets were analyzed to identify transcriptional responses associated with benzene exposure in experimental models (≤5 ppm) and with benzene adduct levels in maternal plasma for human samples. Because placental gene expression exhibits strong sexual dimorphism, murine datasets were stratified by fetal sex. Pathway- and network-level analyses were used to identify conserved biological responses. We observed a striking convergence on activation of innate immune pathways associated with neutrophil degranulation, IL-8 signaling, and Rho GTPase-mediated inflammatory responses. Further, network analyses identified CXCL8 and ERK1/2 as shared regulatory hubs linking transcriptional responses across datasets. Together, these findings uncover an evolutionarily conserved innate immune signature associated with benzene exposure during vertebrate development, suggesting that environmental chemical perturbations may disrupt fundamental immune regulatory programs across species.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13421083/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456865","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":"Exposure timing is a determinant of fine particulate matter (PM2.5) pulmonary, vascular, and metabolic toxicity in male mice.","authors":"Amanda Ribble, Lutz Haberzettl, Jason Hellmann, Petra Haberzettl","doi":"10.1093/toxsci/kfag080","DOIUrl":"10.1093/toxsci/kfag080","url":null,"abstract":"<p><p>Exposure to fine particulate matter (PM2.5) air pollution is associated with an increased cardiometabolic disease risk. However, although exposure timing is recognized as an important toxicity determinant, the chronotoxicity of PM2.5 exposure is less explored. To evaluate whether PM2.5 sensitivity depends on exposure timing, adult male C57/BL6 mice were exposed to concentrated PM2.5 (CAP, 6 h/day, 30 days) either during the inactive (light) phase (Zeitgeber time, ZT1 to 7) or the active (dark) phase (ZT17 to 23). Metabolic health was assessed by measuring body weight, fasting blood glucose, and plasma insulin levels. Oxidative stress and inflammatory responses in aortas and lungs were examined by quantitative real-time (qRT)-PCR, and pulmonary and circulating redox changes were measured calorimetrically. Although CAP exposure during the active phase increased blood glucose levels, inactive-phase exposure more profoundly increased antioxidant enzyme and inflammatory mRNA abundance in lungs and aortas. Inactive-phase exposure also intensified pulmonary and systemic lipid peroxidation and increased the depletion of circulating nitric oxide and lung glutathione. Examining the ability to protect against CAP-induced pulmonary oxidative stress, we found that the pulmonary antioxidant enzyme mRNA expression showed circadian rhythmicity that peaked during the active phase. These data suggest that a superior pulmonary antioxidant defense potential during the active phase could contribute to the protection against the PM2.5-induced vascular and pulmonary effects but not its impact on glucose homeostasis. Our study identified that exposure sensitivity depends on the exposure timing, which is of significance as it informs on timely susceptibility windows that could help to mitigate PM2.5 toxicity.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13362965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148369986","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":"Stress-activated pathways mediate PFAS effects on human placental syncytiotrophoblast cells.","authors":"Keisuke Kozai, Kaela M Varberg","doi":"10.1093/toxsci/kfag060","DOIUrl":"10.1093/toxsci/kfag060","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants associated with placenta-mediated pregnancy complications, including preeclampsia, fetal growth restriction, and preterm birth. The syncytiotrophoblast (STB), which forms the placental barrier at the maternal-fetal interface and is directly exposed to maternal blood, is a primary site of PFAS exposure. Although PFAS induce STB apoptosis, the upstream stress-signaling pathways involved remain poorly defined. Here, we investigated stress-responsive signaling mechanisms mediating PFAS-induced STB cell death. STB differentiated from human trophoblast stem cells were exposed to vehicle or an environmentally relevant mixture of 5 PFAS (perfluorooctanoic acid, perfluorooctanesulfonic acid, perfluorohexane sulfonate, perfluorononanoic acid, and perfluorodecanoic acid; 0.0138 to 34.5 µM) for 3 or 6 h. Cytotoxicity, apoptosis, mitochondrial membrane potential, and stress-signaling pathway activation were assessed by lactate dehydrogenase release, immunoblotting, JC-10 assay, and reverse transcription-quantitative PCR. PFAS mixtures did not induce cytotoxicity at 3 h but significantly increased cytotoxicity at 6 h at 34.5 µM, coinciding with the induction of cleaved caspase-3, cleaved poly(ADP-ribose) polymerase, and NOXA. The pan-caspase inhibitor z-VAD-FMK prevented cytotoxicity, indicating caspase-dependent apoptosis. PFAS exposure reduced mitochondrial membrane potential and activated the integrated stress response (ISR), as evidenced by eukaryotic initiation factor 2α phosphorylation, activating transcription factor 4 (ATF4) induction, and increased ATF4 target gene expression. In parallel, c-Jun N-terminal kinase (JNK) signaling was activated, as evidenced by JNK phosphorylation and induction of immediate-early genes (JUN, FOS, EGR1). Pharmacologic inhibition of the ISR modestly attenuated PFAS-induced cytotoxicity, whereas pharmacologic inhibition of JNK rescued cytotoxicity and apoptotic signaling. Together, these findings identify JNK-driven stress signaling as the dominant mediator of PFAS-induced STB apoptosis, with a secondary contribution from the ISR.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13242702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148006635","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":"RENAsym, a quantitative systems toxicology platform model, designed to predict drug-induced kidney injury indicates polymyxin B and valproate overdose toxicity potential while simultaneously demonstrating acetaminophen and valproate safety at therapeutic levels.","authors":"Celeste Vallejo, Pallavi Bhargava, Nader Hamzavi, Matthew McDaniel, Vinal V Lakhani, Timothy Qi, Christina Battista, Lara Clemens, Lisl K M Shoda, Zackary R Kenz, Shailendra Tallapaka, Yeshitila Gebremichael, Jeffrey L Woodhead","doi":"10.1093/toxsci/kfag047","DOIUrl":"10.1093/toxsci/kfag047","url":null,"abstract":"<p><p>RENAsym is a quantitative systems toxicology (QST) modeling platform designed to predict drug-induced kidney toxicity. The model includes the proximal tubule cell (PTC) life cycle, regeneration of PTCs, sodium reabsorption, nephron death, and drug-induced injury and inflammation within the proximal tubules. The mechanisms of drug-induced toxicity included are overproduction of reactive oxygen species and mitochondrial dysfunction. Inputs into the QST model include the drug's exposure in the kidney and results from in vitro toxicity assays used to parameterize the toxicity mechanisms included in the model. The QST model has a wide array of outputs including fraction of viable PTCs, fraction of viable nephrons, and serum creatinine concentration over time that allow the user to assess the extent of kidney injury induced by a drug. Polymyxin B, valproate, and acetaminophen were three compounds used to test RENAsym's ability to correctly classify compounds as either nephrotoxic or safe. The model successfully identified polymyxin B and valproate as drugs with the potential to cause kidney injury and acetaminophen as a drug that does not cause kidney injury at therapeutic levels, providing increased confidence that the model can be used to indicate kidney injury liability using in vitro inputs before dosing in clinical settings.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13240676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843248","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":"Safety evaluation of glutaric acid as a novel pharmaceutical salt for first-in-human dosing.","authors":"Kelle M Franklin, Ahamat Aboulmali","doi":"10.1093/toxsci/kfag059","DOIUrl":"10.1093/toxsci/kfag059","url":null,"abstract":"<p><p>Salt selection is critical in pharmaceutical development. Glutaric acid, an endogenous dicarboxylic acid, offers potential advantages as a counterion but is underexplored in pharmaceutical applications. The nonclinical safety of glutaric acid as a pharmaceutical counterion was assessed using LY3972406 hemi-glutarate hemi-hydrate (HG) as a model, with direct comparison to the LY3972406-hydrochloride (HCl) salt. Comprehensive safety assessments included genetic toxicology (Ames, in vitro and in vivo micronucleus tests), hazard evaluation (phototoxicity, and dermal and corneal irritation), and repeat-dose toxicity studies in rats and dogs. Comparative studies evaluated LY3972406-HCl versus LY3972406-HG, and chronic studies assessed glutaric acid alone and as part of the LY3972406-HG salt. Glutaric acid was nongenotoxic. LY3972406-HG showed no phototoxicity and only mild, nonadverse dermal and ocular irritation in hazard assessments. Glutaric acid was well-tolerated by rats and dogs in repeat-dose toxicity studies, with no treatment-related adverse effects. When LY3972406-HG was administered at glutaric acid equivalent doses up to 31 mg/kg/d, all findings were nonadverse, and likely attributable to the active pharmaceutical ingredient LY3972406. Glutaric acid demonstrates a favorable nonclinical safety profile with no genotoxicity and was tolerated at up to 40 mg/kg/d in chronic toxicity studies. Direct comparison with HCl salt confirmed equivalent safety and exposure profiles, supporting glutaric acid as a viable alternative to HCl in pharmaceutical development. Glutaric acid is a promising pharmaceutical counterion that lacks regulatory safety data. This first comprehensive Good Laboratory Practice-compliant nonclinical safety evaluation supports the viability of glutaric acid as an alternative pharmaceutical counterion to hydrochloride salts in drug development.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147989022","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":"Pulmonary vascular remodeling in rats following methamphetamine self-administration: toward a model of methamphetamine-associated pulmonary arterial hypertension.","authors":"Prangthip Charoenpong, Nicole M Hall, Courtney M Keller, Ashok Kumar, Ling Chen, Joseph Gatuz, Najam Siddiqui, Fereshteh Sadat Tabatabaei Yazdi, Daffolyn Rachael Fels Elliott, Navneet Kaur Dhillon, Kevin S Murnane, Nicholas E Goeders, Robert E Walter","doi":"10.1093/toxsci/kfag072","DOIUrl":"10.1093/toxsci/kfag072","url":null,"abstract":"<p><p>Pulmonary arterial hypertension (PAH) is a progressive vasculopathy characterized by pulmonary vascular remodeling. Methamphetamine (MA) exposure is strongly associated with PAH in humans, yet prior animal models rely on fixed, non-contingent dosing that does not replicate binge/crash patterns of human MA use. This study introduces an intravenous MA self-administration model to evaluate pulmonary vascular and cardiac consequences of human-like MA exposure. Sixteen male Wistar rats underwent an 8-wk protocol in which 8 rats self-administered MA and 8 yoked-saline controls received volume-matched saline. MA intake, lever-press behavior, and binge/crash dynamics were quantified. Lungs and hearts were harvested for histology, immunofluorescence, medial wall thickness quantification across vessel sizes, ventricular weights, and Fulton index. MA-exposed rats demonstrated escalating intake, with daily self-administered doses increasing from early-week values to a cumulative exposure of 526.7 ± 217.8 mg/kg over 8 wk. Distinct binge-and-crash patterns emerged as intake escalated over the exposure period. Compared with controls, MA-exposed rats exhibited pulmonary vascular remodeling predominantly in distal vessels, including medial hypertrophy, increased muscularization of small arterioles, and focal endothelial proliferation. Additional airway-centered parenchymal changes were observed in a subset of MA rats. No significant differences were found in right or left ventricular weights or Fulton index. Chronic MA self-administration induces early pulmonary vascular remodeling without cardiac hypertrophy, indicating that this behaviorally relevant model captures early pulmonary vascular changes relevant to MA-associated pulmonary vascular disease. This model provides a translational platform for investigating MA-induced pulmonary vascular injury and identifying therapeutic targets.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13302795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148219758","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":"Disease-dependent airway epithelial responses to acute electronic cigarette aerosol exposure: a pilot single-cell analysis.","authors":"Courtney Van, Pin-Hsun Mao, Jackie Nguyen, Kyeong-Joo Jung, Neil Sampath, Roy A Miller, Manjula Karpurapu, Loren E Wold, Dongjun Chung, John W Christman, Sangwoon Chung","doi":"10.1093/toxsci/kfag068","DOIUrl":"10.1093/toxsci/kfag068","url":null,"abstract":"<p><p>Electronic cigarette (e-cig) use is increasingly common among individuals with asthma, yet the cell type-specific airway responses to e-cig exposure remain poorly understood. Because asthma is characterized by altered epithelial composition and heightened inflammatory susceptibility, e-cig exposure could elicit disease-dependent epithelial responses in asthmatic airways. Here, we used single-cell RNA sequencing to define responses to acute e-cig exposure in human primary airway epithelial cells differentiated at the air-liquid interface from healthy and asthmatic donors. Cultures were exposed to e-cig aerosols for 30 min and analyzed 24 h later. Ten epithelial and stromal populations were identified. At baseline, asthma-derived cultures showed descriptive differences in cell-type composition compared with healthy-derived cultures, whereas acute e-cig exposure produced only modest additional changes in relative abundance. In contrast, transcriptional responses were disease dependent. Asthma-derived ATII, basal, goblet, mesenchymal, and mesothelial cells showed distinct inflammatory and immediate-early gene-expression changes, whereas healthy-derived cultures showed defense- and stress-associated responses. Pathway-level analysis showed enrichment of inflammatory signaling, injury/stress-response, and migration/ECM-related pathways in selected asthma-derived populations, whereas healthy-derived ATII and club cells were associated with defense and biotic-response pathways. SenMayo analysis showed cell type-specific patterns of senescence-associated gene set enrichment, with the strongest signal in club cells, together with increased CDKN2A and CDKN1A expression in asthma-derived epithelial populations. These findings suggest that asthma-associated epithelial states shape cell type-specific inflammatory, stress-associated, and senescence-related transcriptional responses to acute e-cig exposure.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13283450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148164603","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}