Toxicology and applied pharmacology最新文献

{"title":"Corrigendum to “Differentiation of sow and mouse ovarian granulosa cells exposed to zearalenone in vitro using RNA-seq gene expression” [Toxicology and Applied Pharmacology, 350 (2018) 78–90]","authors":"Guo-Liang Zhang , Jun-Lin Song , Yi Zhou , Rui-Qian Zhang , Shun-Feng Cheng , Xiao-Feng Sun , Guo-Qing Qin , Wei Shen , Lan Li","doi":"10.1016/j.taap.2024.117189","DOIUrl":"10.1016/j.taap.2024.117189","url":null,"abstract":"","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117189"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792336","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":"Electronic cigarettes alter cardiac rhythm and heart rate variability hyperacutely in mice","authors":"Jocelyn A. Castellanos ,&nbsp;Carson G. Cornett ,&nbsp;David H. Gonzalez ,&nbsp;Liqiao Li ,&nbsp;Karla Luna ,&nbsp;Holly R. Middlekauff ,&nbsp;Rajat Gupta ,&nbsp;Maria C. Jordan ,&nbsp;Dennis Rünger ,&nbsp;Yifang Zhu ,&nbsp;Xuesi M. Shao ,&nbsp;Kenneth P. Roos ,&nbsp;Jesus A. Araujo","doi":"10.1016/j.taap.2024.117174","DOIUrl":"10.1016/j.taap.2024.117174","url":null,"abstract":"<div><h3>Aims</h3><div>There has been an unprecedented rise in electronic cigarette (EC) usage likely because of its perception of being safer than smoking. Recent studies show that EC exposures impact heart rate (HR) and heart rate variability (HRV), but how they are affected by the timing and frequency of exposures remain unclear. We examined the electrocardiographic (EKG) effects induced by brief EC exposures over time, their relation to EC aerosol particle and mass concentrations, and potential to promote prooxidative effects in the lungs.</div></div><div><h3>Methods &amp; results</h3><div>Six 10-week-old C57BL/6J mice, implanted with telemetry devices to monitor EKG activity continuously, were exposed once per week for three weeks to two EC exposures, each lasting 15-min followed by 45-min post-exposure periods. Filtered air (primary) and PBS aerosol (secondary) were used as controls. After combining weeks, EC aerosol induced bradycardia and increased time domain parameters during EC exposures with significant reductions in the post-exposure periods. Log-transformed frequency domain parameters were significantly elevated during and after exposures (<em>p</em> &lt; 0.001). HRV changes occurred within minutes with similar trends observed in particle number and mass concentrations of EC aerosol. HR and HRV varied by week and parameter, with Week 2 and 3 effects overshadowing those in Week 1. ECs induced prooxidative effects in the lungs as evidenced by elevated potential for hydroxyl radical generation in bronchoalveolar lavage fluid of exposed mice (<em>p</em> = 0.003).</div></div><div><h3>Conclusion</h3><div>Short-term EC exposures altered murine HR and HRV within minutes during and after exposures, effects that were modulated by the timing and frequency of EC exposures.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117174"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751682","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":"Dysregulation of mRNA expression by hsa-miR-186 overexpression in arsenic-induced skin carcinogenesis","authors":"Mayukh Banerjee ,&nbsp;Angeliki Lykoudi ,&nbsp;Jae Y. Hwang ,&nbsp;Jianmin Pan ,&nbsp;Shesh N. Rai ,&nbsp;Juw W. Park ,&nbsp;J. Christopher States","doi":"10.1016/j.taap.2024.117209","DOIUrl":"10.1016/j.taap.2024.117209","url":null,"abstract":"<div><div>Dysregulated miRNA expression contributes to development of arsenic-induced cutaneous squamous cell carcinoma (cSCC). hsa-miR-186 (miR-186) is overexpressed in arsenical cSCC tissues as well as in preclinical cell line model of arsenical cSCC. Simultaneous miR-186 overexpression and chronic inorganic trivalent arsenite (iAs; 100 nM) exposure transformed human HaCaT cell line preferentially over miR-186 overexpression or iAs exposure alone. Both iAs and miR-186 regulate the expression of wide range of mRNA targets. However, how their interaction impacts the transcriptome-wide mRNA expression landscape ushering in cancer is unknown. We performed longitudinal RNA-seq analysis in passage-matched HaCaT cell clones (±miR-186 overexpression) with simultaneous chronic iAs exposure (0/100 nM) at 12 and 29 weeks. We determined the impact of each factor and their interaction towards differential gene expression and pathway dysregulation employing two different statistical approaches (t-statistic and 2-factor ANOVA). We show that a core set of pathways are dysregulated deterministically irrespective of the statistical approach chosen, possibly representing necessary changes for transformation. The data suggest that each clonal line could take a unique route to dysregulate this core set of pathways necessary for transformation, highlighting the possible role of stochasticity in cancer development. Evidence is presented to sift the strengths and weaknesses of each statistical methodology in providing biological understanding of events that play crucial roles in carcinogenesis in large datasets with multiple contributing variables.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117209"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885344","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":"Female rat liver after sub-acute dibutyl phthalate treatment: Histological, stereological, biochemical, and global gene expression study","authors":"Ivana Ivelja,&nbsp;Jelena Vukcevic,&nbsp;Bojana Stanic,&nbsp;Danijela Kojic,&nbsp;Kristina Pogrmic-Majkic,&nbsp;Nebojsa Andric,&nbsp;Jelena Markovic Filipovic","doi":"10.1016/j.taap.2024.117182","DOIUrl":"10.1016/j.taap.2024.117182","url":null,"abstract":"<div><div>Although it has been recognized that females are more susceptible to chemical-induced liver injury, the effects of dibutyl phthalate (DBP), a widely used synthetic chemical, on female liver structure and function are under-researched. Here, we sought to investigate the effects of DBP on histological, stereological, and biochemical parameters, as well as global gene expression in female rat liver. Female <em>Wistar</em> rats were exposed to 100, 500, and 5000 mg DBP/kg diet for 28 days, corresponding to 8.6, 41.43, and 447.33 mg DBP/kg body weight (B.W.)/day, respectively. The highest dose (447.33 mg DBP/kg B.W./day) was between the no-observed-adverse-effect level (NOAEL) and the lowest-observed-adverse-effect level for liver toxicity, whereas two lower doses (8.6 and 41.43 mg DBP/kg B.W./day) were below the NOAEL. Analysis of hematoxylin and eosin-stained sections revealed an increased volume of hepatocytes, their nuclei and cytoplasm, while the volume of sinusoids decreased in DBP-exposed groups compared to the control. Examination of Periodic acid-Schiff-stained sections showed reduced glycogen content, which was the most prominent in the highest dose group. Increased glutathione <em>S</em>-transferase and catalase activities, and decreased GSH content and superoxide dismutase activity were observed in DBP-exposed groups. The mRNA sequencing revealed DBP-induced dose-specific changes in various genes and biological functions in female rat liver. The highest number of deregulated genes was observed in the 500 mg DBP/kg diet group. In summary, exposure to DBP caused significant liver microstructural changes, decreased glycogen content, disturbed the redox status, and affected global gene expression in female rat liver.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117182"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780568","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":"Preclinical safety and efficacy of the recombinant CR1 drug product CSL040 in rats and cynomolgus monkeys","authors":"Tanja Ruthsatz ,&nbsp;Sandra Wymann ,&nbsp;Elena Velkoska ,&nbsp;Mariam Mansour ,&nbsp;Daniel Schu ,&nbsp;Marit Lichtfuss ,&nbsp;Paolo Rossato ,&nbsp;Meaghan FitzPatrick ,&nbsp;Sarah Hosback ,&nbsp;Allison Dyson ,&nbsp;Eva Herzog ,&nbsp;Kirstee Martin ,&nbsp;Barbara Dietrich ,&nbsp;Matthew P. Hardy","doi":"10.1016/j.taap.2024.117191","DOIUrl":"10.1016/j.taap.2024.117191","url":null,"abstract":"<div><div>CSL040 is a soluble, recombinant fragment of the complement receptor 1 (CR1) extracellular domain that acts as an inhibitor of all three pathways of the complement system. Systemic toxicity, toxicokinetics (TK), and pharmacodynamics (PD) of CSL040 were assessed in two-week intravenous (IV) bolus studies in Han Wistar rats and cynomolgus monkeys. Recovery from any effects was evaluated during a four-week recovery period. Daily repeat-dose administration for 2 weeks at doses of up to 500 mg/kg CSL040 IV was well tolerated in rats and cynomolgus monkeys, leading to a no observed adverse effect level (NOAEL) of 500 mg/kg for both species. Safety pharmacology parameters such as electrophysiology of the heart, blood pressure, heart rate, and respiratory rate measurements, and general toxicological readouts were considered unaffected by CSL040 treatment. Anti-drug antibodies (ADAs) were observed in all cynomolgus monkeys and in some rats at the highest dose of CSL040, but with no effect on pharmacokinetics (PK), supportive of adequate exposure levels as required for a safety assessment. All three complement pathways were inhibited dose-dependently by CSL040. Additionally, no effect on cytokine levels by CSL040 was detected <em>in vitro</em> using a cytokine release assay. These non-clinical studies with CSL040 demonstrated PD activity consistent with its mode of action, adequate PK properties, and a safety profile supporting a phase 1 clinical strategy. A small follow-up study comparing the PK/PD effects of CSL040 following IV and subcutaneous (SC) administration also suggested that the latter route of administration might be a viable alternative to IV administration.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117191"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142795138","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":"Epigallocatechin gallate ameliorates retinal pigment epithelial cell damage via the CYFIP2 /AKT pathway","authors":"Sijia Li ,&nbsp;Dongmei Su ,&nbsp;Shanshan Hu ,&nbsp;Qiang Hu ,&nbsp;Dawei Sun","doi":"10.1016/j.taap.2024.117124","DOIUrl":"10.1016/j.taap.2024.117124","url":null,"abstract":"<div><div>Age-related macular degeneration (AMD) is a representative age-related ophthalmic disease, and the pathogenesis of AMD remains unclear. This research intended to determine whether epigallocatechin gallate (EGCG) could alleviate the progression of AMD and the possible mechanism. We constructed three groups of mice (young, aged, and EGCG), and HE and TUNEL staining of retinal tissues was performed to observe the structural changes in the retinal pigment epithelial (RPE) layer and the level of apoptosis, respectively. Through RNA-Sequencing analysis of retinal tissues and by RT-qPCR, GO, KEGG, and literature analyses, we identified cytoplasmic fragile X mental retardation 1-interacting protein 2 (CYFIP2) as a possible effector gene for EGCG action and validated its role by immunofluorescent and western blotting experiments. The CCK-8 and Hoechst 33342 apoptosis assays, and western blotting and qRT-PCR assays showed that EGCG reduced hydrogen peroxide (H₂O₂)-induced apoptosis in adult human RPE (ARPE-19) cells, and the expression of Cyfip2 was changed accordingly. RNA interference analysis indicated that Cyfip2 knockdown alleviated H₂O₂-induced ARPE apoptosis, while its overexpression weakened EGCG's protective effect. Western blot analysis showed that Cyfip2 mediated the anti-apoptotic effect of EGCG by modulating the level of protein kinase B (Akt) phosphorylation in ARPE cells, and the activation level of phosphorylated AKT (p-AKT Ser473) in retinal tissue of the EGCG-fed group was higher than that of the aged group. Taken together, this study suggests that EGCG plays a protective role in the development of AMD and the apoptosis of ARPE cells through the Cyfip2/AKT pathway.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117124"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819295","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":"The effects of UGT1A4 and ABCB1 polymorphisms on clozapine and N- desmethyl clozapine plasma levels in Turkish schizophrenia patients","authors":"Fezile Ozdemir ,&nbsp;Merve Demirbugen Oz ,&nbsp;Kenan Can Tok ,&nbsp;Emrah Dural ,&nbsp;Yagmur Kır ,&nbsp;Mehmet Gumustas ,&nbsp;Bora Baskak ,&nbsp;H. Sinan Suzen","doi":"10.1016/j.taap.2024.117219","DOIUrl":"10.1016/j.taap.2024.117219","url":null,"abstract":"<div><div>Clozapine (CLZ) is an antipsychotic which is particularly used in treatment resistant schizophrenia patients who do not respond to other agents. It is preferred because it reduces suicidal behaviours and attempts, reducing aggression and violent behaviour. The aim of the study is to evaluate the effects of <em>ABCB1</em> rs1045642 and <em>UGT1A4</em> rs2011425 polymorphisms on CLZ and its major metabolite N- desmethly clozapine (DCLZ) plasma concentrations in patients with schizophrenia. A total 109 of Turkish patients with schizophrenia on continually administered CLZ monotherapy were included. The plasma concentrations of CLZ and DCLZ were measured using an HPLC after liquid-liquid extraction while, transporter gene <em>ABCB1</em> and phase two enzyme <em>UGT1A4</em> polymorphisms were identified using PCR- RFLP method. Results showed that <em>UGT1A4*3</em> polymorphism has statistically significant effects on CLZ C/D and DCLZ C/D levels in patients with sub/supra therapeutic levels while <em>ABCB1</em> C3435T polymorphism has a significant effect on CLZ/DCLZ ratio among patients who have subtherapeutic levels. This study indicates the influence of genetic differences on plasma levels and highlights the importance of pharmacogenetic studies in clinic. Using the obtained results as pharmacogenetic biomarkers will help clinicians provide effective treatment in individual patients and reduce the undesirable side effects.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117219"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955563","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":"Ginkgolide B binds to GPX4 and FSP1 to alleviate cerebral ischemia/reperfusion injury in rats","authors":"Rong Zou ,&nbsp;Zhaoxia Liu ,&nbsp;Peng Wang ,&nbsp;Ying Liu","doi":"10.1016/j.taap.2025.117237","DOIUrl":"10.1016/j.taap.2025.117237","url":null,"abstract":"<div><div>Ischemia/reperfusion (I/R) injury can increase the anomalous permeability of the blood-brain barrier and the risk of hemorrhagic conversion. Ginkgolide B (Gin B) has been recognized for its neuroprotective properties in stroke treatment. This study aimed to analyze the association of Gin B with GPX4 and FSP1 in cerebral I/R injury treatment. HT22 cells were induced by oxygen-glucose deprivation/reoxygenation (OGD/R) and treated with a series of Gin B (10, 20, 40 μM) for 24 h. It found that the Gin B treatment declined the OGD/R-induced cellular ROS and lipid ROS with increasing concentrations. Moreover, the Gin B treatment improved the OGD/R-induced ferroptotic cell death by activating the GPX4-GSH and FSP1-CoQ10-NADH pathways with increasing concentrations. Molecular docking showed there is a good binding activity of Gin B to GPX4 (score = −6.4 kcal/mol) and FSP1 (score = −6.7 kcal/mol), and the microscale thermophoresis (MST) assay confirmed that Gin B can directly bind to GPX4 and FSP1. In vivo, rats were induced by middle cerebral artery occlusion (MCAO)/R and treated with 20 mg/kg of Gin B to analyze its effects on the GPX4-GSH and FSP1-CoQ10-NADH pathways. The GPX4 inhibitor (RSL3) and the FSP1 inhibitor (iFSP1) were used to confirm the mechanism of Gin B in the MCAO/R-treated rats. It showed that the Gin B treatment alleviated the MACO/R-induced brain injury by activating the GPX4-GSH and FSP1-CoQ10-NADH pathways. This study showed that Gin B improved cerebral I/R-induced ferroptotic cell death by activating the GPX4-GSH and FSP1-CoQ10-NADH pathways, providing a new mechanism of Gin B for cerebral I/R treatment.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117237"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143042035","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 oat fiber intervention for reducing PFAS body burden: A pilot study in male C57Bl/6 J mice","authors":"Jennifer J. Schlezinger ,&nbsp;Kushal Biswas ,&nbsp;Audrey Garcia ,&nbsp;Wendy J. Heiger-Bernays ,&nbsp;Dhimiter Bello","doi":"10.1016/j.taap.2024.117188","DOIUrl":"10.1016/j.taap.2024.117188","url":null,"abstract":"<div><div>Perfluoroalkyl substances (PFAS) are a major public health concern, in part because several PFAS have elimination half-lives on the order of years and are associated with adverse health outcomes. While PFAS can be transported into bile, their efficient reuptake by intestinal transporter proteins results in minimal fecal elimination. Here, we tested the hypothesis that consumption of oat β-glucan, a dietary supplement known to disrupt the enterohepatic recirculation of bile acids, will reduce PFAS body burdens. Male C57Bl/6 J mice were fed diets based on the “What we eat in America” analysis that were supplemented with inulin or oat β-glucan and exposed via drinking water to a seven PFAS mixture (PFHpA, PFOA, PFNA, Nafion Byproduct-2, PFHxS and PFOS) for 6 weeks. One cohort of mice was euthanized at the end of the exposure, and one cohort continued on the experimental diets for 4 more weeks without additional PFAS exposure. The β-glucan fed mice drank significantly more water than the inulin fed mice, resulting in a significantly higher dose of PFAS. Relative to overall exposure, we observed lower serum concentration trends (<em>p</em> &lt; 0.1) in β-glucan fed mice for PFHpA, PFOA and PFOS. Additionally, β-glucan fed mice had lower adipose:body weight ratios and liver and jejunum triglyceride concentrations. Hepatic mRNA expression of <em>Cyp4a10</em>, <em>Cyp2b10</em> and <em>Cyp3a11</em> were elevated in PFAS exposed mice, with only the expression of <em>Cyp3a11</em> decreasing following depuration. <em>This pilot study generates support for the hypothesis that oat β-glucan supplementation can reduce PFAS body burdens and stimulate healthful effects on lipid homeostasis.</em></div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117188"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142795133","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":"Didecyldimethylammonium chloride-induced lung fibrosis may be associated with phospholipidosis","authors":"Wonkyun Jung ,&nbsp;Mi-Jin Yang ,&nbsp;Min-Sung Kang ,&nbsp;Jiyun Lim ,&nbsp;Hyosun Choi ,&nbsp;Ji Ae Lee ,&nbsp;Kyung-Sik Yoon ,&nbsp;Jin-Bae Kim ,&nbsp;Eun-Jung Park","doi":"10.1016/j.taap.2024.117211","DOIUrl":"10.1016/j.taap.2024.117211","url":null,"abstract":"<div><div>In the current study, we dosed didecyldimethylammonium chloride (DDAC) in mice by pharyngeal aspiration for 28 days or 90 days (weekly) and tried to elucidate the relationship between lamellar body formation and the lesions. When exposed for 28 days (0, 5, 10, 50, and 100 μg/head), all the mice in the 50 and 100 μg/head groups died since Day 2 after the third dosing (Day 16 after the first dosing). Edema, necrosis of bronchiolar and alveolar epithelium, and fibrinous exudate were observed in the lungs of all the dead mice, and chronic inflammatory lesions were observed in the lung tissues of alive mice. When dosed with DDAC of 0, 1, 4, and 8 μg/head for 13 weeks, the total number of pulmonary cells and the pulmonary levels of pro- and anti-inflammatory cytokines significantly increased, and chronic inflammatory lesions were detected with the production of collagen, collagen fibers, and lamellar body-like structures. Swelling of the nuclear envelope and nucleoplasmic components and generation of lipid droplets were also notably observed in the lung tissues of DDAC (8 μg/head)-treated mice. Furthermore, transcriptomic analysis performed using human bronchial epithelial cells showed that DDAC affected the expression of DNA damage, ER stress, lipid metabolism, and transcription regulation-related genes at 6 h after treatment, as it did 24 h treatment and that early growth response factor 1 gene was added to a list of the most up-regulated genes. Meanwhile, cytokines that are associated with the pathology of chronic lung diseases (IL-11, IL-24, and TGF-β) were slightly increased in the lung of DDAC-treated mice, and only the pulmonary level of CCL-2, but not CXCL-1 and CCL-3, increased in both sexes of mice. More importantly, the GM-CSF level increased dose-dependently in the lungs of both sexes of mice exposed to DDAC. Considering that the wound-healing process can take several weeks to complete, we suggest that DDAC-induced pulmonary fibrosis may be attributable to disruption of the wound-healing process due to continuous exposure to DDAC. We also hypothesize that the formation of lamellar bodies may be attributable to lysosomal accumulation of phospholipids separated from the destroyed lung tissue membrane.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117211"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877922","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}