Journal of Applied Toxicology最新文献

In Vitro Assessment of Drug-Induced Liver Injury Using Three-Dimensional Cultured HepaSH Cells Derived From Chimeric Mouse Model With Humanized Liver. 人肝嵌合小鼠模型三维培养HepaSH细胞对药物性肝损伤的体外评估。

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-07-21 DOI: 10.1002/jat.4863

Xingming Liu, Yuichiro Higuchi, Yuta Sakamoto, Shota Yanagida, Shotaro Uehara, Hiroshi Suemizu, Yasunari Kanda, Hiroyuki Kawagishi

{"title":"In Vitro Assessment of Drug-Induced Liver Injury Using Three-Dimensional Cultured HepaSH Cells Derived From Chimeric Mouse Model With Humanized Liver.","authors":"Xingming Liu, Yuichiro Higuchi, Yuta Sakamoto, Shota Yanagida, Shotaro Uehara, Hiroshi Suemizu, Yasunari Kanda, Hiroyuki Kawagishi","doi":"10.1002/jat.4863","DOIUrl":"https://doi.org/10.1002/jat.4863","url":null,"abstract":"Drug-induced liver injury (DILI) is a serious adverse event and a common cause of postmarketing drug withdrawal. Despite nonclinical assessments of DILI risk, which are predominantly conducted in experimental animals, DILI remains a frequent adverse event, highlighting the need to improve nonclinical assessments. Extensive studies have demonstrated that primary human hepatocytes (PHHs) and their three-dimensional (3D) cultures, such as spheroids, exhibit high predictability of drug-induced hepatotoxicity in vitro. However, lot-to-lot variations and inconsistent availability of PHHs remain major limitations. In contrast, HepaSH cells, which are hepatocytes derived from humanized liver chimeric mice, are more consistently available than PHHs and display gene expression levels of drug-metabolizing factors similar to those of PHHs with minimal variation. In this study, we investigated whether HepaSH cell-derived spheroids can be used to assess DILI risk. HepaSH cells were cultured in two-dimensional (2D) and three-dimensional (3D) conditions for up to 21 days. Gene expression and phenotypic analyses revealed that 3D-cultured HepaSH cells exhibited greater functional development of hepatic characteristics than 2D-cultured cells. Cytotoxic assessment using DILI-associated drugs listed in the DILIrank public dataset demonstrated that spheroids cultured in chemically defined William's media exhibited the highest sensitivity to drugs classified as having a high risk of DILI. Thus, our data suggest that human hepatic spheroids generated from HepaSH cells can be used to assess DILI risk in vitro. Further studies involving large-scale compound screening using HepaSH cells would be necessary to investigate the predictability of human DILI in nonclinical assessments.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144674909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Intralitter Variability Influences the Developmental Impact of Valproic Acid Exposure in CD-1 Mice. 鼠内变异性影响CD-1小鼠丙戊酸暴露对发育的影响。

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-07-21 DOI: 10.1002/jat.4860

Lauren T L Brown, Megan E Cull, Lihua Xue, Louise M Winn

{"title":"Intralitter Variability Influences the Developmental Impact of Valproic Acid Exposure in CD-1 Mice.","authors":"Lauren T L Brown, Megan E Cull, Lihua Xue, Louise M Winn","doi":"10.1002/jat.4860","DOIUrl":"https://doi.org/10.1002/jat.4860","url":null,"abstract":"Valproic acid (VPA) is an antiepileptic and mood-stabilizing drug that causes teratogenic effects, including neural tube defects (NTDs), when taken during pregnancy. Although animal models are widely used to study VPA teratogenicity, most rely on litter means, which overlook variability within the litter. In litter-bearing species like mice, fetal development can vary by sex, uterine horn location, and intrauterine position. This study examined whether these intralitter variables affect fetal and placental outcomes following VPA exposure. Pregnant CD-1 mice received a subcutaneous injection of saline (vehicle control), 400 mg/kg, or 600 mg/kg VPA on gestational day (GD) 9 and were euthanized on GD 18. Fetuses and placentas were collected, weighed, and stratified by exposure, NTD status, sex, uterine horn location, and intrauterine position. Fetal and placental weights were normalized to maternal weight gain and live litter size or the number of live fetuses in each uterine horn. VPA exposure produced a clear dose-dependent effect, with 600 mg/kg significantly increasing postimplantation losses and NTD frequency. These effects were further influenced by intralitter variables, particularly sex and uterine horn location. Fetal weight increased at 400 mg/kg VPA but was unchanged at 600 mg/kg, while placental weight decreased and placental efficiency increased at both doses, suggesting possible compensatory adaptations. At 600 mg/kg VPA, sex differences in placental weight and efficiency were lost, and fetuses in the left uterine horn were significantly lighter than those in the right, indicating location-dependent susceptibility. Intrauterine position did not significantly affect outcomes. These findings demonstrate that intralitter variables influence fetal and placental responses to VPA and underscore the need to account for these factors to improve the translational relevance of developmental toxicology studies.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effect of Naringenin on Potassium Bromate-Induced Hepatotoxicity In Vivo: A Dose-Dependent Study. 柚皮素对溴酸钾诱导的体内肝毒性的影响：一项剂量依赖性研究。

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-07-18 DOI: 10.1002/jat.4856

Iftekhar Hassan, Hossam Ebaid, Badar Ul Islam, Jameel Al-Tamimi, Ibrahim M Alhazza, Altaaf Khan, Ezzat M Awad

{"title":"Effect of Naringenin on Potassium Bromate-Induced Hepatotoxicity In Vivo: A Dose-Dependent Study.","authors":"Iftekhar Hassan, Hossam Ebaid, Badar Ul Islam, Jameel Al-Tamimi, Ibrahim M Alhazza, Altaaf Khan, Ezzat M Awad","doi":"10.1002/jat.4856","DOIUrl":"https://doi.org/10.1002/jat.4856","url":null,"abstract":"Potassium bromate (PB) is a well-known additive in the food industry and a byproduct of water treatment. Its long-term exposure to any form of life exerts mild to severe toxic insults in a dose-dependent fashion and can even trigger carcinogenesis. This study examines the ameliorative effectiveness of a prominent polyphenol, naringenin (NIR), in rodents previously exposed to PB. The Swiss albino rats were assigned to five treatment groups (n = 5): Group I was the control, and Groups II and III were administered with PB alone (100 mg/kg) and NIR alone (2 mg/kg), respectively. The remaining two groups were treated with NIR at 2 and 4 mg/kg in the PB-preadministered rats. The animals were sacrificed after the treatment course to retrieve their liver and blood for biochemical, molecular, and histological studies. The PB-treated Group II showed a marked rise in liver function and toxicity markers in the serum samples, confirming hepatotoxicity after treatment. Disrupted redox markers (GSH and MDA) and compromised antioxidant enzymes (SOD and CAT) further support the hepatotoxicity induced by PB. Notably, NIR exhibited minimal toxicity, as indicated by Group III, and most of the measured parameters' values were comparable to those of the control. However, the combination groups (IV and V) showed improvement in the PB-mediated hepatotoxicity assessment dose-dependently. In addition, a prominent decline in LDH activity, concomitant with fan-like comet formation in the nuclear DNA, is observed in these groups, suggesting that NIR promotes apoptosis concurrently with reducing necrosis. The histopathological investigation further consolidates these findings, showing marked structural restoration in liver histology, along with improved activity of antioxidant enzymes and a more favorable redox status. Hence, NIR can be utilized in consumer products with PB as an ingredient or to reduce hepatotoxicity induced by PB or similar compounds or potential drugs in vivo.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Vitamin D Protects Against Gentamicin-Induced Kidney Damage in Rats Through Its Antioxidant and Anti-Inflammatory Effects. 维生素D通过抗氧化和抗炎作用防止庆大霉素引起的大鼠肾损伤。

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-07-18 DOI: 10.1002/jat.4862

Elif Aksoz, Fazilet Sen Metin, Nurullah Guclu, Murat Celebi, Sinem Kantarcioglu Coskun, Oguzhan Korkut

{"title":"Vitamin D Protects Against Gentamicin-Induced Kidney Damage in Rats Through Its Antioxidant and Anti-Inflammatory Effects.","authors":"Elif Aksoz, Fazilet Sen Metin, Nurullah Guclu, Murat Celebi, Sinem Kantarcioglu Coskun, Oguzhan Korkut","doi":"10.1002/jat.4862","DOIUrl":"https://doi.org/10.1002/jat.4862","url":null,"abstract":"Nephrotoxicity is one of the most important side effects of aminoglycosides, especially gentamicin. This study investigated the potential protective effect of vitamin D against gentamicin-induced kidney damage in rats. Forty-two male Wistar Albino rats were randomly divided into six groups. The control group received saline. The gentamicin group was treated with intraperitoneal gentamicin (100 mg/kg) for 7 days. Vitamin D (1000 IU/kg) was given to the D1 group for 1 week and to the D2 group for 2 weeks by oral gavage. The simultaneous treatment group received both gentamicin and vitamin D in combination for 1 week. In the pretreatment group, vitamin D was administered during the first week, and then gentamicin and vitamin D were administered together for the second week. At the end of the drug administration, all rats were sacrificed. Blood and kidney samples of rats were analyzed using biochemical methods. Rat kidneys were examined using electron microscopes. Both vitamin D treatments decreased gentamicin-induced elevations in MDA, TNF-α, and IL-6. In addition, in the vitamin D pretreatment group, gentamicin-induced rises in creatinine and urea, and decreases in SOD were also lessened. Ultrastructural indicators were improved, especially with vitamin D pretreatment. The anti-inflammatory and antioxidant properties of vitamin D protect against gentamicin-induced nephrotoxicity. The protective effect was considerably stronger if vitamin D was administered as a pretreatment. In conclusion, vitamin D supplementation before gentamicin treatment in the clinic may be an effective option to prevent the development of nephrotoxicity.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cefotaxime Sodium Ameliorates Infection Control and Inflammatory Response in Patients With Nosocomial Infection During Decompensated Cirrhosis. 头孢噻肟钠改善失代偿期肝硬化患者医院感染的感染控制和炎症反应。

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-07-17 DOI: 10.1002/jat.4813

Yan Zhang, Mei Zhang, Zhongfu Lu

{"title":"Cefotaxime Sodium Ameliorates Infection Control and Inflammatory Response in Patients With Nosocomial Infection During Decompensated Cirrhosis.","authors":"Yan Zhang, Mei Zhang, Zhongfu Lu","doi":"10.1002/jat.4813","DOIUrl":"https://doi.org/10.1002/jat.4813","url":null,"abstract":"It was to evaluate the efficacy and safety of cefotaxime sodium in the treatment of patients with decompensated cirrhosis complicated by nosocomial infections. A retrospective analysis was conducted on 112 patients with decompensated cirrhosis, who were categorized into two groups based on treatment regimen: the antibiotic group (AG) and the conventional group (CG). Differences between the two groups were compared in terms of clinical infections, serum inflammatory markers, microbial clearance rates, therapeutic efficacy, and adverse reactions. After treatment, the AG exhibited significantly lower white blood cell count (WBC), procalcitonin (PCT), C-reactive protein (CRP), and interleukin-1β (IL-1β) compared with the CG, indicating the advantage of cefotaxime sodium in alleviating inflammation. The incidence of nosocomial infections was lower in the AG, and the microbial clearance rate (93.85%) was significantly higher than that of the CG (82.98%). Clinical efficacy, as evaluated by the patient-generated subjective global assessment (PG-SGA) score, was significantly superior in the AG, with a lower incidence of adverse reactions. The overall effective rate in the AG was 96.92%, significantly higher than the 87.23% in the CG (p < 0.05). Cefotaxime sodium demonstrated outstanding performance in controlling infections, reducing inflammatory responses, and improving nutritional status in patients with decompensated cirrhosis complicated by nosocomial infections. It is an effective and safe treatment option for such patients.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Descriptor-Based Explainable QSAR Modeling Approaches for the Prediction of Respiratory Toxicity of Volatile and Gas-Phase Chemicals. 基于描述符的可解释QSAR建模方法用于挥发性和气相化学品的呼吸毒性预测。

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-07-16 DOI: 10.1002/jat.4859

Gul Karaduman, Hasan Yildirim

{"title":"Descriptor-Based Explainable QSAR Modeling Approaches for the Prediction of Respiratory Toxicity of Volatile and Gas-Phase Chemicals.","authors":"Gul Karaduman, Hasan Yildirim","doi":"10.1002/jat.4859","DOIUrl":"https://doi.org/10.1002/jat.4859","url":null,"abstract":"Toxic gases pose significant risks to human health and ecosystems because of their capacity to deplete oxygen levels and disrupt critical physiological functions. Effective management of these hazards is crucial, given their widespread use in various industrial sectors, including agriculture, metallurgy, pharmaceuticals, and plastics. A dataset of 229 gaseous-phase chemicals from authoritative toxicological sources was used to develop robust binary quantitative structure-activity relationship (QSAR) models for predicting toxicity. Employing molecular descriptor selection, correlation analyses, and outlier detection, random forest and XGBoost emerged as the most accurate models, each achieving a high accuracy of 0.915, with ROC areas of 0.992 and 0.986, respectively. SHapley Additive exPlanations (SHAP) were applied to enhance the explainability of the best model, providing global and local insights into the importance and direction of each descriptor. Key features influencing toxicity were identified globally, while locally, descriptors were ranked on a molecule-by-molecule basis, offering guidance for mitigating toxic effects through structural modifications. Although numerous studies have focused on predicting the toxicity of chemical gases, few have systematically analyzed the specific molecular descriptors driving toxicity. This study addresses this gap by providing a descriptor-based analysis, offering deeper mechanistic insights, and enabling more accurate predictions. The QSAR approach aligns with the 4R principles, promoting ethical, cost-effective, and efficient alternatives to animal testing, thus contributing to safer chemical design and environmental monitoring.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Oxidative Stress Biomarkers and Antioxidant Enzymes in Liver and White Muscle of Nile Tilapia, Oreochromis niloticus, Exposed to an Endocrine Disruptor, Triclosan. 暴露于内分泌干扰物三氯生的尼罗罗非鱼肝脏和白肌氧化应激生物标志物和抗氧化酶。

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-07-16 DOI: 10.1002/jat.4861

Raj Sunu, G Prasad

{"title":"Oxidative Stress Biomarkers and Antioxidant Enzymes in Liver and White Muscle of Nile Tilapia, Oreochromis niloticus, Exposed to an Endocrine Disruptor, Triclosan.","authors":"Raj Sunu, G Prasad","doi":"10.1002/jat.4861","DOIUrl":"https://doi.org/10.1002/jat.4861","url":null,"abstract":"Both target and nontarget aquatic creatures have been observed to suffer negative impacts from pharmaceutical residues and metabolites. This study is aimed at evaluating the toxic effects of triclosan (TCS). The sublethal effects of TCS at concentrations 0.146 ppm (1/15), 0.219 ppm (1/10), and 0.438 ppm (1/5) on biochemical responses and oxidative stress biomarkers in the serum, liver, and muscle tissue of freshwater fish Nile tilapia, Oreochromis niloticus, were investigated for 15, 30, and 45 days. Levels of some serum biochemical parameters including protein and glucose reduced while glutamic oxaloacetic transaminase and glutamic pyruvic transaminase raised as concentration of TCS increased. The reactions of superoxide dismutase and glutathione-S-transferase and reduced glutathione were elevated, and the activities of reduced glutathione were reduced in fish liver and muscle. Malate dehydrogenase activity gradually rose, showing a metabolic response to stress, but NADH dehydrogenase activity gradually decreased, indicating mitochondrial malfunction. Chronic exposure to TCS below the lethal threshold can alter O. niloticus serum biochemical indexes and cause oxidative stress. This suggests that the drug exposure and its metabolites should be closely monitored in aquatic environments due to the potential harm they could do, even to organisms that are not the intended target.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Repeated Inhalation of Liquefied Petroleum Gas Inhibited the Expression of Dopamine D2 Receptor, Along With Pulmonary Defense Dysfunction. 反复吸入液化石油气可抑制多巴胺D2受体的表达，并伴有肺防御功能障碍。

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-07-16 DOI: 10.1002/jat.4857

Wonkyun Jung, Junhyuk Choi, Min-Sung Kang, Mi-Jin Yang, Kyung-Sik Yoon, Jin-Bae Kim, Nam Chul Kwon, Seong-Jin Choi, Sungho Maeng, Eun-Jung Park

{"title":"Repeated Inhalation of Liquefied Petroleum Gas Inhibited the Expression of Dopamine D2 Receptor, Along With Pulmonary Defense Dysfunction.","authors":"Wonkyun Jung, Junhyuk Choi, Min-Sung Kang, Mi-Jin Yang, Kyung-Sik Yoon, Jin-Bae Kim, Nam Chul Kwon, Seong-Jin Choi, Sungho Maeng, Eun-Jung Park","doi":"10.1002/jat.4857","DOIUrl":"https://doi.org/10.1002/jat.4857","url":null,"abstract":"Inhalants are volatile household chemicals that can directly affect the respiratory and nervous systems. Due to their legal and economic accessibility, they have emerged as a major social factor impacting the health of children and teenagers seeking pleasure. However, the detailed toxic mechanisms remain unclear. In the current study, we sprayed a single dose and repeated doses (weekly, totaling 1 to 5 times) of liquefied petroleum gas (LPG) to mice (12 male mice/group) and observed both local and systemic toxic effects. During exposure, we noted reduced eye blinking and noticeable tremors. The membrane of pulmonary alveolar macrophages was quickly damaged after inhalation, and pulmonary inflammatory mediator levels were significantly reduced in all groups inhaling LPG compared to the control. More importantly, serum concentrations of dopamine and corticosterone increased, peaking on Day 7 after the second exposure (6.1-fold) and the fourth exposure (3.7-fold), respectively. Next-generation sequencing analysis using total RNA extracted from the hippocampus of mice revealed that the expression of dopaminergic receptor D2 mRNA was downregulated in all groups exposed to LPG (-39.6 ± 0.0-fold at 30 min after the first exposure), and this decrease was confirmed by qRT-PCR analysis. Therefore, we suggest that inhalation of LPG may impair pulmonary defense functions by damaging the membranes of alveolar macrophages and could lead to addiction by downregulating the dopamine D2 receptor expression in the hippocampus. We propose that stringent control of volatile household chemical products is necessary worldwide to prevent diseases caused by misuse or abuse, particularly among young people.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

FOXA1-TET1 Mediate the DNA Hypomethylation of IL-4 Is Involved in Dust Fall PM_2.5 Induced Lung Inflammation. FOXA1-TET1介导IL-4 DNA低甲基化参与降尘PM2.5诱导的肺部炎症

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-07-15 DOI: 10.1002/jat.4858

Yan Cui, Zhan Li, Yingyi Liu, Wencai Wei, Simei Yang, Xin Liu, Lei Chen, Haiquan Yan, Gaoming Li, Qingying Zhou, Qingbi Zhang, Jun Bai

{"title":"FOXA1-TET1 Mediate the DNA Hypomethylation of IL-4 Is Involved in Dust Fall PM2.5 Induced Lung Inflammation.","authors":"Yan Cui, Zhan Li, Yingyi Liu, Wencai Wei, Simei Yang, Xin Liu, Lei Chen, Haiquan Yan, Gaoming Li, Qingying Zhou, Qingbi Zhang, Jun Bai","doi":"10.1002/jat.4858","DOIUrl":"https://doi.org/10.1002/jat.4858","url":null,"abstract":"PM2.5 has been linked to a variety of lung diseases. The objective of this study was to investigate the mechanism of lung inflammation caused by acute exposure to PM2.5 from the perspective of DNA methylation. Sprague-Dawley male rats were exposed to different concentrations of PM2.5 by non-exposure intratracheal instillation every other day for 3 times. Chemically modified si-Foxa1, si-Tet1, and si-NC were administered via the intratracheal instillation, followed by exposure to a medium concentration of PM2.5. Fourteen days following the final exposure, serum, bronchoalveolar lavage fluid (BALF), and lung tissues were collected for the appropriate tests. Acute exposure to PM2.5 resulted in infiltration of inflammatory cells and destruction of the alveolar structure. The levels of IL-4 and eotaxin-1 in serum and BALF were increased, while the levels of interferon-γ (IFN-γ) were decreased. In lung tissues, there was a decrease in the whole genome 5-mC and an increase in 5-hmC. The methylation level of the interleukin-4 (IL-4) DNA promoter CpG islands decreased, accompanied by an increase in the mRNA level. The protein expression of Forkhead box A1 (FOXA1) and ten-eleven translocation methylcytosine dioxygenase 1 (TET1) was upregulated. Downregulation of FOXA1 and TET1 levels reversed those changes. PM2.5 induced the upregulation of FOXA1 and TET1 protein expression, which subsequently affected the DNA methylation levels of IL-4. This, in turn, promoted the release of IL-4 and led to pulmonary inflammation. This study provides insights into the potential DNA methylation regulatory mechanisms underlying lung inflammation induced by acute PM2.5 exposure.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Oxidative Stress Biomarkers in Gasoline Station Workers Chronically Exposed to Heavy Metals in Erbil City. 埃尔比勒市长期暴露于重金属的加油站工人的氧化应激生物标志物

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-07-15 DOI: 10.1002/jat.4853

Sara Abdulkhaliq Yasin, Zhian Rashid Salih

{"title":"Oxidative Stress Biomarkers in Gasoline Station Workers Chronically Exposed to Heavy Metals in Erbil City.","authors":"Sara Abdulkhaliq Yasin, Zhian Rashid Salih","doi":"10.1002/jat.4853","DOIUrl":"https://doi.org/10.1002/jat.4853","url":null,"abstract":"Gasoline station workers are frequently exposed to heavy metals that can induce oxidative stress, contributing to various health complications. This study evaluated oxidative stress biomarkers in 75 gasoline station employees in Erbil City, Iraq, and compared them to 25 unexposed controls. Blood levels of malondialdehyde (MDA), a marker of lipid peroxidation, and glutathione peroxidase 1 (GPX1), a key antioxidant enzyme, were measured using enzyme-linked immunosorbent assay (ELISA). Workers exhibited a significant increase in MDA levels, accompanied by a marked decrease in GPX1 activity (p < 0.001), indicating heightened oxidative stress resulting from chronic occupational exposure. The degree of oxidative imbalance correlated positively with years of exposure and advancing age. Furthermore, MDA concentrations were positively associated with the levels of most metals in hair and dust. At the same time, GPX1 activity was inversely correlated with them, suggesting that heavy metal accumulation plays a pivotal role in oxidative damage. These alterations in oxidative stress markers indicate an impaired antioxidant defense system and increased lipid peroxidation in workers, which may underlie subsequent cellular and tissue damage. The findings highlight the critical impact of prolonged heavy metal exposure on oxidative stress pathways in gasoline station workers. Monitoring oxidative stress biomarkers such as MDA and GPX1 can serve as an effective tool for early detection of occupational toxicity and help guide protective interventions. This study underscores the necessity for implementing rigorous occupational health measures and environmental controls to reduce oxidative stress-related health risks in exposed worker populations.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0