Journal of Applied Toxicology最新文献

{"title":"Physiological Indicators of Cardiovascular and Respiratory Stress Associated With Airborne Heavy Metal Exposure in Gasoline Stations in Erbil City.","authors":"Sara Abdulkhaliq Yasin, Zhian Rashid Salih","doi":"10.1002/jat.4896","DOIUrl":"https://doi.org/10.1002/jat.4896","url":null,"abstract":"<p><p>This study aimed to evaluate the relationship between occupational exposure to heavy metals and alterations in cardiovascular and respiratory parameters among gasoline station workers in Erbil City, Iraq. A total of 100 adult participants were included, comprising 75 gasoline station attendants and 25 non-exposed individuals from a remote mountainous region. Cardiovascular indicators, including systolic blood pressure (SBP), diastolic blood pressure (DBP), and body mass index (BMI), as well as respiratory parameters such as arterial blood oxygen saturation (ABO) and forced vital capacity (FVC), were measured using standardized protocols. Scalp hair and environmental dust samples were collected and analyzed for concentrations of Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Hg, Pb, and V using X-ray fluorescence (XRF) spectrometry. Results showed statistically significant increases in SBP, DBP, and BMI, and marked reductions in ABO and FVC among exposed workers compared to controls (p < 0.001), with severity increasing with years of service and age. Pearson correlation analysis revealed strong positive correlations between hair and dust concentrations of specific heavy metals (Cr, Ni, Hg, Pb) and elevated SBP and DBP, as well as significant negative correlations with ABO and FVC (p ≤ 0.05). These findings indicate that chronic occupational exposure to heavy metals contributes to cardiovascular strain, impaired pulmonary function, and potential metabolic disruption. The use of both biological (hair) and environmental (dust) markers strengthens the evidence of internal and external exposure. This study underscores the urgent need for improved occupational health monitoring and regulatory interventions to reduce pollutant exposure among petroleum workers.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955689","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}

{"title":"Evaluating Solvent Safety in Chromosome Aberration Assays for Genetic Toxicology.","authors":"Satyam N Patel, Chetan K Kajavadara, Rushikesh M Shukla, Darshan T Valani, Laxit K Bhatt, Rajesh Sundar, Mukul R Jain","doi":"10.1002/jat.4894","DOIUrl":"https://doi.org/10.1002/jat.4894","url":null,"abstract":"<p><p>The chromosome aberration test (CAT) is a widely used in vitro assay for detecting structural chromosomal damage induced by clastogenic chemicals. It plays a crucial role in genetic toxicology, helping assess the potential genotoxic effects of pharmaceutical compounds, environmental contaminants, and industrial chemicals. This test is particularly valuable in regulatory studies, as chromosomal aberrations are linked to mutagenicity, carcinogenicity, and hereditary diseases. The test evaluates their occurrence in cultured human peripheral blood lymphocytes (HPBL) or other mammalian cells after exposure to test chemicals. Accurate solubility of test compounds is critical for determining the highest feasible concentration in CAT without compromising cell viability or assay integrity. However, selecting an appropriate solvent remains a challenge in genetic toxicology, as the solvent must ensure chemical stability, support cell growth and metabolic activation, comprise ≤ 1% of the final treatment medium, and be compatible with human blood cells. In this study, we systematically evaluated the cytotoxic effects of various solvents on HPBL at 0.5% and 1% concentrations over a 22-h exposure period, replicating approximately 1.5 normal cell cycle durations without the inclusion of a metabolic activation system. The solvents tested included dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), acetone, acetonitrile, ethyl acetate, ethanol, methanol, p-dioxane, tetrahydrofuran (THF), and dimethylacetamide. Our findings revealed that N,N-dimethylformamide and acetone were noncytotoxic at 0.5%, while ethanol, methanol, acetonitrile, and dimethyl sulfoxide were noncytotoxic at both 0.5% and 1% concentrations, whereas other solvents exhibited cytotoxic effects at both concentrations. These findings provide valuable insights for genetic toxicologists, enabling better selection of optimal solvents for CAT-based genotoxicity assessments. By refining solvent choices, researchers can improve chromosome aberration analysis accuracy, facilitating more reliable regulatory decision-making in genetic toxicology and pharmaceutical safety evaluations.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955650","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}

{"title":"Inflammation and Oxidative Stress Biomarkers in Heavy Metal Toxicity: Bridging the Gap to Personalized Clinical Interventions.","authors":"Tolunigba Abisola Kolawole, Javier Palacios, Danladi Chiroma Husaini, Chukwuemeka R Nwokocha","doi":"10.1002/jat.4874","DOIUrl":"https://doi.org/10.1002/jat.4874","url":null,"abstract":"<p><p>Heavy metal exposure (e.g., Pb, Cd, Hg, and As) remains a critical public health concern because of bioaccumulation and links to chronic diseases like hypertension, diabetes, and cancer. This systematic review (PRISMA compliant) synthesizes evidence from 32 studies (2015-2025) elucidating toxicity mechanisms via oxidative stress, inflammation, endocrine disruption, and epigenetic dysregulation. Key biomarkers-blood/urinary metal levels, oxidative stress markers (8-OHdG and MDA), and inflammatory cytokines (CRP, IL-6, and TNF-α)-enable early detection and toxicity assessment. Pro-inflammatory responses dominated across studies, with Pb and Cd consistently elevating CRP, TNF-α, and IL-6, alongside tissue-specific inflammation (liver and kidneys). ELISA emerged as the primary analytical method, although biomarker variability underscored influences of dose, duration, and individual susceptibility. Critically, anti-inflammatory IL-10 was frequently downregulated. We highlight the clinical utility of biomarkers in public health surveillance, chelation therapy, and preventive strategies. Future directions prioritize omics-based profiling, CRISPR technology, portable biosensors, and standardized protocols for real-time monitoring and personalized risk assessment. Integrating current biomarkers with these innovations will advance precision medicine to mitigate heavy metal toxicity globally.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855333","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}

{"title":"The Second-Generation Antipsychotic Perospirone Inhibits Voltage-Gated K⁺ Channels in Coronary Arterial Smooth Muscle Cells.","authors":"Seo-Yeong Mun, Jin Ryeol An, Wenwen Zhuang, Junsu Jeong, Hye Ryung Kim, Sooa Lee, Hongzoo Park, Won-Kyo Jung, Mi Seon Seo, Won Sun Park","doi":"10.1002/jat.4883","DOIUrl":"https://doi.org/10.1002/jat.4883","url":null,"abstract":"<p><p>Perospirone is a second-generation antipsychotic classified as a serotonin-dopamine antagonist that is primarily used to treat schizophrenia and bipolar disorder. While its therapeutic effects have been attributed to D₂ and 5-HT_2A receptor antagonism and partial 5-HT_1A agonism, its potential interactions with ion channels remain unexplored. In this study, we investigated the effects of perospirone on vascular voltage-gated K⁺ (Kv) channels in freshly isolated rabbit coronary arterial smooth muscle cells. Perospirone inhibited vascular Kv channels in a concentration-dependent manner, with a half-maximal inhibitory concentration (IC₅₀) of 20.54 ± 2.89 μM and a Hill coefficient of 0.92 ± 0.07. Perospirone did not change the activation or inactivation kinetics and did not exhibit use-dependent inhibition, suggesting that the interaction between the drug and the channels did not affect the voltage sensors or conformational states of the channels. Pretreatment with the Kv2.1 inhibitor guangxitoxin or the Kv7 inhibitor linopirdine did not change the extent of the perospirone-induced Kv current inhibition, whereas pretreatment with the Kv1.5 inhibitor DPO-1 partially attenuated the inhibitory effect of perospirone on Kv currents. These findings demonstrate that perospirone inhibits vascular Kv1.5 subtype channels in a concentration-dependent but use-independent manner. This previously unrecognized off-target effect suggests that perospirone can affect vascular function, highlighting its potential cardiovascular implications in clinical settings.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855334","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}

{"title":"Autophagy in Cadmium-Induced Hepatic Injury of Rats: Protective Role of Naringenin.","authors":"Mengmeng Gao, Hao Ling, Chengxiang Guo, Yinan Hu, Jing Zhu, Jicang Wang","doi":"10.1002/jat.4895","DOIUrl":"https://doi.org/10.1002/jat.4895","url":null,"abstract":"<p><p>Cadmium, a bluish-white metallic, possesses a prolonged half-life in organisms, causing damage to multiple tissues and organs. Naringenin, a natural flavonoid antioxidant, mitigates cadmium-induced damage in organisms. However, the mechanism by which naringenin attenuates Cd-associated hepatocellular damage has not been fully elucidated. The present investigation consequently aimed to elucidate the mechanistic involvement of autophagy in cadmium hepatotoxicity using the rat model, with parallel assessment of naringenin's hepatoprotective efficacy. In this experiment, 24 SD rats underwent randomization to four experimental groups: (1) control (intraperitoneal saline injection), (2) Cd (1 mg/kg b.w. CdCl₂ intraperitoneal injection), (3) Cd + Nar (1 mg/kg b.w. CdCl₂ injection + 50 mg/kg b.w. naringenin oral gavage), and (4) Nar (50 mg/kg b.w. naringenin oral gavage) groups. After the 14-day interventions, serum and liver tissues were collected post-euthanasia. Hepatic injury markers (AST and ALT) and antioxidant enzymes (CAT and SOD) were quantified. Histopathology utilized HE and TUNEL staining. RT-qPCR and western blot analyses determined mRNA and protein expression levels of autophagy-related factors (p62 and LC3) and apoptosis-related factor (Caspase-3). The results demonstrated that cadmium exposure significantly reduced body weight, increased relative liver weight, elevated serum AST/ALT levels, and diminished hepatic CAT/SOD activity. Cadmium significantly upregulated both mRNA and protein expression levels of p62 and Caspase-3 while suppressing LC3 expression. Naringenin co-administration attenuated cadmium-induced hepatic injury, oxidative stress, impaired autophagy, and enhanced apoptosis. These findings collectively demonstrate that cadmium exposure induces hepatic injury and oxidative stress in rats through autophagy inhibition and apoptotic activation, while naringenin exerts protective effects by modulating these pathological processes.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855331","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}

{"title":"Impact of Embryonic Exposure of Atrazine on the Physiological and Behavioral Parameters in Drosophila melanogaster.","authors":"Radhika Soni, Girima Nagda","doi":"10.1002/jat.4893","DOIUrl":"https://doi.org/10.1002/jat.4893","url":null,"abstract":"<p><p>Atrazine is an extensively used herbicide for pre-and post-emergence of grassy and broadleaf weeds. It has become a common environmental contaminant with subsequent residual contamination of water and food, which causes adverse effects on non-target organisms. It is known to induce neurotoxicity, immunotoxicity, genotoxicity, and oxidative stress. The primary objective of the current study was to determine the effect of atrazine on the physiology and behavior of both larvae and adult flies. Newly fertilized eggs were exposed to different concentrations of atrazine (50% WP) (20, 25, 30, and 35 μg/mL) in the diet until the adult fly emerged. To evaluate behavioral changes, larval crawling assay, temperature sensitivity assay (both thermal and cold sensitivity), pupation height preference, adult climbing assay, negative geotaxis, and survival rate were determined on larvae and adult flies fed on atrazine. Capillary feeding assay and metabolic rate were determined in newly emerged flies treated with the same concentration of atrazine during development to measure physiological changes. It was observed that atrazine exposure decreased temperature sensitivity and larval crawling, and also, the pupation height index was lowered. Moreover, it decreased the pupation and survival rate as compared to control, whereas it had no impact on the rate of emergence of flies. Furthermore, the results revealed that with the increase in atrazine concentration, a corresponding decrease in the climbing, feeding, and metabolic rate of the adult flies was observed. In conclusion, the present study demonstrates that atrazine affects a range of physiological and behavioral factors, especially food intake and metabolism, and it also affects neuromuscular activity as apparent from the larval crawling assay and adult climbing assay.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855332","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}

{"title":"Human Umbilical Vein Endothelial Cells (HUVECs) in Pharmacology and Toxicology: A Review.","authors":"Yi Cao","doi":"10.1002/jat.4885","DOIUrl":"https://doi.org/10.1002/jat.4885","url":null,"abstract":"<p><p>Endothelial cells (ECs) are interior surface cells covering blood vessels, which play a crucial role in maintaining vascular homeostasis. In vascular pharmacology and toxicology, ECs directly contact drugs or toxicants entering circulation. Therefore, the bio-effects of pharmacological/toxicological substances on ECs have gained extensive research interest, which needs to be evaluated by reliable models. Human umbilical vein endothelial cells (HUVECs) have been served as versatile platforms to mimic diverse pathophysiological processes in vitro, stemming from their unique fetal arterial-like exposure microenvironment, expression of key EC markers, and comparable EC responses to various pathophysiological stimuli. This review provides an overview of the application of HUVECs in pharmacology and toxicology, with a focus on their utility and limitations. HUVECs have been widely used to model the effects of pharmacological or toxicological substances on material exchange, barrier functions, cell death, endothelial nitric oxide synthase (eNOS) uncoupling, and EC dysfunction, angiogenesis, and thrombosis. However, their applicability is constrained primarily due to vascular-type and organ-specific heterogeneity. The review highlights key mechanisms investigated using HUVECs, including oxidative stress, inflammation, organelle damage, and autophagy, metabolic reprogramming (endometabolism), and epigenetic regulation. Strategies to overcome HUVECs' limitations, such as microfluidic techniques, co-culture, and organoid models, are discussed. Finally, future directions are outlined, emphasizing the integration of HUVECs into multi-scale models, dynamic microenvironment simulations, artificial intelligence (AI)-assisted big data analysis, and patient-derived ECs for precision toxicology and personalized medicine. This review aims to guide researchers in optimizing the use of HUVECs in pharmacological and toxicological studies.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144846637","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}

{"title":"Evaluation of the Potential Effects of Three Chemicals on the Hypothalamic-Pituitary-Thyroid (HPT) and Hypothalamic-Pituitary-Gonadal (HPG) Axes Using the Larval Amphibian Growth and Development Assay (LAGDA).","authors":"Alaa Kamel, Sharlene Matten, Karen Hamernik, Jeffrey C Wolf, Thomas Leak, Emily Lent, Amy Thomas, Vincent J Brown, Kevin J Todhunter, Douglas J Fort, Scott G Lynn","doi":"10.1002/jat.4849","DOIUrl":"https://doi.org/10.1002/jat.4849","url":null,"abstract":"<p><p>Three chemicals, 2-ethylhexyl 4-hydroxybenzoate (2-EHHB), 5-chloro-2-(2,4-dichlorophenoxy) phenol (triclosan), and 4-nonylphenol, branched (4-NP), were evaluated using the larval amphibian growth and development assay (LAGDA) to investigate potential endocrine-mediated effects. Xenopus laevis larvae at Nieuwkoop and Faber (NF) developmental Stage 8-10 were nominally exposed to 2-EHHB, triclosan (at 3.6, 10.9, 33.0, and 100 μg/L), or 4-NP (at 1.8, 5.5, 16.5, and 50 μg/L) until 10 weeks after the median time to metamorphosis (TTM). Each chemical increased the median TTM (NF Stage 62) at all tested concentrations, but the times between NF Stages 62 and 66 were less than the controls, resulting in similar times to NF Stage 66 for all treatments, including the controls. Exposure to 2-EHHB increased body weight at NF Stage 62, while 4-NP and triclosan reduced body weight at NF Stage 66. For juveniles at 10 weeks post metamorphosis, none of the test substances affected phenotypic sex ratios, consistency between phenotype and genotype, or liver-somatic index. An increase in body weight in juveniles was observed in male and female frogs exposed to 4-NP, and exposure to 2-EHHB increased snout-to-vent length. Exposure to 4-NP resulted in a marked acceleration of Müllerian duct development in male and female frogs. Gonadal ducts were also affected in 2-EHHB and triclosan-exposed frogs. No treatment-related pathological liver effects were observed. Triclosan and 2-EHHB exacerbated background findings in the kidney including mineralization, tubule dilation, interstitial fibrosis, and mononuclear cell infiltrates.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835212","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}

{"title":"Exploring the Diagnostic Potential of Core Targets of 6PPD and Its Metabolite 6PPD-Q in Cardiovascular Diseases: An Integrated Analysis Based on Network Toxicology, Molecular Docking, and In Vitro Validation.","authors":"Bing Guo, Xing Jiang, Lemei Zhu, Xuan He","doi":"10.1002/jat.4892","DOIUrl":"https://doi.org/10.1002/jat.4892","url":null,"abstract":"<p><p>6PPD (N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine) and its oxidized form, 6PPD-Q (2-((4-methylpentan-2-yl)amino)-5-(phenylamino)cyclohexa-2,5-diene-1,4-dione), are commonly used in rubber-based materials and have been increasingly found in the environment. Recent studies suggest that these compounds may be toxic to the cardiovascular system, but the exact molecular mechanisms are not well understood. This study used a combination of network toxicology, molecular docking, and bioinformatics to investigate how 6PPD and 6PPD-Q affect the heart, particularly in relation to atherosclerosis, acute myocardial infarction, and heart failure. By screening multiple databases and analyzing Gene Expression Omnibus (GEO) transcriptome data, we identified key targets that are involved in these diseases. We built PPI networks and performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to explore the related pathways. Additionally, we validated four core targets-nuclear receptor subfamily 4 group A member 3 (NR4A3), sphingosine-1-phosphate receptor 3 (S1PR3), nicotinamide phosphoribosyltransferase (NAMPT), and formyl peptide receptor 1 (FPR1)-that showed high diagnostic value in all three diseases using receiver operating characteristic (ROC) analysis. Molecular docking revealed that both 6PPD and 6PPD-Q strongly bind to these targets. Further in vitro experiments revealed that 6PPD and 6PPD-Q induce damage in H9c2 cells. The mechanism may be associated with these four targets. This study sheds light on how these environmental pollutants harm the cardiovascular system and demonstrates the value of combining network toxicology with omics and structural biology in risk assessment and therapeutic development.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835213","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}

{"title":"TCDD Induces Hepatocytes Lipid Deposition via Downregulation of MFN2.","authors":"Changming Xing, Yongjun Ai, Yue Wu, Xiping Wang, Haoyu Ding, Chunxi Wei, Guangfei Xu, Wenxing Sun","doi":"10.1002/jat.4890","DOIUrl":"https://doi.org/10.1002/jat.4890","url":null,"abstract":"<p><p>The persistent environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been implicated in hepatic lipid metabolism disorders and steatosis. However, the precise mechanisms underlying TCDD-induced hepatic lipid deposition remain incompletely elucidated. Mitofusin 2 (MFN2), a key mitochondrial dynamics protein, plays a critical role in lipid metabolism, as its deficiency leads to metabolic dysregulation. In this study, we investigate the role of MFN2 in TCDD-induced lipid deposition. Our findings demonstrate that TCDD exposure significantly reduces MFN2 protein expression both in vivo and in vitro, while concomitantly decreasing mitochondrial membrane potential and increasing reactive oxygen species (ROS) levels in Huh7 cells. Notably, overexpression of MFN2 effectively mitigates TCDD-induced pathological effects, preventing lipid accumulation, restoring mitochondrial membrane potential, and reducing ROS levels. Mechanistically, although TCDD does not alter the MFN2 mRNA expression, it promotes protein degradation through enhanced ubiquitination in vitro. These findings demonstrate that TCDD induces lipid accumulation in Huh7 cells through ubiquitination-mediated degradation of MFN2. Our study thus identifies MFN2 as a novel target in TCDD-induced hepatic steatosis.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144821551","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}