Toxicology最新文献

{"title":"Tripartite motif-containing 32 regulated by miR-6236-p5 inhibited silica-induced apoptosis of alveolar macrophages","authors":"Manyu Zhao ,&nbsp;Qing Chen ,&nbsp;Xuxi Chen ,&nbsp;Shuyu Gong ,&nbsp;Mengzhu Wang ,&nbsp;Shanshan Zhao ,&nbsp;Sihan Wang ,&nbsp;Wen Du ,&nbsp;Yunyi Xu ,&nbsp;Lijun Peng ,&nbsp;Yuqin Yao","doi":"10.1016/j.tox.2024.154042","DOIUrl":"10.1016/j.tox.2024.154042","url":null,"abstract":"<div><div>Apoptosis of alveolar macrophages (AMs) induced by silica is one of the crucial driving factors of silicosis inflammation and fibrosis. However, the mechanism of silica-induced AMs apoptosis remains unclear. In this study, transcriptome sequencing identified 11 differentially expressed (DE)-mRNAs enriched in the regulation of apoptotic signaling pathways in AMs treated with 250 μg/mL silica for 24 h, of which tripartite motif-containing 32 (Trim32) was the most significant and down-regulated. The decreased Trim32 promoted AMs apoptosis, while Trim32 overexpression inhibited the apoptosis of AMs induced by silica at 250 μg/mL for 24 h. MiR-6236-p5 was then identified by MiRNA sequencing as the most significant DE-miRNA potentially regulating Trim32 expression, and the interaction between miR-6236-p5 and Trim32 3′-UTR was confirmed by dual luciferase reporter gene assay. Treated with 100 nM miR-6236-p5 inhibitor increased the expression of Trim32 and inhibited the apoptosis of AMs induced by silica at 250 μg/mL for 24 h, while miR-6236-p5 mimic promoted the apoptosis of silica-induced AMs. In conclusion, this study identified Trim32 regulated by miR-6236-p5 played an important role in silica-induced AMs apoptosis based on RNA sequencing, which provided a novel clue for exploring the mechanism of silica-induced AMs apoptosis.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154042"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915590","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":"Roles of N6-methyladenosine in LncRNA changes and oxidative damage in cadmium-induced pancreatic β-cells","authors":"Guofen Liu ,&nbsp;Jie Yang ,&nbsp;Rongxian Li ,&nbsp;Wenhong Li ,&nbsp;De Liu ,&nbsp;Nan Zhang ,&nbsp;Yuan Zhao ,&nbsp;Zuoshun He ,&nbsp;Shiyan Gu","doi":"10.1016/j.tox.2025.154053","DOIUrl":"10.1016/j.tox.2025.154053","url":null,"abstract":"<div><div>N⁶-methyladenosine (m⁶A) modification and LncRNAs play crucial regulatory roles in various pathophysiological processes, yet roles of m⁶A modification and the relationship between m⁶A modification and LncRNAs in cadmium-induced oxidative damage of pancreatic β-cells have not been fully elucidated. In this study, m⁶A agonist entacapone and inhibitor 3-deazadenosine were used to identify the effects of m⁶A on cadmium-induced oxidative damage as well as LncRNA changes. Our results indicate that elevated levels of m⁶A modification by entacapone can rescue the cell viability and attenuate the cell apoptosis, while the inhibition levels of m⁶A modification can exacerbate the cell death. Furthermore, the elevation of m⁶A modification can recover cadmium-induced oxidative damage to pancreatic β-cells, which characterized as inhibition the ROS accumulation, MDA contents, protein expressions of Nrf2 and Ho-1, while elevation the expressions of Sod1 and Gclc. On the contrary, the reduction levels of m⁶A modification can exacerbate the cadmium-induced oxidative damage. More importantly, six significantly differentially expressed LncRNAs were selected according to our preliminary sequencing data (<span><span>https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE253072</span><svg><path></path></svg></span>) and there is a clear correlation between the levels of these LncRNAs and m⁶A modification after cadmium treatment. Interestingly, the intervention of m⁶A modification levels can significantly affect the levels of these LncRNAs. In detail, the stimulation of m⁶A modification reversed the changes of cadmium-induced LncRNAs, while the m⁶A modification inhibition can significantly exacerbate the changes of cadmium-induced LncRNAs. In conclusion, our data revealed critical roles of m⁶A modification in cadmium-induced LncRNAs and oxidative damage. Our findings point to a new direction for future studies on the molecular mechanisms of pancreatic β-cell damage induced by cadmium.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154053"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972203","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":"Chronic environmental exposure to polystyrene microplastics increases the risk of nonalcoholic fatty liver disease","authors":"Yujie Shi ,&nbsp;Runyang Hong ,&nbsp;Zhencheng Fan ,&nbsp;Ran Huan ,&nbsp;Yajie Gao ,&nbsp;Min Ma ,&nbsp;Tingting Liu ,&nbsp;Chun Pan","doi":"10.1016/j.tox.2025.154067","DOIUrl":"10.1016/j.tox.2025.154067","url":null,"abstract":"<div><div>Microplastics (MPs), as the crucial environmental pollutants, can be easily transported into the human body and accumulate in the liver. However, current studies mainly focus on acute exposure to MPs, investigations on long-term interactions with MPs alone remain limited. Thereby, we examined noxious properties of MPs and selected the most common polystyrene (PS) MPs as the research object, including unmodified PS MPs (PS-MPs) and positive-charged PS MPs (PS-NH₂) at 10 mg/L employing oral drinking water methods in mice for six consecutive months <em>in vivo</em>. <em>In vitro</em>, we treated the human hepatocyte cells with MPs at 25 μg/mL to explore involved mechanisms. The results revealed that six-month MPs exposure led to nonalcoholic fatty liver disease (NAFLD) including impaired liver functions, extensive lipid depositions accompanied by abnormal levels of metabolic genes and PS-NH₂ MPs exerted a stronger effect than PS-MPs. Concurrently, mice treated with MPs revealed the accumulation of senescent hepatocytes, leading to increased secretions of senescent phenotypes in the liver. We also discovered that MPs initiated the HO-1/Nrf2 axis consequently inducing ferroptosis <em>in vivo</em> and <em>in vitro</em>, as shown by massive iron deposition, extensive lipid peroxidation along with significant protein expressions in ferroptosis-related markers. Additionally, targeting the HO-1/Nrf2 pathway to further alleviate ferroptosis with corresponding inhibitors could efficiently alleviate cell senescence. Therefore, our study reveals new evidence of the relationship between chronic exposure to MPs and NAFLD and furthers the understanding of how plastic pollution affects human health.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154067"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047975","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":"InterDIA: Interpretable prediction of drug-induced autoimmunity through ensemble machine learning approaches","authors":"Lina Huang,&nbsp;Peineng Liu,&nbsp;Xiaojie Huang","doi":"10.1016/j.tox.2025.154064","DOIUrl":"10.1016/j.tox.2025.154064","url":null,"abstract":"<div><div>Drug-induced autoimmunity (DIA) is a non-IgE immune-related adverse drug reaction that poses substantial challenges in predictive toxicology due to its idiosyncratic nature, complex pathogenesis, and diverse clinical manifestations. To address these challenges, we developed InterDIA, an interpretable machine learning framework for predicting DIA toxicity based on molecular physicochemical properties. Multi-strategy feature selection and advanced ensemble resampling approaches were integrated to enhance prediction accuracy and overcome data imbalance. The optimized Easy Ensemble Classifier achieved robust performance in both 10-fold cross-validation (AUC value of 0.8836 and accuracy of 82.81 %) and external validation (AUC value of 0.8930 and accuracy of 85.00 %). Paired case studies of hydralazine/phthalazine and procainamide/N-acetylprocainamide demonstrated the model’s capacity to discriminate between structurally similar compounds with distinct immunogenic potentials. Mechanistic interpretation through SHAP (SHapley Additive exPlanations) analysis revealed critical physicochemical determinants of DIA, including molecular lipophilicity, partial charge distribution, electronic states, polarizability, and topological features. These molecular signatures were mechanistically linked to key processes in DIA pathogenesis, such as membrane permeability and tissue distribution, metabolic bioactivation susceptibility, immune protein recognition and binding specificity. SHAP dependence plots analysis identified specific threshold values for key molecular features, providing novel insights into structure-toxicity relationships in DIA. To facilitate practical application, we developed an open-access web platform enabling batch prediction with real-time visualization of molecular feature contributions through SHAP waterfall plots. This integrated framework not only advances our mechanistic understanding of DIA pathogenesis from a molecular perspective but also provides a valuable tool for early assessment of autoimmune toxicity risk during drug development.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154064"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143053770","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":"Effective analysis of thyroid toxicity and mechanisms of acetyltributyl citrate using network toxicology, molecular docking, and machine learning strategies","authors":"Yujian Lan ,&nbsp;Qingping Peng ,&nbsp;Bowen Fu ,&nbsp;Huan Liu","doi":"10.1016/j.tox.2024.154029","DOIUrl":"10.1016/j.tox.2024.154029","url":null,"abstract":"<div><div>The growing prevalence of environmental pollutants has raised concerns about their potential role in thyroid dysfunction and related disorders. Previous research suggests that various chemicals, including plasticizers like acetyl tributyl citrate (ATBC), may adversely affect thyroid health, yet the precise mechanisms remain poorly understood. The objective of this study was to elucidate the complex effects of acetyl tributyl citrate (ATBC) on the thyroid gland and to clarify the potential molecular mechanisms by which environmental pollutants influence the disease process. Through an exhaustive exploration of databases such as ChEMBL, STITCH, and GEO, we identified a comprehensive list of 19 potential targets closely associated with ATBC and the thyroid gland. After rigorous screening using the STRING platform and Cytoscape software, we narrowed this list to 15 candidate targets, ultimately identifying five core targets: CBX5, HADHB, TRIM33, TP53, and CUL4A, utilizing three well-established machine learning methods. In-depth Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses conducted in the DAVID database revealed that the primary pathways through which ATBC affects the thyroid gland involve key signaling cascades, including the FoxO signaling pathway and metabolic pathways such as fatty acid metabolism. Furthermore, molecular docking simulations using Molecular Operating Environment software confirmed strong binding interactions between ATBC and these core targets, enhancing our understanding of their interactions. Overall, our findings provide a theoretical framework for comprehending the intricate molecular mechanisms underlying ATBC's effects on thyroid damage and pave the way for the development of preventive and therapeutic strategies against thyroid disorders caused by exposure to ATBC-containing plastics or overexposure to ATBC.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154029"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807500","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 inflammatory responses and retention dynamics of cellulose nanofibrils","authors":"Katsuhide Fujita,&nbsp;Sawae Obara,&nbsp;Junko Maru,&nbsp;Yuka Kawai,&nbsp;Shigehisa Endoh","doi":"10.1016/j.tox.2024.154038","DOIUrl":"10.1016/j.tox.2024.154038","url":null,"abstract":"<div><div>Cellulose nanofibrils (CNFs) are advanced biomaterials valued for their strength, lightweight nature, and low thermal expansion, making them suitable for diverse industrial applications. However, their potential inhalation risks necessitate thorough safety evaluations. This study investigates the pulmonary inflammatory effects and retention of CNFs following intratracheal instillation in rats. TEMPO-oxidized CNF (CNF1; 11.5 nm × 1.8 μm), mechanically fibrillated CNF (CNF2; 23.9 nm × 2.4 μm), and shorter-fibrillated CNF (CNF3; 21.6 nm × 1.2 μm) were administered at 2.0 mg/kg body weight. Endotoxin contamination was assessed using lipopolysaccharide (LPS) controls. Pulmonary inflammation was evaluated 28 days post-instillation, and lung retention of chemically stained CNFs was tracked for 90 days. Results indicated: (1) CNFs were taken up by alveolar macrophages, but no significant acute inflammation was observed; (2) CNF characteristics, particularly fiber diameter and length, play a key role in influencing lung inflammation responses and determining inflammation sites; (3) endotoxin levels in the CNF dispersions may have limited effects on inflammatory responses; and (4) CNFs persist in lung tissue for extended periods, indicating slow clearance. While immediate inflammatory responses were minimal, the prolonged retention of CNFs in the lungs could contribute to chronic low-grade inflammation. Given the variability in CNF properties influenced by raw materials and manufacturing processes, it is essential to test each CNF type individually, including toxicological endpoints beyond inflammation, to accurately assess their potential health risks.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154038"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883030","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":"Cadmium exposure induces inflammation, oxidative stress and DNA damage in HUVEC and promotes THP-1 adhesion: A possible mechanism on the formation of atherosclerotic plaque","authors":"Haotian Liu ,&nbsp;Mingyang Fu ,&nbsp;Ziqi Ren,&nbsp;Zhaoshuo Liu,&nbsp;Xiangyu Cao,&nbsp;Jiahe Chen,&nbsp;Yulin Pang,&nbsp;Jianli Liu","doi":"10.1016/j.tox.2025.154046","DOIUrl":"10.1016/j.tox.2025.154046","url":null,"abstract":"<div><div>Observational studies have shown that cadmium exposure increases the risk of cardiovascular disease, but the underlying mechanism is still unclear. Atherosclerotic plaque can cause vascular obstruction, which is important for the death from cardiovascular disease. Cell damage and monocyte adhesion are two early events in atherosclerotic plaque formation that can be induced by cadmium exposure, but the mechanism remains to be determined. This study was carried out to investigate the toxicity of cadmium in HUVECs and the effect of cadmium on the adhesion of THP-1 cells, and further explored the possible mechanisms. Rhodamine staining, DCFH-DA staining, Hoechst33258 staining, morphological observation and western blot were used to detect mitochondrial membrane potential, ROS, apoptosis, cell adhesion, signaling pathways and cell adhesion factors respectively. The results indicated that cadmium exposure increased the level of ROS, activated MAPK signaling pathway and resulted in cellular oxidative stress in HUVECs. Exposure to cadmium made nuclear shrinkage, activated DNA damage response pathways and mitochondria-mediated intrinsic apoptosis pathway in HUVECs. Cadmium exposure activated the NLRP3 inflammasome and NF-κB signaling pathway, led to the upregulation of inflammatory cytokines in HUVECs. In addition, cadmium exposure also upregulated the adhesion factors including ICAM-1, VCAM-1 and E-Selectin via NF-κB signaling pathway and resulted in the adhesion of THP-1 cells. The present study elucidated that cadmium could damage the HUVECs and promote the adhesion of THP-1 cells, which clarified the toxicity of cadmium in HUVECs and revealed the possible mechanism for the occurrence of cardiovascular disease induced by cadmium.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154046"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955599","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":"Methamphetamine inhibits huntingtin-associated protein 1-mediated tyrosine receptor kinase B endocytosis resulting the neuroprotective dysfunction of brain-derived neurotrophic factor","authors":"Baoyu Shen ,&nbsp;Zhenling Wu ,&nbsp;Mengran Lv ,&nbsp;Genmeng Yang,&nbsp;Yuanyuan Cao,&nbsp;Yuan Zhang,&nbsp;Junjie Shu,&nbsp;Wenjuan Dong,&nbsp;Zhenping Hou,&nbsp;Di Jing,&nbsp;Xinjie Zhang,&nbsp;Yuhan Hou,&nbsp;Jing Xu,&nbsp;Shijun Hong,&nbsp;Lihua Li","doi":"10.1016/j.tox.2025.154047","DOIUrl":"10.1016/j.tox.2025.154047","url":null,"abstract":"<div><div>Methamphetamine (METH), a synthetic stimulant, has seen an escalating abuse situation globally over the past decade. Although the molecular mechanism underlying METH-induced neurotoxicity has been explored, the dysfunction of brain-derived neurotrophic factor (BDNF) neuroprotection in the context of METH neurotoxicity remains insufficiently understood. Our previous studies have found that METH induced neurotoxicity and BDNF expression in rat primary neurons, necessitating further research into this paradox. Specifically, BDNF-dependent tyrosine receptor kinase B (TrkB) endocytosis was crucial for BDNF to confer neuroprotection in neurons. Therefore, we investigated the effect and molecular mechanism of METH on TrkB endocytosis. This work attempted to explain the potential reasons why BDNF did not exert neuroprotection in the context of METH exposure. In the current study, excessive apoptosis, elevated BDNF and reduced huntingtin-associated protein 1 (HAP1) expression were observed in the hippocampus of METH users. METH also induced cell degeneration, cytotoxicity, and BDNF expression and release in HT-22 cells in both a concentration- (0.25, 0.5, 1, 2, and 4 mM) and time-dependent manner (3, 6, 12, 24, and 48 h). Furthermore, following 24 h of exposure to METH (2 mM), apoptosis, impaired TrkB endocytosis, and reduced HAP1 expression were evident in HT-22 cells and organotypic hippocampal slices from mice. Notably, overexpression of HAP1 attenuated METH-induced cell degeneration, cytotoxicity, apoptosis, and TrkB endocytosis disruption in HT-22 cells. These findings suggest that HAP1 is a key molecule in the disruption of BDNF-mediated neuroprotective signaling by METH, and that targeting HAP1-mediated TrkB endocytosis may represent a promising therapeutic avenue for METH-induced neurotoxicity.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154047"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971064","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":"Loss of Urat1 exacerbates APAP-induced liver injury in mice","authors":"Kunlu Zhao ,&nbsp;Shuaishuai Zhang ,&nbsp;Jinhong Tian ,&nbsp;Siyan Wu ,&nbsp;Yongjun Chen ,&nbsp;Zhenkun Wu ,&nbsp;Jiacheng Liang ,&nbsp;Huicong Wu ,&nbsp;Jianxin Pang ,&nbsp;Ting Wu","doi":"10.1016/j.tox.2025.154070","DOIUrl":"10.1016/j.tox.2025.154070","url":null,"abstract":"<div><div>Acetaminophen (APAP) overdose stands as the paramount contributor to drug-elicited liver damage in clinical settings. Despite this, the intricate interplay between uric acid (UA) levels, its metabolism-linked regulatory genes, and their effects on APAP metabolism and hepatic functions remains elusive. Our study sheds light on this nexus, uncovering that uric acid concentrations and urate transporter-1 (URAT1) expression are intricately intertwined in APAP-induced hepatotoxicity. Notably, elevated serum uric acid levels concomitant with a marked downregulation of hepatic URAT1 expression were discernible in APAP-mediated liver injury models. We also found that high UA exacerbated APAP-induced liver injury <em>in vitro</em> and <em>in vivo</em>. To delve deeper, we devised genetic knockout mice models, specifically targeting URAT1, to unravel its pivotal role in this pathological process. Strikingly, <em>Urat1</em> knockout (<em>Urat1</em>^-/-) mice exhibited exacerbated APAP-triggered hepatotoxicity when juxtaposed against their genetically intact wild-type (<em>Urat1</em>^+/+) counterparts, accompanied by increased serum and hepatic UA contents. However, the changes in UA levels might not be the only factor exacerbating APAP liver injury in <em>Urat1</em>^-/- mice, as <em>Urat1</em> knockout has also been proved to affect many other metabolites associated with the redox homeostasis. Mechanistically, we found that the ablation of <em>Urat1</em> not only intensified triglyceride accumulation instigated by APAP via inhibiting PPAR-α pathway but also ignited the NLRP3/NF-κB and JNK/ERK signaling cascades, and disrupted oxidative stress homeostasis via downregulating KEAP1/NRF2 pathway. Collectively, our findings underscore that URAT1 acts as a multifaceted facilitator of APAP-induced liver injury in mice, thereby positioning it as a genetic vulnerability factor in APAP overdose scenarios.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154070"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075591","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 liver toxicity models: Advantages, limitations and recommendations","authors":"Devaraj Ezhilarasan ,&nbsp;Sivanesan Karthikeyan ,&nbsp;Mustapha Najimi ,&nbsp;Paramasivan Vijayalakshmi ,&nbsp;Ganapathy Bhavani ,&nbsp;Muthukrishnan Jansi Rani","doi":"10.1016/j.tox.2024.154020","DOIUrl":"10.1016/j.tox.2024.154020","url":null,"abstract":"<div><div>Experimental animal models are crucial for elucidating the pathophysiology of liver injuries and for assessing new hepatoprotective agents. Drugs and chemicals such as acetaminophen, isoniazid, valproic acid, ethanol, carbon tetrachloride (CCl₄), dimethylnitrosamine (DMN), and thioacetamide (TAA) are metabolized by the CYP2E1 enzyme, producing hepatotoxic metabolites that lead to both acute and chronic liver injuries. In experimental settings, acetaminophen (centrilobular necrosis), carbamazepine (centrilobular necrosis and inflammation), sodium valproate (necrosis, hydropic degeneration and mild inflammation), methotrexate (sinusoidal congestion and inflammation), and TAA (centrilobular necrosis and inflammation) are commonly used to induce various types of acute liver injuries. Repeated and intermittent low-dose administration of CCl₄, TAA, and DMN activates quiescent hepatic stellate cells, transdifferentiating them into myofibroblasts, which results in abnormal extracellular matrix production and fibrosis induction, more rapidly with DMN and CCL₄ than TAA (DMN &gt; CCl₄ &gt; TAA). Regarding toxicity and mortality, CCl₄ is more toxic than DMN and TAA (CCl₄ &gt; DMN &gt; TAA). Models used to induce metabolic dysfunction-associated liver disease (MAFLD) vary, but MAFLD’s multifactorial nature driven by factors like obesity, fatty liver, dyslipidaemia, type II diabetes, hypertension, and cardiovascular disease makes it challenging to replicate human metabolic dysfunction-associated steatohepatitis accurately. From an experimental point of view, the degree and pattern of liver injury are influenced by various factors, including the type of hepatotoxic agent, exposure duration, route of exposure, dosage, frequency of administration, and the animal model utilized. Therefore, there is a pressing need for standardized protocols and regulatory guidelines to streamline the selection of animal models in preclinical studies.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154020"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142786856","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}