Toxicology最新文献

{"title":"Optimization of the drug-induced cholestasis index based on advanced modeling for predicting liver toxicity","authors":"Annika Drees ,&nbsp;Vahid Nassiri ,&nbsp;Andrés Tabernilla ,&nbsp;Jan Serroyen ,&nbsp;Emmanuel Gustin ,&nbsp;Bruna dos Santos Rodrigues ,&nbsp;Darren Michael Moss ,&nbsp;Ann De Smedt ,&nbsp;Mathieu Vinken ,&nbsp;Freddy Van Goethem ,&nbsp;Julen Sanz-Serrano","doi":"10.1016/j.tox.2025.154119","DOIUrl":"10.1016/j.tox.2025.154119","url":null,"abstract":"<div><div>Cholestatic drug-induced liver injury (cDILI) is a frequent reason for drug failure and withdrawal during premarketing and postmarketing stages of drug development. Strategies for reliable detection of cDILI in early drug development are therefore urgently needed. The drug-induced cholestasis index (DICI) concept was previously introduced as a tool for assessing the cholestatic potential of drug candidates. DICI is calculated as the ratio between the viability values obtained in drug-treated liver cells in the presence and absence of bile acids. The present in vitro study was set up to investigate the applicability of DICI in a novel high-throughput and large sample setting. Furthermore, the improvement of the predictivity of the DICI by introduction of advanced modeling was explored. Fifty-eight well-documented drugs were selected and categorized as drugs inducing cDILI, non-cholestatic DILI (ncDILI), and not inducing DILI (non-DILI). Cultures of human hepatoma HepaRG cells in 3D spheroid configuration were exposed to 9 half-log concentrations of each drug for 1, 3 and 7 days in the absence or presence of a concentrated mixture of human bile acids. The highest concentration of each drug was based on solubility and the maximum concentrations in human plasma (total Cmax). DICI values were computed for all drugs and time points. In addition, the area under the curve ratio and the occurrence of a trend in the cytotoxicity profiles were included as modeling descriptors. As such, 3 time-related scenarios were considered upon modeling, while categories were modeled on a nominal or an ordinal scale. Applying DICI with a cut-off value of 0.8 resulted in a high sensitivity for the cDILI class, but in turn, a low sensitivity for the non- DILI class. From the 28 predictive models generated, the best performing models integrated all descriptors and the ordinal scale for either the 7-day time point from a 3-time-point model or the 3-day time point. While these models were unable to accurately identify ncDILI drugs, the 7-day time point identified 84 % of the cDILI drugs and the 3-day time point correctly identified 94 % of non-DILI drugs. Based on the obtained results, it can be concluded that the reported DICI modeling provides an optimized approach that could be applied in an integrated DILI testing strategy</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"514 ","pages":"Article 154119"},"PeriodicalIF":4.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664554","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":"Thallium induces metallothionein gene expression in Huh-7 human hepatoma cells","authors":"Toshihiko Aki,&nbsp;Takeshi Funakoshi,&nbsp;Kana Unuma","doi":"10.1016/j.tox.2025.154121","DOIUrl":"10.1016/j.tox.2025.154121","url":null,"abstract":"<div><div>Thallium (Tl) is one of the most toxic heavy metals and is found ubiquitously in the earth’s crust. To investigate the cellular responses to and against Tl cytotoxicity, we conducted DNA microarray analysis using three human cell lines of different origins: SH-SY5Y (neuroblast-derived), HEK293T (embryonic kidney-derived), and Huh-7 (hepatoma-derived) cells. All of the ten genes that showed the highest inductions in Huh-7 cells treated with 60 µM Tl₂SO₄ for 72 hours are metallothionein (MT) genes. The induction of the MT genes appears specific to Huh-7 cells; increases of 50–140-fold in the ten MT genes were observed in Huh-7 cells, while the increases were less than 4-fold in HEK293T and SH-SY5Y cells by microarray analysis. Investigation of the pathway responsible for Tl₂SO₄-induced MT expression in Huh-7 cells revealed that the RNA interference-mediated forced downregulation of MTF1 transcription factor resulted in the suppression of Tl₂SO₄-induced MT gene expressions, but not Tl₂SO₄-induced cell death, suggesting that MTF1-mediated MT gene expression is insufficient to protect Huh-7 cells against death by Tl₂SO₄. In contrast, the knockdown of nrf1 worsened Tl₂SO₄-induced cell death without suppressing MT gene expressions. These results indicate that MT gene induction in response to Tl₂SO₄ is mediated at least in part by MTF1 in Huh-7 cells. Nevertheless, MT gene induction through MTF1 seems insufficient to prevent the cell death caused by Tl₂SO₄. Nrf1 appears to be involved in protection against Tl₂SO₄ toxicity through mechanisms other than MT gene induction.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"514 ","pages":"Article 154121"},"PeriodicalIF":4.8,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143642961","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":"Subacute exposure of male adolescent rats to 2,2′,5,5′-tetrachlorobiphenyl-4-ol via a polymeric implant causes gene expression changes in the brain and metabolomic disruption in serum","authors":"Hui Wang ,&nbsp;Amanda J. Bullert ,&nbsp;Morgan J. Linahon ,&nbsp;Michael E. Dailey ,&nbsp;Jonathan A. Doorn ,&nbsp;Aloysius J. Klingelhutz ,&nbsp;James A. Ankrum ,&nbsp;Hans-Joachim Lehmler","doi":"10.1016/j.tox.2025.154120","DOIUrl":"10.1016/j.tox.2025.154120","url":null,"abstract":"<div><div>Polychlorinated biphenyls (PCBs) remain an environmental health concern due to their persistence and ongoing release from legacy and emerging sources. 2,2′,5,5′-Tetrachlorobiphenyl (PCB52), a PCB congener frequently detected in the environment and human blood, is oxidized to 2,2′,5,5′-tetrachlorobiphenyl-4-ol (4−52). The neurotoxicity of this hydroxylated (OH-PCB) metabolite remains poorly characterized. In this study, we exposed 4-week-old male Sprague Dawley rats to 4–52 via a polymeric implant drug delivery system grafted in the subcutaneous cavity at 4–52 concentrations of 0 %, 1 %, 5 %, and 10 % in the implant (w/w) for 28 days. Metabolomic analyses were performed in the serum. RNA sequencing, immunofluorescence, and dopamine (DA) measurement with electrochemical detection were used to characterize the effects of 4–52 on the striatum and cerebellum, brain regions implicated in PCB neurotoxicity. Serum metabolomic analysis revealed disruptions in the \"arginine biosynthesis\" pathway following 4–52 exposure. Exposure to 4–52 caused moderate transcriptomic changes in pathways related to \"oxidative phosphorylation\" and \"neuroactive ligand-receptor interactions.\" Immunofluorescence showed no significant alterations in microglial, astrocytic, or apoptotic biomarkers. In the medium dose group, the levels of the DA metabolite DOPAL (3,4-dihydroxyphenylacetaldehyde) were significantly reduced in the striatum. Subsequent multi-omics network analysis identified interactions among OH-PCBs, endogenous metabolites, and the transcriptome. For example, levels of glutamic acid, aspartic acid, choline, and glycerophosphocholine negatively correlated with 4–52 in the striatum. Expression levels of heat shock protein (HSP) family genes, <em>Hsp90b1</em>, <em>Hspa8</em>, and <em>Hspa5</em>, positively correlated with serum metabolites, including proline, 1-methylguanidine, and methionine sulfoxide. These findings identify novel biomarkers and targets of 4–52-induced neurotoxicity.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"514 ","pages":"Article 154120"},"PeriodicalIF":4.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143650850","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":"Peritubular myoid cells of the testis produce monocyte chemotactic protein 1 upon direct exposure to Mono-(2-Ethylhexyl) phthalate through the IL-1 signaling pathway","authors":"Narayan Acharya,&nbsp;John H. Richburg","doi":"10.1016/j.tox.2025.154118","DOIUrl":"10.1016/j.tox.2025.154118","url":null,"abstract":"<div><div>Mono-(2-ethylhexyl) phthalate (MEHP) is a metabolite of the diester parent compound Di(2-ethylhexyl) phthalate (DEHP), a widespread environmental toxicant known for its harmful effects on Sertoli cells and the subsequent loss of germ cells through apoptosis in postnatal animals. Peritubular myoid cells (PTMCs) produce various signaling factors, including the chemokine monocyte chemotactic protein 1 (MCP-1); however, the MEHP exposure-induced BTB disruption followed by MCP-1 secretion by PTMCs, the recruitment, and activation of macrophages as well as molecular mechanisms that initiate the secretion in the testis has yet to be closely examined. In this study, we demonstrate for the first time that PTMCs generate MCP-1 via the interleukin-1 signaling pathway upon MEHP exposure. Primary PTMCs isolated from the testis of peripubertal rats were cultured and exposed to 100 μM and 200 µM MEHP. Total RNA was used for bulk RNA sequencing, qRT-PCR, and protein lysates for proteomic analysis. Testis and their interstitial fluid (IF) were obtained from MEHP-exposed animals to evaluate the levels of pro-inflammatory cytokines and chemokines in IF through a multiplex assay and in tissue sections through immunofluorescence studies. The RNA sequencing data show significant enrichment of the interleukin-1 signaling pathway after MEHP (200 µM) exposure for 48 hours. This finding is further supported by the qRT-PCR results for select genes associated with the IL-1 signaling pathway, highlighting the crucial role of this pathway in the response of PTMCs to MEHP exposure. In summary, MEHP exposure stimulates MCP-1 production by PTMCs, and mechanistically, the IL-1 signal transduction pathway governs this response. <strong>Keywords</strong>: MCP-1, PTMCs, Rats, Testis, Chemokine, IL-1 signaling</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"514 ","pages":"Article 154118"},"PeriodicalIF":4.8,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634652","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":"Bisphenol S promotes clear cell renal cell carcinoma progression by modulating the WNT5A-dependent EMT pathway","authors":"Hua Zhang ,&nbsp;Fei Lin ,&nbsp;Bo-Han Lin ,&nbsp;Xiong-Lin Sun ,&nbsp;Qing-Shui Zheng ,&nbsp;Rui Gao ,&nbsp;Yong Wei ,&nbsp;Shao-Hao Chen ,&nbsp;Xue-Yi Xue","doi":"10.1016/j.tox.2025.154117","DOIUrl":"10.1016/j.tox.2025.154117","url":null,"abstract":"<div><div>Bisphenol S (BPS) is widely used in the production of food containers and children's toys and is known to have endocrine-disrupting effects linked to various cancers; however, its role in renal cell carcinoma (RCC) development remains unclear. This study investigates the mechanisms by which BPS may promote RCC progression. The effects of BPS on proliferation and migration were evaluated in HK-2 and 786-O cells using CCK-8, scratch, and Transwell assays. A LASSO regression model and functional analysis were employed to identify candidate genes involved in BPS-related renal cancer progression and to construct a prognostic model, which was validated using Kaplan-Meier and ROC curves. Additionally, the impact of BPS on epithelial-mesenchymal transition (EMT)-related markers was examined. Results showed that BPS did not significantly affect the proliferation of HK-2 and 786-O cells at concentrations of 0–10 μM but significantly enhanced cell migration and invasion, inducing EMT. The LASSO model identified nine key genes associated with BPS-related renal cancer progression, with WNT5A expression positively correlated with BPS concentration. Knockdown of WNT5A significantly inhibited BPS-induced migration of HK-2 and 786-O cells and disrupted the EMT process. These findings demonstrate that BPS promotes HK-2 and 786-O cell migration through the WNT5A-dependent EMT pathway, and inhibition of WNT5A expression can suppress this process. This study provides novel insights into the role of BPS in renal cancer progression and highlights potential therapeutic targets for RCC.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"514 ","pages":"Article 154117"},"PeriodicalIF":4.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630818","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":"Nonclinical safety and biodistribution evaluation of HC009 mRNA vaccine against COVID-19 in rat","authors":"Juan Liu,&nbsp;Xicheng Chen,&nbsp;Chuanqian Chen,&nbsp;Jie Wu,&nbsp;Fengyang Xie,&nbsp;Jing Li,&nbsp;Huafeng Han,&nbsp;Yingying Zhao,&nbsp;Yongsheng Yang","doi":"10.1016/j.tox.2025.154107","DOIUrl":"10.1016/j.tox.2025.154107","url":null,"abstract":"<div><div>mRNA-based technology has been evaluated in clinical trials for rapid control and prevention of emergencies and diseases. HC009, a mRNA vaccine encoding the full-length SARS-CoV-2 spike protein delivered via the QTsome platform, was tested in rats for immunogenicity, toxicity, and biodistribution. For immunogenicity and toxicity, rats received three intramuscular injections of HC009 at 3-week intervals followed by a 4-week observation period. In the biodistribution study, rats received a single intramuscular injection, with mRNA levels measured in organs at various time points. Results showed that HC009 elicited effective, long-lasting humoral immunity and Th1-biased cellular responses. The mRNA primarily localized to the injection site and spleen, with no observed vaccine-related toxicological reactions. These findings support HC009’s potential for inducing an effective immune response with a favorable safety profile, warranting further clinical investigation.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"514 ","pages":"Article 154107"},"PeriodicalIF":4.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597830","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":"Assessment of toxicity associated with inhalation of potentially toxic elements present in combustible tobacco products: cigars, pipe tobacco, bidis and cigarettes – An evaluation of risk assessment issues","authors":"Paweł Hać ,&nbsp;Satoki Okabayashi ,&nbsp;Motohiro Tsuboi ,&nbsp;Bartłomiej Michał Cieślik ,&nbsp;Piotr Konieczka","doi":"10.1016/j.tox.2025.154092","DOIUrl":"10.1016/j.tox.2025.154092","url":null,"abstract":"<div><div>Smoking-related diseases represent a substantial global health challenge, particularly given the direct inhalation of smoke into the vulnerable respiratory system. This method of consumption presents a challenge in classifying smoking in terms of exposure to toxins, in comparison to other forms of environmental contamination, such as food or air pollution. Combustible tobacco products (CTPs), including cigars, pipe tobaccos, bidis, and cigarettes, are therefore among the most toxic materials with a wide range of adverse health effects. The majority of studies on toxic elements in CTPs concentrate on cigarettes, with other forms of tobacco receiving comparatively little attention. Furthermore, there is currently no established methodology for estimating consumer exposure to these elements regarding smoke inhalation. The aim of this study was to estimate the exposure of consumers to potentially toxic elements (PTEs) in various CTPs, utilising a model adapted from food chemistry but considering air pollution exposure levels and the distinctive characteristics of smoking. The findings indicate that the inhalation of smoke from less than 0.5 g of tobacco can deliver hazardous doses of elements, such as Ni (noncancer risk) or As (carcinogenic risk). This suggests that inhalation of toxic elements in cigarette smoke significantly contributes to tobacco-related health risks.</div></div><div><h3>Statement of Environmental Implication</h3><div><ul><li><span>1.</span><span><div>The analyzed tobacco and the determined potentially toxic elements themselves are contaminating materials and compounds as they have hazardous effects on the environment and humans.</div></span></li></ul><ul><li><span>2.</span><span><div>The results of the study represent environmentally relevant conditions, as the analysis was made on real tobacco product samples and the calculations were appropriately modelled to estimate actual human exposure conditions.</div></span></li></ul></div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"514 ","pages":"Article 154092"},"PeriodicalIF":4.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587138","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":"NAM-based analysis of contaminant short-term organ toxicity in HepaRG and RPTEC/TERT1 cells","authors":"Kristina Jochum ,&nbsp;Andrea Miccoli ,&nbsp;Cornelia Sommersdorf ,&nbsp;Oliver Poetz ,&nbsp;Albert Braeuning ,&nbsp;Tewes Tralau ,&nbsp;Philip Marx-Stoelting","doi":"10.1016/j.tox.2025.154104","DOIUrl":"10.1016/j.tox.2025.154104","url":null,"abstract":"<div><div>New Approach Methodologies (NAMs), including cell culture and multi-level omics analyses, are promising alternatives to animal testing. To become useable for risk assessment purposes, they have to be applicable for different substance groups. One important group of substances is food contaminants, including synthetic chemicals, such as perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), and natural compounds, such as mycotoxins and pyrrolizidine alkaloids. We tested five known contaminants affecting the liver and/or the kidney – PFOS, PFOA, Aflatoxin B₁ (AB₁), lasiocarpine (Las), and cadmium chloride – using HepaRG and RPTEC/TERT1 cells at non-cytotoxic concentrations for 36 and 72 h. Our NAM-based testing protocol included marker protein analysis for cellular functions and targeted transcriptomics followed by bioinformatics pathway analysis. The effects observed were compared with established <em>in vivo</em> results. Protein analysis indicated various affected pathways in HepaRG cells, with generally fewer effects in RPTEC/TERT1 cells. The strongest transcriptional impact was noted for Las in HepaRG cells. This study demonstrated the test protocol's applicability across different substances, revealing significant differences between HepaRG and RPTEC/TERT1 cell lines. RPTEC/TERT1 cells, while expressing renal-specific CYP enzymes, were less suitable for detecting effects of substances requiring hepatic metabolic activation, like Las and AB₁. Our data supports the concept of specific pathway toxicity, with pathway analysis enabling the prediction of effects based on mechanism rather than target organ. Employing multiple omics techniques provided comprehensive insights into various compound effects, including steatosis, reactive oxygen species production and DNA damage, highlighting the potential of an extended omics approach for advancing toxicological assessments.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"514 ","pages":"Article 154104"},"PeriodicalIF":4.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587140","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":"H3K18 lactylation-mediated SIX1 upregulation contributes to silica-induced epithelial-mesenchymal transition in airway epithelial cells","authors":"Songtao Liu ,&nbsp;Yiting He ,&nbsp;Linling Jin ,&nbsp;Shuangshuang Shi ,&nbsp;Jiayi Zhang ,&nbsp;Weiping Xie ,&nbsp;Mingxia Yang ,&nbsp;Qun Zhang ,&nbsp;Hui Kong","doi":"10.1016/j.tox.2025.154109","DOIUrl":"10.1016/j.tox.2025.154109","url":null,"abstract":"<div><div>Silica exposure-induced airway epithelial-mesenchymal transition (EMT) is a critical pathological process in pulmonary fibrosis. This study investigated the role of NLRP3 inflammasome, glycolysis, and histone lactylation in silica-induced EMT of human bronchial epithelial cells (16HBE). Silica exposure activated NLRP3 inflammasome, enhanced glycolysis and H3K18 lactylation, as well as induced EMT in 16HBE cells. Selective inhibition of NLRP3 inflammasome with MCC950, blockade of the interleukin 1 (IL-1) receptor with AF12198, or suppression of lactate production with oxamate effectively reduced glycolysis-mediated histone lactylation and mitigated silica-induced EMT. Moreover, silica-induced upregulation of PFKFB3, a key enzyme of glycolysis, was significantly mitigated by MCC950 or AF12198. Cut&amp;Tag analysis revealed silica treatment led to H3K18 lactylation enrichment at transcription start sites (TSS), particularly within the promoter region of the sine oculis homeobox 1 (SIX1), which enhanced transcription of SIX1, a key transcription factor involved in EMT. Consistently, inhibition of histone lactylation by the histone acetyltransferase P300 inhibitor A-485 suppressed silica-induced SIX1 expression and EMT. These findings indicate that silica activates NLRP3 inflammasome and promotes interleukin 1β (IL-1β) production, thereafter enhancing PFKFB3-mediated glycolysis by IL-1 receptor. Lactate accumulation by glycolysis enhances H3K18 lactylation at the TSS facilitating expression of SIX1. Together, this inflammation-glycolysis-lactylation cascade involved in EMT provides new insights into the molecular mechanisms underlying silica-induced pulmonary fibrosis.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"514 ","pages":"Article 154109"},"PeriodicalIF":4.8,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143574064","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":"Enhancing DILI toxicity prediction through integrated graph attention (GATNN) and dense neural networks (DNN)","authors":"Agung Surya Wibowo ,&nbsp;Kil To Chong ,&nbsp;Hilal Tayara","doi":"10.1016/j.tox.2025.154108","DOIUrl":"10.1016/j.tox.2025.154108","url":null,"abstract":"<div><div>Drug-induced liver injury (DILI) toxicity is a condition when drugs have a destructive effect on the liver organ. The prediction of this toxicity becomes crucial in the drug development process to guarantee that drugs are safe from toxicity. Assessment is usually carried out in the conventional laboratory, which causes a high cost in materials and time. To help solve the problem, computational technology is used to predict DILI toxicity in compounds and drugs. Many researchers have developed the model by using various molecular datasets. The Simplified molecular input line entry system (SMILES) code data was used to represent drugs or compounds. In this work, we proposed the modified model using the reliable dataset from the previous work. We reproduced the best previous model and combined it with the graph attention neural network. After running the proposed model, the performances outperformed almost all performance metrics of the previous model by 75.14 % precision, 85.2 % sensitivity, 39.9 % MCC value, 75.7 % AUC value and 82.5 % F1 score. All the source code used in the experiment can be accessed freely at this link: <span><span>https://github.com/asw1982/GATNN</span><svg><path></path></svg></span> DNN DILI Toxicity.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"514 ","pages":"Article 154108"},"PeriodicalIF":4.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143543663","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}