Toxicological Sciences最新文献

{"title":"Differential hepatic activation of mouse and human peroxisome proliferator-activated receptor-α by perfluorohexane sulfonate.","authors":"Yahya Khan, Annalee M Schmidt, Kyle J Oldro, Xiaoyang Zhu, Angelina R Kramer, Sarah R Hamilton, Katherine O Bleil, Ryan M Krisko, Jeremiah D Zitzow, Yuan Tian, Shu-Ching Chang, Vonn Walter, Samuel M Cohen, Frank J Gonzalez, Andrew D Patterson, Jeffrey M Peters","doi":"10.1093/toxsci/kfaf026","DOIUrl":"10.1093/toxsci/kfaf026","url":null,"abstract":"<p><p>Exposure of perfluorohexane sulfonate (PFHxS) is associated with hepatomegaly and accumulation of lipids that may be mediated by nuclear receptors like peroxisome proliferator-activated receptor-α (PPARα), constitutive androstane receptor (CAR), or pregnane X receptor (PXR). This study tested the hypotheses that: (i) PFHxS causes changes in liver by activating PPARα, CAR, or PXR, and (ii) there is a species difference in PPARα activity by PFHxS. Wild-type, Ppara-null, and PPARA-humanized mice were fed either a control diet, or one containing 2.2 mg PFHxS/kg diet or 25.8 mg PFHxS/kg diet for either 7 or 28 days, and target gene expression was examined. Relative liver weights were similar after 7 days with either 2.2 or 25.8 mg PFHxS/kg dietary exposure compared with controls. Relative liver weights were higher after treatment for 28 days in all 3 genotypes fed 25.8 mg PFHxS/kg diet compared with controls. The concentration of PFHxS was dose-dependently increased in serum and liver compared with controls. PFHxS exposure of 2.2 and 25.8 mg PFHxS/kg diet caused an increase in expression of PPARα target genes in wild-type mice and this effect was not observed in similarly treated Ppara-null mice or PPARA-humanized mice. Administration of PFHxS caused increased expression of the CAR target gene Cyp2b10 in all 3 genotypes at both timepoints, and the PXR target gene Cyp3a11 in all 3 genotypes after 28 days. Exposure to PFHxS can increase liver weight due in part to the activation of mouse, but not human, PPARα. Activation of CAR and PXR by PFHxS also likely contributes to the observed hepatomegaly in all 3 genotypes.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"47-52"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12225666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143558147","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":"Structure-specific variation in per- and polyfluoroalkyl substances toxicity among genetically diverse Caenorhabditis elegans strains.","authors":"Tess C Leuthner, Sharon Zhang, Brendan F Kohrn, Heather M Stapleton, L Ryan Baugh","doi":"10.1093/toxsci/kfaf014","DOIUrl":"10.1093/toxsci/kfaf014","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFAS) are in 99% of humans and are associated with a range of adverse health outcomes. It is impossible to test the >14,500 structurally diverse \"forever chemicals\" for safety, therefore improved assays to quantify structure-activity relationships are needed. Here, we determined the toxicity of a structurally distinct set of PFAS in 12 genetically diverse strains of the genetic model system Caenorhabditis elegans. Dose-response curves for perfluoroalkyl carboxylic acids (PFNA, PFOA, PFPeA, and PFBA), perfluoroalkyl sulfonic acids (PFOS and PFBS), perfluoroalkyl sulfonamides (PFOSA and PFBSA), fluoroether carboxylic acids (GenX and PFMOAA), fluoroether sulfonic acid (PFEESA), and fluorotelomers (6:2 FTCA and 6:2 FTS) were determined in the C. elegans laboratory reference strain, N2, and 11 genetically diverse wild strains. Body length was quantified after 48 h of developmental exposure of L1 arrest-synchronized larvae to estimate effective concentration values (EC50). PFAS toxicity ranged by 3 orders of magnitude. Long-chain PFAS had greater toxicity than short-chain. Fluorosulfonamides were more toxic than carboxylic and sulfonic acids. Genetic variation resulted in variation in susceptibility among 12 strains to almost all chemicals. Different C. elegans strains varied in susceptibility to different PFAS, which suggests distinct molecular responses to specific structural attributes. Harnessing the natural genetic diversity of C. elegans and the structural complexity of PFAS is a powerful approach that can be used to investigate mechanisms of toxicity which may identify potentially susceptible individuals or populations and predict toxicity of untested PFAS to inform regulatory policies and improve human and environmental health.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"205-219"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12038255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477041","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":"Deciphering per- and polyfluoroalkyl substances mode of action: comparative gene expression analysis in human liver spheroids.","authors":"Andrea Rowan-Carroll, Matthew J Meier, Carole L Yauk, Andrew Williams, Karen Leingartner, Lauren Bradford, Luigi Lorusso, Ella Atlas","doi":"10.1093/toxsci/kfaf023","DOIUrl":"10.1093/toxsci/kfaf023","url":null,"abstract":"<p><p>Understanding the mechanisms by which environmental chemicals cause toxicity is necessary for effective human health risk assessment. High-throughput transcriptomics (HTTr) can be used to inform risk assessment on toxicological mechanisms, hazards, and potencies. We applied HTTr to elucidate the molecular mechanisms by which per- and polyfluoroalkyl substances (PFAS) cause liver perturbations. We contrasted transcriptomic profiles of PFOA, PFBS, PFOS, and PFDS against transcriptomic profiles from established liver-toxic and non-toxic reference compounds, alongside peroxisome proliferator-activated receptors (PPARs) agonists. Our analysis was conducted on metabolically competent 3-D human liver spheroids produced from primary cells from 10 donors. Pathway analysis showed that PFOS and PFDS perturb many of the same pathways as the known liver-toxic compounds in the spheroids, and that the cholesterol biosynthesis pathways are significantly affected by exposure to these compounds. PFOA alters lipid metabolism-related pathways but its expression profile does not closely match reference compounds. PFBS upregulates many degradation-related pathways and targets many of the same pathways as the PPAR agonists and acetaminophen. Our transcriptional analysis does not support the claim that these PFAS are DNA-damaging in this model. A multidimensional scaling (MDS) analysis revealed that PFOS, PFOA, and PFDS cluster together in the same multidimensional space as liver-damaging compounds, whereas PFBS clusters more closely with the non-liver-damaging compounds. Benchmark concentration-response modeling predicts that all the PFAS are bioactive in the liver. Overall, our results show that these PFAS produce unique transcriptional changes but also alter pathways associated with established liver-toxic chemicals in this liver spheroid model.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"124-142"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12279298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143558142","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":"Evaluation of phenotypic and behavioral toxicity of micro- and nano-plastic polystyrene particles in larval zebrafish (Danio rerio).","authors":"Bailey Levesque, Sabahudin Hrapovic, Fabrice Berrué, Anja Vogt, Lee D Ellis, Ludovic Hermabessiere","doi":"10.1093/toxsci/kfaf015","DOIUrl":"10.1093/toxsci/kfaf015","url":null,"abstract":"<p><p>Plastic particles have been found in all environments and it is necessary to understand the risks these particles pose in, and to, the environment. The objectives of this work were to understand the toxic effects of varying size and concentration of polystyrene (PS) micro- and nano-plastics in zebrafish embryos and their fate within the larvae. In this work, larval zebrafish (Danio rerio) were exposed to six sizes (0.05, 0.25, 0.53, 2.1, 6.02, and 10.2 µm diameter) and concentrations (0.0005 to 0.2 µg/µL) of PS micro/nanoplastics particles. The zebrafish embryo toxicity (ZET) and the general and behavioral toxicity (GBT) assays were used to determine particle toxicity in embryos. Behavioral analysis was performed and micro/nanoplastics uptake and organ distribution were assessed. Phenotypic and behavioral toxicity was observed in all exposures with the exception of 0.25 µm particle-exposed larvae. Significant phenotypic toxicity was seen at the highest tested exposure concentration, with some sizes showing potential recovery as time increased in the assay. Behavioral analysis demonstrated a decrease in baseline activity across all micro- and nano-plastic sizes. Significant increases in light-dark responses were recorded in ZET assays of smaller-sized particles and no significant effects were observed at larger sizes. Significant decreases in this response were reported in the GBT assays of all tested sizes with the exception of the 0.05-µm particles. These assays demonstrate the general, developmental, and neurotoxicity of micro/nanoplastics to a model organism, which can be used to infer individual and population-level effects of exposure.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"154-165"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12038248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374580","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":"Transcriptomic analysis identifies muscle-specific mitochondrial and vesicular transport genes as methylmercury toxicity targets in a Drosophila model of congenital Minamata disease.","authors":"Catherine R Beamish, Jennifer Becker, Lok Ming Tam, Tanzy Love, Matthew D Rand","doi":"10.1093/toxsci/kfaf018","DOIUrl":"10.1093/toxsci/kfaf018","url":null,"abstract":"<p><p>Prenatal methylmercury (MeHg) exposure presents a heightened concern in early human development, as has been exemplified in historic cases of congenital minimata disease (CMD). Children who experience CMD characteristically present with various degrees of cognitive and motor symptoms and signs, much like cerebral palsy. MeHg has thus been characterized as a neurotoxicant, where motor deficits are ascribed to central nervous system targets. Skeletal muscle as a post-synaptic MeHg target and contributor to the etiology of CMD has garnered far less attention. Prior studies using Drosophila to model CMD revealed that developmental exposure of MeHg in the larval/pupal stages can elicit graded and latent dose responses affecting adult flight behavior at lower doses (0.4-2.5 ppm in food) and eclosion (emergence from the pupa case) at higher doses (>2.5 ppm in food). The latter phenotype is accompanied by dysmorphogenesis of skeletal muscles. Here, we investigate respective roles for muscle and neural targets in MeHg toxicity. Using RNA-seq analysis, we find that developmental MeHg exposure produces 10 times as many differentially expressed transcripts in indirect flight muscle compared to the ventral nerve cord. Among known MeHg response genes, Nrf2 antioxidant response pathway genes showed muscle-specific MeHg-induced expression changes. Within the muscle transcriptome, the most enriched and significant Gene Ontology terms identified genes required for mitochondrial ribosomal translation at the pupa stage and mitochondrial function (respiratory chain complex I) and vesicle trafficking (ESCRT III) pathways in adults, all showing decreased expression with MeHg exposure. By using an intact, whole-animal developmental model, we identify preferential candidates to evaluate a novel role for muscle-specific mitochondria and intercellular vesicular communication mechanisms as targets in MeHg toxicity and the etiology of CMD.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"106-123"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12038250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143415295","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":"Lessons learned from evaluating defined chemical mixtures in a high-throughput estrogen receptor assay system.","authors":"Fred Parham, Kristin M Eccles, Cynthia V Rider, Srilatha Sakamuru, Menghang Xia, Ruili Huang, Raymond R Tice, Gregg E Dinse, Michael J DeVito","doi":"10.1093/toxsci/kfaf020","DOIUrl":"10.1093/toxsci/kfaf020","url":null,"abstract":"<p><p>In this article, we provide a proof of concept evaluating the utility of the U.S. Tox21 high-throughput screening approach to assess the hazard of chemical mixtures using 2 estrogen receptor (ER) assays. A subset of chemicals identified in Phase I of the Tox21 program as active in the ER agonist assay were used to design mixtures for testing in Phase II. Individual chemicals and mixtures were evaluated in 2 cell-based ER alpha (ERα) activation assays: One incorporating a transfected ligand-binding domain in an ERα β-lactamase reporter cell line (ER-bla) and the full-length endogenous receptor in the MCF7 cell line with a luciferase reporter gene (ER-luc). Concentration-response data from individual chemicals were used to predict the joint effect based on mixtures modeling methods and were compared with observed mixtures data to assess model fit. The models tended to overpredict mixture responses in the ER-bla assay, whereas predictions were closer to observed responses in the ER-luc assay, indicating that a full-length endogenous ER is a preferred model for high-throughput mixture analysis. Lessons learned from this research include the importance of analyzing the individual chemicals used for predictions and the mixtures in the same experimental paradigm to minimize variation, developing methods for imputing missing values from incomplete concentration-response curves, and establishing criteria to determine when inactive chemicals should be omitted from mixture predictions.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"191-204"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12038247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143459410","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":"Of Hammers and Nails: Understanding Academic Challenges with \"Context of Use\" and \"Fit for Purpose\".","authors":"Ivan Rusyn","doi":"10.1093/toxsci/kfaf058","DOIUrl":"10.1093/toxsci/kfaf058","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050062","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":"Single-cell RNA-seq reveals that granulosa cells are a target of phthalate toxicity in the ovary.","authors":"Erik Mattson, Genoa R Warner","doi":"10.1093/toxsci/kfaf001","DOIUrl":"10.1093/toxsci/kfaf001","url":null,"abstract":"<p><p>Phthalates are known endocrine-disrupting chemicals and ovarian toxicants that are used widely in consumer products. Phthalates have been shown to exert ovarian toxicity on multiple endpoints, altering transcription of genes responsible for normal ovarian function. However, the molecular mechanisms by which phthalates act on the ovary are not well understood. In this study, we hypothesized that phthalates specifically target granulosa cells within the ovarian follicle. To test our hypothesis, we cultured whole mouse antral follicles for 96 h in the presence of vehicle or 10 µg/ml of a phthalate metabolite mixture. At the end of the culture period, follicles were dissociated into single-cell suspensions and subjected to single-cell RNA-sequencing. We used markers from published studies to identify cell-type clusters, the largest of which were granulosa and theca/stroma cells. We further identified subpopulations of granulosa, theca, and stromal cells and analyzed differentially expressed genes between the phthalate treatment and control. Granulosa cells, specifically mural granulosa cells, had the most differentially expressed genes. Pathway analysis of differentially expressed genes from the overall granulosa cell cluster revealed disruption of cell cycle and mitosis, whereas pathway analysis of the mural granulosa cell subcluster identified terms related to translation, ribosome, and endoplasmic reticulum. Our findings suggest that phthalates have both broad impacts on cell types and specific impacts on cellular subtypes, emphasizing the complexity of phthalate toxicity and highlighting how bulk sequencing can mask effects on vulnerable cell types.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"169-180"},"PeriodicalIF":3.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11939077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928321","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":"Quantifying liver-toxic responses from dose-dependent chemical exposures using a rat genome-scale metabolic model.","authors":"Venkat R Pannala, Archana Hari, Mohamed Diwan M AbdulHameed, Michele R Balik-Meisner, Deepak Mav, Dhiral P Phadke, Elizabeth H Scholl, Ruchir R Shah, Scott S Auerbach, Anders Wallqvist","doi":"10.1093/toxsci/kfaf005","DOIUrl":"10.1093/toxsci/kfaf005","url":null,"abstract":"<p><p>Because the liver plays a vital role in the clearance of exogenous chemical compounds, it is susceptible to chemical-induced toxicity. Animal-based testing is routinely used to assess the hepatotoxic potential of chemicals. Although large-scale high-throughput sequencing data can indicate the genes affected by chemical exposures, we need system-level approaches to interpret these changes. To this end, we developed an updated rat genome-scale metabolic model to integrate large-scale transcriptomics data and utilized a chemical structure similarity-based ToxProfiler tool to identify chemicals that bind to specific toxicity targets to understand the mechanisms of toxicity. We used high-throughput transcriptomics data from a 5-day in vivo study where rats were exposed to different non-toxic and hepatotoxic chemicals at increasing concentrations and investigated how liver metabolism was differentially altered between the non-toxic and hepatotoxic chemical exposures. Our analysis indicated that the genes identified via toxicity target analysis and those mapped to the metabolic model showed a distinct gene expression pattern, with the majority showing upregulation for hepatotoxicants compared with non-toxic chemicals. Similarly, when we mapped the metabolic genes at the pathway level, we identified several pathways in carbohydrate, amino acid, and lipid metabolism that were significantly upregulated for hepatotoxic chemicals. Furthermore, using our system-level integration of gene expression data with the rat metabolic model, we could differentiate metabolites in these pathways that were systematically elevated or suppressed due to hepatotoxic versus non-toxic chemicals. Thus, using our combined approach, we were able to identify a set of potential gene signatures that clearly differentiated liver toxic responses from non-toxic chemicals, which helped us identify potential metabolic pathways and metabolites that are systematically associated with the toxicant exposure.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"154-168"},"PeriodicalIF":3.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11939075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012097","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":"TAK-994 mechanistic investigation into drug-induced liver injury.","authors":"Tadahiro Shinozawa, Kazumasa Miyamoto, Kevin S Baker, Samantha C Faber, Ramon Flores, Jack Uetrecht, Christian von Hehn, Tomoya Yukawa, Kimio Tohyama, Harisha Kadali, Marcin von Grotthuss, Yusuke Sudo, Erin N Smith, Dorothée Diogo, Andy Z X Zhu, Yvonne Dragan, Gvido Cebers, Matthew P Wagoner","doi":"10.1093/toxsci/kfaf003","DOIUrl":"10.1093/toxsci/kfaf003","url":null,"abstract":"<p><p>The frequency of drug-induced liver injury (DILI) in clinical trials remains a challenge for drug developers despite advances in human hepatotoxicity models and improvements in reducing liver-related attrition in preclinical species. TAK-994, an oral orexin receptor 2 agonist, was withdrawn from phase II clinical trials due to the appearance of severe DILI. Here, we investigate the likely mechanism of TAK-994 DILI in hepatic cell culture systems examined cytotoxicity, mitochondrial toxicity, impact on drug transporter proteins, and covalent binding. Hepatic liabilities were absent in rat and nonhuman primate safety studies, however, murine studies initiated during clinical trials revealed hepatic single-cell necrosis following cytochrome P450 induction at clinically relevant doses. Hepatic cell culture experiments uncovered wide margins to known mechanisms of intrinsic DILI, including cytotoxicity (>100× Cmax/IC50), mitochondrial toxicity (>100× Cmax/IC50), and bile salt efflux pump inhibition (>20× Css, avg/IC50). A potential covalent binding liability was uncovered with TAK-994 following hepatic metabolism consistent with idiosyncratic DILI and the delayed-onset clinical toxicity. Although idiosyncratic DILI is challenging to detect preclinically, reductions in total daily dose and covalent binding can reduce the covalent body binding burden and, subsequently, the clinical incidence of idiosyncratic DILI.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"143-153"},"PeriodicalIF":3.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11939078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955678","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}