Toxicological Sciences最新文献

{"title":"Integrating mechanistic data to contextualize in vivo apical observations using the developmental neurotoxicity in vitro battery.","authors":"Brianna L Jackson, Yaoxing Wu, Kian Afsharian, Christopher Schlosser, Angela H Hofstra, Laura M Minnema, Jördis Klose, Ellen Fritsche, Manasvinee Mayil Vahanan, Timothy J Shafer, Kelly E Carstens, Agnes L Karmaus","doi":"10.1093/toxsci/kfag089","DOIUrl":"10.1093/toxsci/kfag089","url":null,"abstract":"<p><p>Regulatory toxicity studies traditionally rely on in vivo apical endpoints for hazard characterization and risk assessment; when available, relevant and reliable in vitro assays are anticipated to aid this interpretation. Developmental neurotoxicity (DNT)-related parameters such as brain morphometry can be especially challenging to interpret, based on technical challenges such as sample preparation artifacts. This study employed the Developmental Neurotoxicity In Vitro Battery (DNT-IVB), designed to provide functional insights on key neurodevelopmental processes (KNDPs), to provide context for equivocal brain morphometry effects observed in a legacy in vivo DNT study conducted with acibenzolar-S-methyl (ASM), a plant host defense inducer. ASM and its major mammalian metabolite, acibenzolar acid (AA), were tested in all 17 in vitro assays comprised within the current iteration of the DNT-IVB. In vitro testing concentrations were derived to match the existing in vivo DNT study by applying physiologically based pharmacokinetic (PBPK) modeling with adjustment for rat versus human toxicokinetics. All concentration-response DNT-IVB assay data were analyzed using the US EPA ToxCast Pipeline. ASM showed no effect on any KNDP in vitro. AA was active only in the rat network formation assay with low potency AC50 ranges of 96.1 to 150 µM that modeling shows will not be achieved in vivo at doses where the apical effects in question were observed. This case study demonstrates the potential of the DNT-IVB to be used as a tool to assess equivocal findings from in vivo DNT studies and contribute to a weight of evidence to support conclusions on chemical-mediated DNT.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13489716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148607709","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":"Hepatic responses as potential biomarkers of idiosyncratic drug reaction risk.","authors":"Jiamin Liao, Xiaotian Lyu, Kristy Yang, Lucia Chen, Jack Uetrecht","doi":"10.1093/toxsci/kfag087","DOIUrl":"10.1093/toxsci/kfag087","url":null,"abstract":"<p><p>Idiosyncratic drug reactions (IDRs) and, in particular, idiosyncratic drug-induced liver injury (iDILI) represent a significant risk for drug development. There are multiple lines of evidence that such reactions are mediated by the adaptive immune system. The idiosyncratic nature of adaptive immune responses makes it difficult to develop biomarkers to predict the risk that drug candidates will cause such adverse reactions. However, an adaptive immune response requires an innate immune response to activate antigen-presenting cells such as macrophages, and the innate immune response to drugs should not be idiosyncratic. We had previously shown that clozapine and nevirapine produce a marked innate immune response in rodents. We sought to extend these studies to additional drugs that cause IDRs; namely, amodiaquine, carbamazepine, isoniazid, and ximelagatran. Ximelagatran was specifically chosen because, unlike the others, it does not appear to form a reactive metabolite. Amodiaquine and carbamazepine also produced changes associated with an innate immune response, such as an increase in serum corticosterone and GDF-15 and changes in hepatic mRNA for Dusp1, Gadd45b, and Cebpd. These changes resolved within hours. Not surprisingly, ximelagatran did not produce significant changes. However, it was surprising that isoniazid produced few such changes. There is evidence that ximelagatran can directly activate macrophages, and it is plausible that isoniazid can also directly activate macrophages. It is likely that changes in hepatic mRNA consistent with a stress/innate immune response would represents biomarkers of iDILI risk; however, some drugs may directly activate macrophages without the need of factors released from the liver.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13452458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148607559","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":"In vitro characterization of the role of aryl hydrocarbon receptor and bisphenol A on IL-17A regulation in mouse and human CD4+ T cells.","authors":"Lance K Blevins, Robert B Crawford, Norbert E Kaminski","doi":"10.1093/toxsci/kfag101","DOIUrl":"10.1093/toxsci/kfag101","url":null,"abstract":"<p><p>The objective of this investigation was to determine whether direct addition of BPA to cultured primary mouse or human naïve CD4+ T cells promotes IL-17A production and Th17 cell differentiation and to assess the role of aryl hydrocarbon receptor (AHR) in promoting IL-17A regulation. Kinetic studies showed IL-17 concentrations peaked by day 4 post-activation in the mouse and on day 6 in human CD4+ T cells under Th17 polarizing and nonpolarizing conditions. AHR activation in murine CD4+ T cells by TCDD or FICZ promoted IL-17A and IL-22 secretion compared with vehicle controls under non-Th17 polarizing conditions. In contrast, AHR antagonism by CH223191 promoted IL-17 production in human CD4+ T cells while IL-22 secretion was reduced compared with controls. AHR activation by FICZ in human CD4+ T cells decreased IL-17 while increasing IL-22 secretion. Conversely, AHR antagonism in murine CD4+ T cells suppressed IL-17A and IL-22 responses. BPA treatment of CD4+ T cells from either species did not produce a significant increase in IL-17A-positive cells or increased IL-17 secretion, whereas FICZ and CH223191 treatment induced IL-17A increases under nonpolarizing and/or polarizing conditions in CD4+ T cells from mouse and human, respectively. These studies suggest that BPA treatment of mature, naïve CD4+ T cells from either species does not induce IL-17A or IL-22 secretion, whereas AHR activation inversely regulates IL-17A responses between species. These results confirm published results showing CD4+ T cells are refractory to BPA-mediated effects on IL-17, suggesting reported BPA effects in murine CD4+ T cells may be strain-dependent.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13505627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148724087","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":"T-cell chromatin states reflect individual differences in ex vivo cytokine release and cytotoxicity induced by T-cell engager ERY22 in cynomolgus monkeys.","authors":"Yoshika Iwata, Yuta Narushima, Asako Harada, Akihisa Sakamoto, Hisashi Ikegami, Masayuki Mishima, Hiromi Suzuki","doi":"10.1093/toxsci/kfag076","DOIUrl":"10.1093/toxsci/kfag076","url":null,"abstract":"<p><p>T-cell engager therapies, including CD3-bispecific antibodies, have demonstrated potent antitumor activity but frequently cause cytokine release syndrome (CRS). CRS is a systemic inflammatory response characterized by high levels of circulating cytokines and immune-cell hyperactivation, with symptoms ranging from mild features such as fever and fatigue to severe, life-threatening conditions including shock and multiorgan failure. Currently, both prophylactic measures and prompt post-onset treatment are essential for therapy with T-cell engagers. Although CRS mitigation strategies reduce its incidence and severity, marked interindividual variability in CRS remains: Some patients show no symptoms, whereas others develop severe symptoms under identical preventive measures. This study aimed to elucidate the mechanisms underlying the interindividual variability in cytokine release and cytotoxicity following stimulation with a T-cell engager. We used ERY22, a T-cell engager developed as a monkey surrogate of the human therapeutic candidate ERY974, an anti-GPC3/CD3 T-cell engager. ERY22 has been previously reported to induce severe CRS in cynomolgus monkeys following in vivo administration. When PBMCs from 16 cynomolgus monkeys and GPC3-expressing target cells were co-cultured ex vivo with ERY22, there was substantial interindividual variability in cytokine production and cytotoxicity. We hypothesized that epigenetic states in T cells modulate these responses; accordingly, we profiled pretreatment T-cell chromatin accessibility using ATAC-seq. Interindividual variability in cytokine production and cytotoxicity correlated with chromatin accessibility at loci associated with these processes. These findings advance understanding of personalized risk prediction and management of CRS in clinical settings.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148353732","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":"Molecular dosimetry of DNA adducts in mice exposed to ethylene oxide.","authors":"Chih-Wei Liu, Jingya Peng, Jiahao Feng, Haoduo Zhao, Xueying Wang, B Bhaskar Gollapudi, Abby A Li, James S Bus, Kun Lu","doi":"10.1093/toxsci/kfag063","DOIUrl":"10.1093/toxsci/kfag063","url":null,"abstract":"<p><p>Ethylene oxide (EtO) is a highly reactive industrial chemical and known human carcinogen with a mutagenic mode of action (MOA). Its genotoxicity is primarily mediated through alkylation of DNA, forming the mutagenic adduct O6-(2-hydroxyethyl)-2'-deoxyguanosine (O6-HE-dG), albeit in small quantities, and the more abundant but less- or nonmutagenic N7-(2-hydroxyethyl)guanine (N7-HE-G) adduct. However, dose-response relationships of these DNA adducts, particularly at low inhalation exposure levels (< 3 ppm), remain unknown. These data are necessary to inform the biological plausibility of different statistical dose-response models that have been applied to human or animal data used for cancer risk assessment. In this study, B6C3F1 mice were exposed to EtO (0 to 200 ppm) for 6 h/d over 28 consecutive days. DNA adducts in lung, liver, bone marrow, and mammary gland were quantified using highly sensitive mass spectrometry platforms. N7-HE-G was detected in all tissues and exposure groups, showing linear dose-response relationships in the low-dose range (≤ 1 ppm) and increased sharply and exposure-disproportionately in the high-dose range (≥ 50 ppm). Despite high sensitivity, O6-HE-dG was undetectable in any tissue at exposure < 50 ppm, reflecting adduct levels that are below the current quantifiable limit. At higher exposures (≥ 50 ppm), O6-HE-dG exhibited a dose-response pattern of N7-HE-G. Notably, the mammary gland, despite being anatomically distant from the site of inhalation, exhibited the second-highest levels of both adducts at higher doses. This study provides the first reliable quantitative dose-response evidence of DNA adducts in tumor target and nontarget (liver) tissues across a wide range of EtO exposures. The two DNA adducts differ markedly in their abundance, repairability and mutagenic potential and together provide a molecular MOA dose-response framework to provide the biological foundation for informing quantitative cancer risk assessment and genotoxic hazard characterization.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148376962","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":"ToxMet: a web tool for toxicogenomic data analysis using genome-scale metabolic modeling.","authors":"Archana Hari, Zhen Xu, Zachary Smith, John I Hendry, Scott S Auerbach, Mohamed Diwan M AbdulHameed, Valmik Desai, Anders Wallqvist, Venkat R Pannala","doi":"10.1093/toxsci/kfag079","DOIUrl":"10.1093/toxsci/kfag079","url":null,"abstract":"<p><p>Chemical toxicity assessment commonly includes in vivo rat exposure experiments, with transcriptomic measurements collected at various exposure times and chemical doses. The mechanisms underlying chemical-induced toxicity are then inferred by analyzing changes in gene expression. Recently, genome-scale metabolic models (GSMs), which represent the metabolic network of a cell/organism and contain metabolites, reactions, genes, and the relationship between the genes and reactions, have been used to provide a systems-level understanding of gene expression. However, most of the algorithms that integrate gene expression with GSMs require familiarity with MATLAB or Python programming, making them less accessible for users without computational experience. Here, we introduce ToxMet (https://toxmet.bhsai.org), an open-access, user-friendly web application that provides tabular and graph-based network views to visualize the latest rat GSM (iRno v4.2) and predicts chemical-induced metabolic perturbations in rat tissues by integrating toxicogenomic measurements with the rat GSM. ToxMet uses two well-validated computational algorithms, TIMBR and Pheflux, to predict metabolic perturbations and provides the prediction results as interactive and downloadable tables, scatter plots, and network visualizations. As such, the web tool can process a maximum of 10 conditions for a single job, and the results can be used for dose-response studies to monitor organ metabolism at the subsystem level. We evaluated ToxMet's ability to predict toxicity mechanisms by applying it to publicly available toxicogenomic data for two exemplar toxicants: Gentamicin and thioacetamide, which are known to induce kidney and liver injury, respectively. ToxMet predicted known toxicity mechanisms for both chemicals, thus demonstrating its ability to provide novel insights into the metabolic mechanisms of chemical-induced toxicity and aid in the discovery of biomarkers and therapeutics using gene expression data.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148353681","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":"A fond farewell to Jeffrey Peters, editor-in-chief of ToxSci.","authors":"Alison Harrill","doi":"10.1093/toxsci/kfag071","DOIUrl":"https://doi.org/10.1093/toxsci/kfag071","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":"209 7","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148362426","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":"DILI-context: a dose- and exposure-enriched knowledge base for translational liver safety assessment.","authors":"Rohola Zandie, Robert Betancort, Farhan Khodaee","doi":"10.1093/toxsci/kfag077","DOIUrl":"10.1093/toxsci/kfag077","url":null,"abstract":"<p><p>Drug-induced liver injury (DILI) is a major cause of drug development failure and post-marketing withdrawal. Although assessing clinical hepatotoxic risk is critical for decision-making, most benchmark datasets represent DILI with categorical hazard labels rather than exposure-dependent risk measures. As a result, the current understanding of DILI risk focuses on hazard rather than context-dependent exposure risk. To address this limitation, we present DILI-Context, a dose- and exposure-enriched knowledge base that integrates hazard annotations with high-content regulatory and toxicological data sources. This framework incorporates therapeutic dose, treatment duration, and preclinical safety thresholds to contextualize hepatotoxic liability. Using this harmonized resource, we observe a consistent monotonic relationship between therapeutic dose and DILI severity, with higher daily dose requirements associated with greater hepatotoxic concern. Our results show that drugs with elevated DILI risk operate within significantly narrower therapeutic windows, demonstrated by systematic declines in both acute Therapeutic Index and chronic Margin of Safety across DILI categories. We also demonstrate that chronic no-effect thresholds (NOAEL-based metrics) more effectively discriminate DILI risk than lowest-effect endpoints (LOAEL). To further capture cumulative burden, we introduce Chronic Load Score that integrates dose magnitude and treatment duration. This metric significantly stratifies DILI concern levels and aligns with independent regulatory signals, including hepatic dose adjustment requirements in prescribing information. Together, these findings demonstrate that hepatotoxic liability is strongly linked to required systemic exposure and constrained safety margins. We further characterize the chemical-property landscape of included small molecules and provide a minimalist benchmark comparing Morgan fingerprint-only classifiers against classifiers enriched with exposure-derived covariates, demonstrating complementary predictive signals beyond structure alone under the cohort constraints of DILIrank 2.0. DILI-Context thus provides both a reproducible supplementary feature layer and an explicit resource for advancing exposure-aware DILI modeling.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148346350","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":"Tetrabromobisphenol S-induced developmental toxicity in zebrafish embryos: impacts on cytoskeletal proteins during gastrulation.","authors":"Rosemaria Serradimigni, Heidi M Sabatini, Christopher Chouinard, Subham Dasgupta","doi":"10.1093/toxsci/kfag075","DOIUrl":"10.1093/toxsci/kfag075","url":null,"abstract":"<p><p>3,3',5,5'-Tetrabromobisphenol S (TBBPS) is an emerging brominated flame retardant that is widely detected in the environment, yet its toxic effects remain poorly understood. The objective of this study was to use zebrafish as a model and determine the effects of TBBPS exposure on gastrulation stages of embryogenesis. We initiated TBBPS exposures (0 or 40 µM) at 0.75 h post fertilization (hpf), phenotyped hourly through cleavage, blastula, and gastrula stages, and showed that TBBPS-treated embryos exhibited delay in development beginning at ∼4 hpf, a stage corresponding to early gastrulation, with significant mortality during late gastrulation. To examine the genetic basis of TBBPS-induced effects, we conducted mRNA sequencing on exposures from 0.75 to 7 hpf, revealing downregulation of cytoskeletal organization and tight junction assembly. We then fluorescent-stained for multiple cytoskeletal and tight junction proteins (α-tubulin, β-tubulin, Zonula occludens-1, filamentous actin [F-actin]) following exposures to a wide range of TBBPS concentrations (0, 0.004, 0.04, 0.4, 4, and 40 µM). F-actin expression was consistently upregulated across all exposed TBBPS concentrations. To determine whether activation of p38, a key regulator of F-actin polymerization, plays a role in TBBPS-induced F-actin disruption, we co-exposed embryos with TBBPS (0 or 40 µM) and a known p38 inhibitor (5 µM SB 203580) and assessed developmental phenotypes and F-actin levels. Treatment with p38 inhibitor significantly rescued TBBPS-induced effects, with co-exposure groups exhibiting cell stages and F-actin expression similar to controls. Collectively, these findings demonstrate that TBBPS exposures target gastrulation stages and define a novel mechanism in which TBBPS increases F-actin polymerization through p38/mitogen-activated protein kinase signaling pathways.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148240219","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":"Hepatic inflammation after exposure to a mixture of low-dose arsenic and cadmium in a murine model of fatty liver disease.","authors":"Nivetha K Subramaniam, Natascha Gagnon, Cynthia Guilbert, Rushmi Perinpanathan, Madelyn Abraham, Christophe Goncalves, Jaymie R Meliker, Sonia Del Rincon, Koren K Mann","doi":"10.1093/toxsci/kfag073","DOIUrl":"10.1093/toxsci/kfag073","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health burden and a major contributor to chronic liver disease. Evidence suggests arsenic (As) and/or cadmium (Cd) exposure may influence MASLD development, yet the effects of chronic low-dose metal mixtures on hepatic inflammation and immune responses remain unclear. Using the apolipoprotein E-knockout mouse model, we examined low-dose As and Cd exposure in male and female mice. We focused on hepatic steatosis and inflammation. Steatosis-related changes were assessed via lipid metabolism gene expression and PLIN2 levels. No significant changes were observed in males; however, females exposed to the metal mixture showed increased PLIN2 expression. In contrast, males exhibited an inflammatory phenotype following combined exposure. High-plex single-cell imaging (PhenoCycler) in male livers revealed increased Ki67+ hepatocytes, enhanced β-catenin signal, and elevated CD8+ T-cell infiltration, indicating enhanced proliferation and immune activation. These findings suggest sex-dependent responses to low-dose As and Cd, with females showing subtle steatotic changes and males a pronounced inflammatory signature. Collectively, combined metal exposure induces hepatic priming in both sexes; males show an increased inflammatory response with cellular proliferation in the absence of overt steatosis or fibrosis, whereas females demonstrate increased steatosis without inflammation or fibrosis.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13401448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148228363","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}