Toxicological Sciences最新文献

{"title":"ToxCompl Completion of the DrugMatrix Toxicogenomics Database: An Integrated Resource for Toxicological Hypothesis Generation.","authors":"Laura J Word, Guojing Cong, Robert M Patton, Frank Chao, Daniel L Svoboda, Warren M Casey, Charles P Schmitt, Jeremy N Erickson, Parker Combs, Scott S Auerbach","doi":"10.1093/toxsci/kfag113","DOIUrl":"https://doi.org/10.1093/toxsci/kfag113","url":null,"abstract":"<p><p>The DrugMatrix database contains systematically generated toxicogenomics data from short-term in vivo studies for over 600 chemicals. However, most potential endpoints are missing due to a lack of experimental measurements. Therefore, we leveraged matrix factorization and machine learning methods to predict the missing values, which includes gene expression across eight tissues on two expression platforms along with paired clinical chemistry, hematology, and histopathology. We propose a method, ToxCompl, that applies systematic hybrid sampling guided by Bayesian optimization in conjunction with low-rank matrix factorization to predict the missing values. In-depth validation of the ToxCompl predicted data from machine learning, biological, and toxicological perspectives shows that the predicted differential gene expression aligns well with what would be anticipated. This includes examining the connectivity pattern of predicted gene expression responses, characterizing molecular pathway-level responses from sets of differentially expressed genes, evaluating known transcriptional biomarkers of tissue toxicity, and characterizing predicted apical endpoints. For example, we identified kidney toxicants using the transcriptional biomarker Havcr1. All measured and predicted DrugMatrix data (i.e., gene expression, clinical chemistry, hematology, and histopathology) are available to the public (https://rstudio.niehs.nih.gov/toxcompl/). Notably, predicted clinical chemistry of subtle effects and histopathological prediction are two areas we will continue to improve. The main advantage of the ToxCompl approach is that it drastically extends the toxicogenomic landscape into many data-poor tissues in the absence of acquiring additional experimental data, thereby allowing researchers to formulate mechanistic hypotheses about effects in tissues that have been underrepresented in the literature.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148888415","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":"Assessing drug-induced liver injury liabilities in human and animal hepatocytes under static and perfused spheroid culture conditions.","authors":"Chander K Negi, Chi Lam T Chan, Han-Hsuan D Tsai, Ibrahim Alshammari, Courtney Sakolish, Weihsueh A Chiu, Philip Hewitt, Stephen S Ferguson, Remi Villenave, Dimitrios Bitounis, Ivan Rusyn","doi":"10.1093/toxsci/kfag114","DOIUrl":"https://doi.org/10.1093/toxsci/kfag114","url":null,"abstract":"<p><p>Drug-induced liver injury (DILI) remains a major challenge in drug development, highlighting the need for reliable in vitro tools to assess hepatotoxicity and improve translation from animal to human studies. Models using hepatocytes from preclinical species are also needed to evaluate species-specific toxicity. In this study, we evaluated the basal function and DILI sensitivity of primary hepatocytes from human, monkey, rat, and dog cultured for up to 14 days in static monolayers, static spheroids, and spheroids cultured in a microfluidics-based microphysiological system (MPS). Hepatocyte function and injury responses were assessed using albumin, urea, and liver enzymes. Cells were exposed to species-specific DILI compounds chlorpromazine (CPZ), bosentan (BOS), and fialuridine (FIAU). Across platforms, human and monkey hepatocytes exhibited greater functional stability and sensitivity to DILI compounds than rat and dog hepatocytes. CPZ and BOS induced cytotoxicity primarily in human and monkey hepatocytes, while FIAU produced species-dependent effects consistent with known in vivo outcomes. The microfluidics-based MPS exhibited modestly improved hepatocyte spheroid function relative to static models, although limited MPS throughput constrained our ability for testing drugs beyond FIAU. Overall, these results demonstrate that integrating multi-species hepatocyte spheroids across static and microfluidic platforms enables comparative DILI assessment and supports improved preclinical-to-clinical translation.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892274","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":"Cigarette Smoke and E-Cigarette Aerosol Extracts Induce Myelopoiesis and Suppress Inflammatory Cytokine Production.","authors":"Jeanette Y C Sullivan, Helen X Huang, Jianhong C Heidmann, Francisco Diaz, Camille Brzechffa, Jane H Chen, Eli M Soyfer, Nneamaka Iwobi, Irene Hasen, Amanda Ting, Nicole Sparks, Michael T Kleinman, Angela G Fleischman","doi":"10.1093/toxsci/kfag096","DOIUrl":"https://doi.org/10.1093/toxsci/kfag096","url":null,"abstract":"<p><p>Tobacco and nicotine use remain leading preventable drivers of cancer risk, and both combustible cigarettes and electronic nicotine devices perturb immune function and hematopoiesis. However, side-by-side comparisons of their effects across the hematopoietic hierarchy remain limited. Here, we evaluate the impact of cigarette smoke extract (CSE) and e-cigarette vapor extract (EVE) on inflammatory responses in mature myeloid cells and on hematopoietic stem and progenitor cell function using complementary in vitro and in vivo approaches. Using a standardized protocol applied across multiple macrophage models, including RAW264.7 cells, THP-1 macrophages, primary mouse bone marrow-derived macrophages, and human peripheral blood mononuclear cells, we found that CSE consistently suppressed LPS-induced TNF-α secretion in a dose-dependent manner, while EVE alone had minimal effect. CSE also induced foam cell formation in macrophages through a reactive oxygen species-dependent mechanism. Additionally, both CSE and EVE suppressed hematopoietic progenitor colony formation. To model real-world exposure patterns, we used a nose-only inhalation system to deliver combustible cigarette smoke followed by e-cigarette aerosol to mice. Sequential smoke and e-cigarette exposure increased platelet counts and myeloid cell frequency, effects not observed with smoking cessation alone. Myeloid skewing persisted through secondary transplantation, indicating durable, cell-intrinsic changes to the hematopoietic stem cell compartment. Together, these findings demonstrate that tobacco and e-cigarette exposures blunt innate immune responsiveness while driving lasting myeloid-biased hematopoiesis, with implications for infection susceptibility, cardiovascular disease, and hematologic malignancy risk.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148888398","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":"Proteomic characterization of ocular tear fluid reveals preclinical markers of sulfur mustard toxicity.","authors":"Sreekala P V Shenoy, Cameron A Sousa, Aaron T Doney, Adrienne B Stone, Christel Y Anthony, Steven Cayea, Hadi Pourhadi, Jingyun Lee, Saleh Ahmed, Ashok Sharma, Sarfaraz Ahmad, Ratnakar Tripathi, Patrick M McNutt","doi":"10.1093/toxsci/kfag108","DOIUrl":"10.1093/toxsci/kfag108","url":null,"abstract":"<p><p>Sulfur mustard (SM) vapor causes ocular injury after a short latent period, when molecular damage has occurred, but clinical signs are not yet apparent. Characterizing ocular responses during this early phase is important for understanding SM pathogenesis, identifying molecular readouts of injury progression, and developing biomarkers of exposure. Tear fluid is well-suited for this purpose because it can be collected noninvasively and captures responses from injured ocular tissues. We tested whether temporal changes in the tear fluid proteome reflect cellular and molecular responses to corneal SM exposure. Rabbits were exposed to SM vapor using a corneal vapor cap, and tear fluid was collected at baseline, 4 h, 1 d, and 5 d, corresponding to the latent period, acute lesion, and early recovery. A large proteomic response was detected at 4 h, involving extracellular injury signaling, epithelial injury, and innate immune activation. By 1 d, the tear fluid proteome transitioned to inflammatory cell activation with metabolic, redox, and proteostasis stress. By 5 d, evidence of acute injury response was reduced but the proteome retained a residual signature of immune, epithelial, and stress responses. This temporal progression is consistent with the molecular mechanisms of SM toxicity and provides insight into acute ocular vesicant injury. These findings establish tear fluid as a noninvasive molecular reporter of ocular SM injury progression. They also reveal a molecular signature of vesicant exposure, which emerges prior to clinical signs, and provide foundational data for developing tear-based biomarkers of chemical exposure, injury assessment, and therapeutic testing.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798220","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":"Detecting drug-induced nephrotoxicity using simultaneous label-free autofluorescence multiharmonic microscopy.","authors":"Aneesh Alex, Jindou Shi, Eric J Chaney, Minh Doan, Ciarán P Fisher, Leslie Obert, Crysthiane Ishiy, Alexander Ho, Darold R Spillman, Marina Marjanovic, Jan Roger, M Reid Groseclose, Steve R Hood, Stephen A Boppart","doi":"10.1093/toxsci/kfag098","DOIUrl":"10.1093/toxsci/kfag098","url":null,"abstract":"<p><p>Drug-induced nephrotoxicity (DIN) is a major cause of drug development failure, yet many cases are detected only late in clinical trials or after approval. Conventional methods to detect DIN often lack sensitivity and specificity, particularly for early or region-specific kidney injury. Here, we evaluate Simultaneous Label-free Autofluorescence Multiharmonic (SLAM) microscopy as a rapid, label-free imaging approach to quantify kidney microstructural and functional metabolic changes associated with DIN. SLAM simultaneously captures endogenous NAD(P)H and FAD autofluorescence, collagen-derived second harmonic generation, and third-harmonic generation from structural interfaces. SLAM images were acquired from the cortex and outer medulla (OM) of rat kidneys after cisplatin dosing at days 1, 6, and 29 post-administration. Imaging revealed region-specific injury, with the OM showing greater sensitivity to DIN than the cortex. The most prominent changes-tubular degeneration and hyaline casts-peaked at day 6, whereas tubular dilation and fibrosis-related features persisted to day 29. Feature-based classification captured these spatial and temporal patterns, achieving higher balanced accuracy in the OM (0.944) than in the cortex (0.860). Key model drivers included granularity and inter-channel correlations, underscoring the value of multi-channel SLAM data. Overall, these results demonstrate the potential of SLAM microscopy for sensitive, region-specific detection and characterization of DIN in preclinical safety studies. SLAM microscopy provides a rapid, label-free way to detect, localize, and classify drug-induced nephrotoxicity with improved sensitivity and regional specificity, potentially strengthening preclinical kidney safety screening and reducing late-stage development failures.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13537822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798203","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":"Nicotine analogs in e-cigarettes: unrecognized health risks and insufficient regulatory oversight.","authors":"Alexis A Graham, Elizabeth M Corteselli","doi":"10.1093/toxsci/kfag104","DOIUrl":"10.1093/toxsci/kfag104","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148832350","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":"Integrating new approach methodologies and artificial intelligence to advance central nervous system toxicity prediction: lessons from preclinical and clinical case studies.","authors":"Mamta Behl, Fiona S Daly, Helena T Hogberg, Brian R Berridge, Jaime D'Agostino, James Eric McDuffie, Hyesun H Oh, Satjit Brar, Simon Authier","doi":"10.1093/toxsci/kfag100","DOIUrl":"10.1093/toxsci/kfag100","url":null,"abstract":"<p><p>Central nervous system (CNS) toxicities remain a major cause of drug attrition and represent a persistent challenge in predicting neurological risk during drug development. Limitations in the predictive resolution and translational relevance of conventional nonclinical paradigms contribute to uncertainty in identifying and interpreting neurotoxicity signals. This manuscript examines key challenges in CNS safety assessment and highlights emerging strategies to improve early detection and prediction of neurological risk. Through a series of case studies, we demonstrate practical approaches for interpreting CNS safety signals and integrating emerging methodologies into nonclinical safety assessment. Examples include sensory and seizure-related endpoints in nonclinical studies and the use of electroencephalography (EEG) to improve detection and characterization of seizure liability. We also highlight the expanding role of advanced sensor technologies and artificial intelligence (AI) in enabling continuous, noninvasive monitoring of animal behavior. In addition, an Integrated Approach to Testing and Assessment (IATA) case study demonstrates how systematic integration of mechanistic data, traditional toxicology findings, and exposure modeling can support regulatory decision-making while aligning with the 3Rs principles (replace, reduce, refine animal testing). Finally, we present regulatory CNS case studies in drug development. Collectively, these approaches enable quantitative assessment of neurological function across circadian cycles, reduce reliance on episodic observer-dependent measurements, and illustrate how integrating refined in vivo methods with New Approach Methodologies (NAMs) and digital technologies can improve prediction of neurological risk and strengthen translation from nonclinical findings to human outcomes in CNS drug development.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148701971","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":"Developmental susceptibility to PFOS toxicity in Drosophila shows genetic variation in toxicodynamics and rescue via enhanced muscle mitochondrial function.","authors":"Lauren E Gregory, Matthew D Rand","doi":"10.1093/toxsci/kfag102","DOIUrl":"10.1093/toxsci/kfag102","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFAS) are ubiquitous environmental contaminants causing widespread concern for developmental toxicity in humans. PFAS can cause adverse developmental outcomes, yet factors determining PFAS susceptibility remain poorly understood. Whether PFAS resistance reflects generalized stress tolerance shared with other toxicants has not been explored. To address this, we assayed a panel of Drosophila melanogaster lines with established traits of resistance and susceptibility to methylmercury (MeHg) for developmental toxicity with several PFAS compounds, including perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS), and hexafluoropropylene oxide dimer acid (GenX). With larval exposures, PFOS showed the greatest potency, producing failures in both pupariation and eclosion at concentrations as low as 5 µM (2.5 ppm) in food. PFOS and MeHg resistance profiles across the genotype panel did not correspond, indicating toxicant-specific mechanisms control susceptibility apart from generalized stress tolerance pathways. Accounting for PFOS body burden after exposure, resistant and susceptible lines displayed markedly different developmental outcomes at similar internal concentrations, indicating that variation in susceptibility reflects toxicodynamic differences aside from variance in accumulation. Drawing on a prior role for mitochondrial dysfunction in the toxicity of both PFAS and heavy metals, we implemented neural and muscle-specific modulation of mitochondrial function via expression of dPGC-1 and ND1. Increased dPGC-1 or ND1 in muscle, compared with neural tissues, showed enhanced resistance to PFOS across all developmental outcomes. Notably, muscle-targeted overexpression of these mitochondria-related genes conferred developmental protection without reducing PFOS accumulation, supporting a toxicodynamic basis of resistance. Although PFOS toxicity arises through mechanisms distinct from MeHg, muscle mitochondria serve as a potential physiological nexus influencing developmental toxicity.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798161","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":"Correction to: Neurotoxicants driving glial aging: role of astrocytic aging in non-cell autonomous neurodegeneration.","authors":"","doi":"10.1093/toxsci/kfag028","DOIUrl":"https://doi.org/10.1093/toxsci/kfag028","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":"209 9","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148888433","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":"The aryl hydrocarbon receptor as a tissue-specific modulator of insulin sensitivity: Evidence from conditional deletion studies.","authors":"Mauricio Di Fulvio","doi":"10.1093/toxsci/kfag103","DOIUrl":"https://doi.org/10.1093/toxsci/kfag103","url":null,"abstract":"<p><p>The aryl hydrocarbon receptor (AhR) has emerged as a consequential regulator of fuel homeostasis and insulin action, yet its tissue-specific contributions remain incompletely resolved. Using evidence from conditional and inducible AhR deletion models, the purpose of this review is to evaluate the role of AhR in metabolically active tissues including adipose, liver, skeletal muscle, intestinal epithelium, kidney, pancreatic β-cells and the central nervous system. Tissue-specific phenotypes reveal that AhR may modulate insulin sensitivity in a context-dependent manner shaped by at least three critical variables: i) the timing of receptor deletion (developmental vs. post-developmental), ii) sex (with divergent mechanisms operating in males vs. females), and iii) dietary context (chow vs. metabolic challenge). In adipocytes, for instance, post-developmental AhR deletion protects females against diet-induced metabolic dysfunction by mechanisms potentially associated with estrogen receptor-dependent enhancement of hypothalamic leptin sensitivity, while males show only partial protection mediated in part through reduced adipose tissue inflammation. Hepatocyte-specific AhR deletion worsens steatosis but may improve systemic metabolism through FGF21-dependent mechanisms, suggesting opposing local vs. endocrine effects. Specific deletion in insulin-secreting β-cells suggests that AhR may contribute to dioxin-induced glucose dysregulation in a sex-contingent manner. Collectively, these tissue-specific phenotypes suggest that physiological AhR signaling contributes to metabolic homeostasis under basal conditions, whereas dietary lipid excess or xenobiotic exposure may reveal tissue-specific functions that either impair or preserve insulin sensitivity. These observations position AhR as a tissue-restricted modulator of insulin action whose physiological impact is shaped by cellular context, hormonal milieu and ligand environment.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148809088","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}