Toxicological Sciences最新文献

{"title":"A workflow for human health hazard evaluation using transcriptomic data and Key Characteristics-based gene sets.","authors":"Han-Hsuan D Tsai, King D Oware, Fred A Wright, Weihsueh A Chiu, Ivan Rusyn","doi":"10.1093/toxsci/kfaf036","DOIUrl":"10.1093/toxsci/kfaf036","url":null,"abstract":"<p><p>Key characteristics (KCs) are properties of chemicals that are associated with different types of human health hazards. KCs are used for systematic reviews in support of hazard identification. Transcriptomic data are a rich source of mechanistic data and are frequently interpreted through \"enriched\" pathways/gene sets. Such analyses may be challenging to interpret in regulatory science because of redundancy among pathways, complex data analyses, and unclear relevance to hazard identification. We hypothesized that by cross-mapping pathways/gene sets and KCs, the interpretability of transcriptomic data can be improved. We summarized 72 published KCs across 7 hazard traits into 34 umbrella KC terms. Gene sets from Reactome and Kyoto Encyclopedia of Genes and Genomes (KEGG) were mapped to these, resulting in \"KC gene sets.\" These sets exhibit minimal overlap and vary in the number of genes. Comparisons of the same KC gene sets mapped from Reactome and KEGG revealed low similarity, indicating complementarity. Performance of these KC gene sets was tested using publicly available transcriptomic datasets of chemicals with known organ-specific toxicity: benzene and 2,3,7,8-tetrachlorodibenzo-p-dioxin tested in mouse liver and drugs sunitinib and amoxicillin tested in human-induced pluripotent stem cell-derived cardiomyocytes. We found that KC terms related to the mechanisms affected by tested compounds were highly enriched, while the negative control (amoxicillin) showed limited enrichment with marginal significance. This study's impact is in presenting a computational approach based on KCs for the analysis of toxicogenomic data and facilitating transparent interpretation of these data in the process of chemical hazard identification.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"310-325"},"PeriodicalIF":3.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12118962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670973","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":"Maternal α-cypermethrin and permethrin exert differential effects on fetal growth, placental morphology, and fetal neurodevelopment in mice.","authors":"Benjamin A Elser, Benjamin Hing, Samuel Eliasen, Malik A Afrifa, Naomi Meurice, Farzana Rimi, Michael Chimenti, Laura C Schulz, Michael E Dailey, Katherine N Gibson-Corley, Hanna E Stevens","doi":"10.1093/toxsci/kfaf079","DOIUrl":"10.1093/toxsci/kfaf079","url":null,"abstract":"<p><p>Pyrethroid insecticides represent a broad class of chemicals used widely in agriculture and household applications. Human studies show mixed effects of maternal pyrethroid exposure on fetal growth and neurodevelopment. Assessment of shared pyrethroid metabolites as a biomarker for exposure obscures effects of specific chemicals within this broader class. To better characterize pyrethroid effects on fetal development, we investigated maternal exposure to permethrin, a type I pyrethroid, and α-cypermethrin, a type II pyrethroid, on fetal development in mice. Pregnant CD1 mice were exposed to permethrin (1.5, 15, or 50 mg/kg), α-cypermethrin (0.3, 3, or 10 mg/kg), or corn oil vehicle via oral gavage on gestational days (GDs) 6 to 16. Effects on fetal growth, placental toxicity, and neurodevelopment were evaluated at GD 16. Cypermethrin, but not permethrin, significantly reduced fetal growth and altered placental layer morphology. Placental RNAseq analysis revealed downregulation of genes involved in extracellular matrix remodeling in response to α-cypermethrin. Both pyrethroids induced shifts in fetal dorsal forebrain microglia morphology from ramified to ameboid states; however, the effects of α-cypermethrin were more pronounced. The α-cypermethrin transcriptome of fetal dorsal forebrain implicated altered glutamate receptor signaling, synaptogenesis, and c-AMP signaling. Coregulated gene modules in individual placenta and fetal dorsal forebrain pairs were correlated and overlapped in biological processes characterizing synapses, mitotic cell cycle, and chromatin organization, suggesting placenta-fetal brain shared mechanisms with α-cypermethrin exposure. In summary, maternal exposure to the type II pyrethroid α-cypermethrin, but not type I pyrethroid permethrin, significantly affected placental development, fetal growth, and neurodevelopment, and these effects were linked.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302902","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":"Environmental exposome meets muscle wasting: unraveling the VOC-sarcopenia nexus through urinary metabolomics, inflammatory mediation, and network pharmacology in the NHANES cohort.","authors":"Mingjie Shi, Yue Wei, Weijie Zhang, Wenfeng Wei, Runmin Guo, Fei Luo","doi":"10.1093/toxsci/kfaf077","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf077","url":null,"abstract":"<p><p>Volatile organic compounds (VOCs) are pervasive environmental pollutants. However, their impact on sarcopenia, a condition characterized by progressive muscle loss and closely linked to numerous adverse health outcomes, remains poorly understood. Using data from the National Health and Nutrition Examination Survey (NHANES, 2011 to 2018), we analyzed 16 urinary metabolites of VOCs, adjusted for creatinine, to explore potential associations between VOC exposure and sarcopenia. Our findings consistently revealed a positive correlation across statistical models, with 2-aminothiazoline-4-carboxylic acid (a cyanide metabolite) contributing the greatest weight to the overall association. Subgroup analyses revealed particularly robust associations among younger women (≤50 years) and individuals with obesity (BMI ≥30), with inflammatory pathways emerging as key mediators. Through network toxicology, we identified pivotal targets and pathways involved in immune response, infection defense, apoptosis, and metabolic regulation. Notably, natural compounds such as quercetin have emerged as promising candidates for mitigating sarcopenia risk or slowing its progression. Together, these findings not only advance our understanding of the environmental determinants of sarcopenia but also highlight opportunities for targeted interventions.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144286544","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 mixture of organophosphate esters sex-specifically impacts monocyte-macrophages in Sprague-Dawley rats.","authors":"Braeden H Giles, Nivetha Kamalavannan Subramaniam, Vincenza Caruana, Nikola Kukolj, Bernard Robaire, Koren K Mann","doi":"10.1093/toxsci/kfaf078","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf078","url":null,"abstract":"<p><p>Exposure to individual organophosphate esters (OPEs) has been linked to immune dysfunction. However, the effect of OPEs as environmentally relevant mixtures on the immune system remain poorly understood. This study examines how parental exposure to an OPE mixture impacts the immune status of Sprague-Dawley rats and their offspring. Sprague-Dawley rats were fed a control or OPE-supplemented diet containing 13 OPEs detected in > 85% of Canadian homes. Only male offspring of OPE-exposed animals showed a significant reduction in CD43lowHis48hi splenic monocyte-macrophages. There were no significant changes in CD43lowHis48hi splenic monocyte-macrophages in the F0 generation or in female offspring. However, the OPE mixture significantly altered serum cytokine levels in both sexes and generations, with females and offspring experiencing more pronounced changes. Notably, female progeny had elevated levels of chemokines associated with monocyte recruitment. In vitro follow-up studies revealed that the OPE mixture delays monocyte-to-macrophage transition and monocyte migration in both sexes. These results indicate that an environmentally relevant OPE mixture disrupts immune function by affecting monocyte recruitment and differentiation but does not reveal clear sex differences. However, when combined with cytokine findings, these results support a hypothesis that OPE exposure causes male-specific decreases in CD43lowHis48hi monocyte-macrophages that are absent in females due to compensatory inflammation. Impact statement: These studies demonstrate that an environmentally relevant mixture of organophosphate esters can alter basal immune status in the offspring of exposed animals. This work will be useful for risk assessment studies and regulations protecting human health.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144175003","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":"Elucidating CD4+ and CD8+ T-cell involvement in patients with vancomycin-induced DRESS.","authors":"Joshua Gardner, Silvia Martinez-Rivera, James Line, Paul Thomson, Elsie Clarke, Andrew Gibson, Matthew S Krantz, Michael Ardern-Jones, Elizabeth J Phillips, Dean J Naisbitt","doi":"10.1093/toxsci/kfaf074","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf074","url":null,"abstract":"<p><p>Vancomycin, a glycopeptide antibiotic used to treat severe Gram-positive bacterial infections, is associated with the development of drug reaction with eosinophilia and systemic symptoms (DRESS) in individuals expressing HLA-A*32:01. Previous studies have identified the potential role of T-cells using HLA-A*32:01 positive healthy donor models. However, DRESS pathogenesis remains poorly defined and a deeper mechanistic understanding is required to aid the diagnosis and prediction of vancomycin-induced DRESS. The present study aims to elucidate CD4+ and CD8+ T-cell involvement within the pathogenesis of vancomycin-induced DRESS following the isolation and functional study of cloned T-cells from hypersensitive patients. CD4+ and CD8+ vancomycin-responsive T-cell clones (TCCs) were generated by serial dilution from PBMCs collected from suspected vancomycin-DRESS patients. Functionality of drug-responsive TCCs was assessed using T-cell proliferation ([3H]-thymidine). Cytokine analysis was performed using intracellular cytokine staining (ICS), ELISpot assay and LEGENDplex immunoassays. Vancomycin-responsive TCCs expressing CD4+ and CD8+ phenotypes were successfully generated from suspected vancomycin-DRESS patients (n = 3). CD45RO+ memory T-cells were the primary activated population, with both CD4+ and CD8+ T-cells associated with the release of IFN-γ, IL-5, IL-13, granzyme B and perforin. Vancomycin-responsive CD4+ and CD8+ T-cells are activated by direct, pharmacological interactions, with antigen presentation possible through HLA class I and HLA class II molecules. This study provides in vitro evidence for the dual role of antigen-specific CD4+ and CD8+ T-cells within the pathogenesis of vancomycin-induced DRESS. This has been demonstrated following the generation of cloned T-cells with strong vancomycin specificity from patients presenting with vancomycin-DRESS and positive for expression of HLA-A*32:01.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161150","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":"Acetate derived from metabolism of ethanol affects gene expression in bone and contributes to delays in chondrogenic differentiation.","authors":"Kim B Pedersen, Cheyleann Del Valle Ponce De Leon, Hardy Hang, Jin-Ran Chen, Christopher E Randolph, Jovanny Zabaleta, Christopher M Taylor, Meng Luo, Alexandra Denys, Martin J J Ronis","doi":"10.1093/toxsci/kfaf073","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf073","url":null,"abstract":"<p><p>Alcohol intake is a risk factor for development of osteopenia. Ethanol perturbs gene expression in osteoblasts and osteoclasts and disrupts growth plate morphology. Hepatic metabolism of ethanol to acetate elevates concentrations of acetate in the circulation. We investigated whether acetate could in part mediate the toxicity of ethanol in bone and on chondrocyte differentiation. When ethanol and acetate were compared by gavage for four consecutive days, none of eleven genes involved in bone homeostasis were significantly affected by acetate, but acetate responses significantly correlated with ethanol responses. Intraperitoneal injection with acetate to transiently elevate serum acetate for four consecutive days significantly increased expression of two markers of osteoclast differentiation, calcitonin receptor (Calcr) and Ocstamp. Early chondrogenic differentiation of ATDC5 cells for 7 days in vitro characterized by aggrecan (Acan) and collagen 2a1 (Col2a1) mRNA expression and proteoglycan production was inhibited by both 50 mM ethanol and 5 mM acetate. Ethanol effects were not blocked by the alcohol dehydrogenase inhibitor 4-methylpyrazole. 50 mM ethanol retarded both ATDC5 cell growth and culture medium acidification. Inhibition of chondrogenic differentiation by 5 mM acetate was associated with elevated phosphorylation of ERK1 and ERK2 and decreased expression of transcription factors Sox9 and Runx2. In acetate-exposed cells, blocking of ERK1 and ERK2 phosphorylation with Trametinib prevented further reduction of Acan and Col2a1 mRNA expression. We conclude that ethanol-derived acetate mediates at least part of the induction of Calcr and Ocstamp expression, and that acetate mimics effects of ethanol on early chondrogenic differentiation.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128481","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":"Environmentally Relevant Lead Exposure Impacts Gene Expression in SH-SY5Y Cells Throughout Neuronal Differentiation.","authors":"Rachel K Morgan, Anagha Tapaswi, Katelyn M Polemi, Elizabeth C Tolrud, Kelly M Bakulski, Laurie K Svoboda, Dana C Dolinoy, Justin A Colacino","doi":"10.1093/toxsci/kfaf072","DOIUrl":"10.1093/toxsci/kfaf072","url":null,"abstract":"<p><p>Lead (Pb) causes learning and memory impairments, but the molecular effects of continuous, environmentally relevant levels of exposure on key neurodevelopmental processes are not fully characterized. Here we examine the effects of a range of environmentally relevant Pb concentrations (0.16 µM, 1.26 µM, and 10 µM Pb) relative to control on neural differentiation in the SH-SY5Y cell model. Pb exposure began on differentiation day 5 and was continuous for remaining days, and we assessed the transcriptome via RNA sequencing at several time points. The bulk of detected changes in gene expression occurred with the 10 µM Pb condition. Interestingly, changes associated with the lower two exposures were differentiation stage-specific, with aberrant expression of several genes (e.g., COL3A1, HMOX1, NQO1, and CCL2) observed during differentiation on days 9, 12, and 15 in both the 0.16 µM and 1.26 µM Pb conditions, and which disappeared by the time differentiation concluded on day 18. We observed six co-expression clusters of genes during differentiation, and 10 µM Pb significantly perturbed two clusters, one involved in cell cycling and DNA repair and the other in protein synthesis. Benchmark concentration analysis identified many genes affected by levels of Pb at or below the current US reference value (3.5 µg/dL) and Pb-affected genes were enriched for pathways including stress responses, DNA repair, misfolded protein response, mitosis, and neurotransmitter production. This work highlights potential new mechanisms by which environmentally relevant concentrations of Pb impact gene expression throughout neural differentiation and may result in long-lasting implications for neural health and cognition.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120928","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":"Bayesian Refinement of a Physiologically Based Pharmacokinetic Model for Ethylbenzene Pharmacokinetics in Mice, Rats, and Humans.","authors":"Y S Lin, N H Hsieh, P Schlosser, M Dzierlenga, H Ju","doi":"10.1093/toxsci/kfaf070","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf070","url":null,"abstract":"<p><p>Although several physiologically based pharmacokinetic (PBPK) models exist for ethylbenzene (EB), a systematic evaluation of variability and uncertainty across species is still missing. This study aims to develop and validate a universal population-based, Bayesian PBPK model to study EB inhalation kinetics for mice, rats, and humans using a Markov Chain Monte Carlo (MCMC) approach to enhance model parameterization and its predictions. A comprehensive database was used for calibration and evaluation. This refined model demonstrates a superior or comparable fit to the data when contrasted with earlier published PBPK models for EB. Except for mouse fat and lung tissues, the concentrations of EB in tissues and its metabolites were generally within residual errors of 3-fold across species. Specifically, urinary concentrations of mandelic acid (MA), the primary downstream metabolite of EB, are generally well predicted in both rats and humans. Our approach offers a better characterization of pharmacokinetic variability and uncertainty than previous EB models, with strong agreement between predictions and experimental data. This supports efforts to adopt PBPK modeling for data extrapolation from animal studies to inform human health assessments, thereby greatly promoting public health. The confidence in applying the current refined PBPK model could be increased by confirming the predictions made by our analysis with additional targeted data collection.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144080547","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":"Quantitative and qualitative concordance between clinical and nonclinical toxicity data.","authors":"Chelsea A Weitekamp, Katie Paul Friedman, Alison H Harrill, Scott Auerbach, Omari Bandele, Tara S Barton-Maclaren, Suzanne Fitzpatrick, Roman Mezencev, Michael Santillo, Ulla Simanainen, Doris Smith, Maurice Whelan, Russell S Thomas","doi":"10.1093/toxsci/kfaf071","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf071","url":null,"abstract":"<p><p>While rodent toxicity testing plays an important role in evaluating human hazards of environmental and industrial chemicals, evaluating the concordance of the rodent testing results with human effects is challenging since these chemicals cannot be tested in humans. In this study, we evaluate the quantitative and qualitative concordance of lowest observed adverse effect levels (LOAEL) and adverse endpoints between in vivo and in vitro models of human health and human clinical trials of pharmaceuticals. Rodent human equivalent dose-adjusted LOAEL (LOAELHED) values and human LOAEL values for the sensitive effect in each species were moderately correlated in a protective context. When matched rodent and human effects were evaluated, the quantitative correlation in dose did not improve, and the qualitative balanced accuracy in effects was low suggesting limited predictivity. Absolute differences in rodent LOAELHED and human LOAEL values were nearly 1 log10 unit with rodent LOAELHED values consistently higher; however, rodent LOAELHED values were less than the human LOAEL values for >95% of drugs when divided by typical composite uncertainty factors. In comparison, in vitro bioactivity administered equivalent dose (AED) values showed a similar moderate correlation and absolute differences with human LOAEL values, but in vitro bioactivity AED values were consistently lower. When in vitro bioactivity AED values were compared with rodent LOAELHED values, the correlation was lower and differences larger relative to human LOAEL comparison. Overall, the study expands previous efforts evaluating the concordance of rodent toxicological testing results with human responses and presents objective expectations for alternative toxicity testing approaches.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144080552","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 Network Analysis and Machine Learning to Elucidate Chemical-Induced Pancreatic Toxicity in Zebrafish Embryos.","authors":"Ashley V Schwartz, Karilyn E Sant, Uduak Z George","doi":"10.1093/toxsci/kfaf069","DOIUrl":"10.1093/toxsci/kfaf069","url":null,"abstract":"<p><p>Zebrafish (Danio rerio) are a popular vertebrate model for high-throughput toxicity testing, serving as a model for embryonic development and disease etiology. However, standardized protocols using zebrafish tend to explore pathologies and behaviors at the organism level, rather than at the organ-specific level. This study investigates the effects of chemical exposures on pancreatic function in whole-embryo zebrafish by integrating network analysis and machine learning, leveraging widely-available datasets to probe an organ-specific effect. We compiled transcriptomics data for zebrafish exposed to 53 exposures from 25 unique chemicals, including halogenated organic compounds, pesticides/herbicides, endocrine-disrupting chemicals, pharmaceuticals, parabens, and solvents. All raw sequencing data were processed through a uniform bioinformatics pipeline for re-analysis and quality control, identifying differentially expressed genes and altered pathways related to pancreatic function and development. Clustering analysis revealed five distinct clusters of chemical exposures with similar impacts on pancreatic pathways with gene co-expression network analysis identifying key driver genes within these clusters, providing insights into potential biomarkers of chemical-induced pancreatic toxicity. Machine learning was utilized to identify chemical properties that influence pancreatic pathway response, including average mass, biodegradation half-life. The random forest model achieved robust performance (4-fold cross-validation accuracy: 74%) over eXtreme Gradient Boosting, support vector machine, and multiclass logistic regression. This integrative approach enhances our understanding of the relationships between chemical properties and biological responses in a target organ, supporting the use of zebrafish whole-embryos as a high-throughput vertebrate model. This computational workflow can be leveraged to investigate the complex effects of other exposures on organ-specific development.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144080549","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}