Toxicological Sciences最新文献

{"title":"Interference with systemic negative feedback as a potential mechanism for nonmonotonic dose-responses of endocrine-disrupting chemicals.","authors":"Zhenzhen Shi, Shuo Xiao, Qiang Zhang","doi":"10.1093/toxsci/kfaf060","DOIUrl":"10.1093/toxsci/kfaf060","url":null,"abstract":"<p><p>Environmental endocrine-disrupting chemicals (EDCs) often exhibit nonmonotonic dose-response (NMDR) relationships, posing significant challenges to health risk assessment and regulations. Several molecular mechanisms operating locally in cells have been proposed; however, whether and how systemic negative feedback-a global structure of all homeostatic endocrine systems-may render NMDRs is poorly understood. We hypothesized that an EDC may produce nonmonotonic effects by competing with the endogenous hormone for receptors simultaneously (i) at the central site to interfere with the feedback regulation and (ii) at the peripheral site to disrupt the hormone's endocrine action. We constructed a dynamical model of a generic hypothalamic-pituitary-endocrine axis with negative feedback to evaluate the hypothesis and biological conditions that favor NMDR. Our modeling found that when an EDC interferes sufficiently with the central feedback action, the net endocrine effect at the peripheral target site can be opposite to what is expected of an agonist or antagonist at low concentrations. J/U or Bell-shaped NMDRs arise when the EDC has differential binding affinities and/or efficacies, relative to the endogenous hormone, for the peripheral and central receptors. Novel quantitative relationships between these biological parameter variabilities and associated distributions were discovered, which can distinguish J/U and Bell-shaped NMDRs from monotonic responses. In conclusion, the ubiquitous negative feedback regulation in endocrine systems may act as a universal mechanism for counterintuitive and nonmonotonic effects of EDCs. Depending on the key receptor kinetic and signaling properties of EDCs and endogenous hormones, certain individuals may be more susceptible to these complex endocrine effects.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"354-372"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12342977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982047","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":"Perfluorooctane sulfonate exposure and alcohol-associated liver disease severity in a mouse chronic-binge ethanol feeding model.","authors":"Frederick A Ekuban, Tyler C Gripshover, Paxton Ames, Kushal Biswas, Oluwanifemi E Bolatimi, Joshua Abramson, Megana Iyer, Jianzhu Luo, Abigail Ekuban, Jae Yeon Hwang, Juw Won Park, Mayukh Banerjee, Walter H Watson, Banrida Wahlang, Dhimiter Bello, Jennifer J Schlezinger, Craig J McClain, Matthew C Cave","doi":"10.1093/toxsci/kfaf066","DOIUrl":"10.1093/toxsci/kfaf066","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Exposure to pollutants, including the ubiquitous \"forever chemical,\" perfluorooctane sulfonate (PFOS) has increasingly been associated with metabolic dysfunction-associated steatotic liver disease. Recent epidemiological evidence has identified associations between per- and polyfluoroalkyl substances (PFAS) exposure and increased liver injury in alcohol consumers, suggesting potential interactions between these exposures. However, the intersection of pollutant exposures and alcohol-associated liver disease (ALD) is not well studied. We hypothesize that pollutants may disrupt hepatic metabolism to modify ALD severity. Recently, we developed a two-hit (ethanol [EtOH] plus pollutant) mouse model, enabling testing of this hypothesis. Here, we elucidate the metabolic and disease-modifying effects of PFOS in this model. Male C57BL/6J mice were fed isocaloric control or 5% EtOH Lieber-DeCarli diet for 15 days. From day 6 of feeding, mice were concurrently gavaged with 1 mg/kg PFOS or 2% tween-80 vehicle for 10 days, followed by a 5 g/kg EtOH binge dose and euthanized 5 to 6 h later. Approximately 60% of the administered PFOS dose accumulated in the liver. PFOS exacerbated EtOH-induced hepatic steatosis and was associated by higher levels of plasma very low-density lipoprotein and alanine aminotransferase. PFOS upregulated hepatic EtOH-metabolizing enzymes and lowered blood alcohol levels. Ingenuity Pathway Analysis (IPA) Top Toxicity Functions/Lists associated with hepatic gene expression following PFOS co-exposure in EtOH-fed mice included: Fatty acid metabolism and liver steatosis; nuclear receptor activation, cytochrome P450, and reactive oxygen species; apoptosis; liver fibrosis; and hepatocellular carcinoma (HCC). Gene Ontology/Kyoto Encyclopedia of Genes and Genomes analyses similarly revealed enrichment in fatty acid, xenobiotic, alcohol, or glutathione metabolic processes; and peroxisome proliferator-activated receptor (PPAR) signaling. PFOS upregulated hepatic expression of several nuclear receptors (e.g. Pparα, Car, and Pxr) and their P450 target genes (e.g. Cyp4a10, Cyp2b10, and Cyp3a11) by real-time-PCR or Western blot, confirming key IPA predictions. PFOS is a metabolism-disrupting chemical that worsens ALD severity. PFOS activated hepatic nuclear receptors and enriched hepatic transcriptional pathways associated with steatosis, xenobiotic metabolism, oxidative stress, cell death, fibrosis, and HCC. These data demonstrate a novel mechanism whereby PFOS exacerbates ALD through coordinated dysregulation of lipid homeostasis and liver injury, potentially mediated by nuclear receptor activation. The identification of PFOS as an ALD risk modifier highlights the critical need to evaluate environmental pollutants as potential contributors to liver disease progression. More data are required on environmental pollution as a disease-modifying factor in ALD. Impact Statement: The present study demonstrates that PFOS exacerbates alcohol-induced l","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"388-408"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12329793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144011793","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":"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 5 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 and 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":"330-353"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12342976/pdf/","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":"OA","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":"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 peripheral blood mononuclear cells 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, enzyme-linked immunospot 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":"420-432"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","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":"Dual inhibition of TGFβ2,3 is severely toxic, whereas selective inhibition of TGFβ1, 2, or 3 and dual inhibition of TGFβ1,2 is generally tolerated in mouse and cynomolgus monkey toxicology studies.","authors":"Mayur S Mitra, Wendy Halpern, Michelle Lepherd, Janice Corpuz, Adeyemi O Adedeji, Rajbharan Yadav, Isabel Duarte, Tianhe Sun, Joseph R Arron, Shannon J Turley, Wei-Ching Liang, Yan Wu","doi":"10.1093/toxsci/kfaf059","DOIUrl":"10.1093/toxsci/kfaf059","url":null,"abstract":"<p><p>The transforming growth factor-β (TGFβ) cytokine family, which comprises 3 pleiotropic cytokines (TGFβ1, TGFβ2, and TGFβ3), plays a key role in many diseases including cancer and fibrosis. The role of TGFβ in disease is well established and efforts to develop therapies via inhibition of the 3 isoforms and their receptors have been pursued for decades. Unfortunately, progress in this pursuit has been limited as complete inhibition of the TGFβ signaling pathway using small molecule inhibitors of TGFβ receptor or following administration of potent pan-TGFβ (inhibiting TGFβ1, TGFβ2, and TGFβ3) neutralizing monoclonal antibodies (mAb) has been associated with adverse toxicities including cardiac valvulopathies, hemorrhage, and anemia in nonclinical toxicology species. Here we have evaluated the toxicities associated with selective inhibition of individual (TGFβ1 alone, TGFβ2 alone, or TGFβ3 alone) or dual (TGFβ1,2 or TGFβ2,3) TGFβ isoforms in mice and/or cynomolgus monkeys using mAbs targeted against these isoforms. Our data show that dual inhibition of TGFβ2,3 resulted in adverse toxicities in several organs, including cardiovascular toxicity. However, selective isoform-specific inhibition of TGFβ1, 2, or 3 is generally tolerated and devoid of adverse toxicities in nonclinical toxicology studies. Importantly, RO7303509 (MTBT1466A), an anti-TGFβ3 inhibiting mAb that is currently in Phase 1 clinical trials, was well tolerated in GLP mouse and cynomolgus monkey toxicology studies and the RO7303509-related effects were limited to nonadverse histopathologic findings in the teeth and injection-site reactions. In conclusion, inhibition of TGFβ in an isoform-specific manner is generally safe in nonclinical toxicology species and could be explored for therapeutic intervention.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"445-455"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050164","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":"Response to comment on: \"Microplastic presence in dog and human testis and its potential association with sperm count and weights of testis and epididymis\".","authors":"Chelin Jamie Hu, Marcus A Garcia, Alexander Nihart, Rui Liu, Lei Yin, Natalie Adolphi, Daniel F Gallego, Huining Kang, Matthew J Campen, Xiaozhong Yu","doi":"10.1093/toxsci/kfae137","DOIUrl":"10.1093/toxsci/kfae137","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"458-459"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12342990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142475446","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":"Bayesian refinement of a physiologically based pharmacokinetic model for ethylbenzene pharmacokinetics in mice, rats, and humans.","authors":"Yu-Sheng Lin, Nan-Hung Hsieh, Paul M Schlosser, Michael W Dzierlenga, Hyunsu Ju","doi":"10.1093/toxsci/kfaf070","DOIUrl":"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, 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. Impact Statement: This study presents a refined Bayesian PBPK model that captures EB pharmacokinetics across species. It outperforms previous EB models and improves interspecies extrapolation for human health risk assessment.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"233-252"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","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":"Incorporating Metabolic Competence into High-Throughput Profiling Assays.","authors":"Amanda Jurgelewicz, Kristen Breaux, Clinton M Willis, Felix R Harris, Gabrielle Byrd, Joshua Witten, Derik E Haggard, Joseph L Bundy, Logan J Everett, Chad Deisenroth, Joshua A Harrill","doi":"10.1093/toxsci/kfaf061","DOIUrl":"10.1093/toxsci/kfaf061","url":null,"abstract":"<p><p>High-throughput profiling assays such as high-throughput phenotypic profiling (HTPP) with Cell Painting and high-throughput transcriptomics (HTTr) with TempO-Seq have been used to characterize the bioactivity and potential hazards associated with large inventories of chemicals. Although both methods offer broad coverage of molecular targets, a limitation is that the cell types used in these in vitro assays typically lack the xenobiotic metabolism capabilities of humans or laboratory animals used for in vivo testing. To address this limitation, this proof-of-concept study coupled the Alginate Immobilization of Metabolic Enzymes (AIME) platform to both assays and evaluated the impact of metabolism on chemical bioactivity in a breast cancer cell line, VM7Luc4E2. HTPP detected concentration-dependent increases in chemical bioactivity corresponding to increased estrogen receptor (ER) activation measured using an ER transactivation assay (ERTA) that had been previously coupled to the AIME platform in VM7Luc4E2 cells. Additionally, HTTr detected a greater number of active genes in the metabolic condition associated with increased ER activation. This corresponded to a greater number of active ER high-confidence (ERHC) gene signatures and/or metabolism-induced shifts in ERHC signature enrichment as a transcriptomic readout of ER activity. This study demonstrates that the high-throughput profiling assays can detect changes in chemical bioactivity between parent compounds and metabolites generated using the AIME platform in a reproducible way. Incorporating metabolic competence into high-throughput profiling assays will better inform next-generation risk assessment by capturing potential metabolite-based changes in bioactivity of test chemicals that may be missed by current screening approaches.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"313-329"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027642","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":"Comment on: \"Microplastic presence in dog and human testis and its potential association with sperm count and weights of testis and epididymis\".","authors":"Rao M Uppu, Willie Peijnenburg, Sean M Hays","doi":"10.1093/toxsci/kfae136","DOIUrl":"10.1093/toxsci/kfae136","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"456-457"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12343010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547642","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":"Identifying environmental chemicals impacting neurodevelopment using a random mixture-based screening approach.","authors":"Wenxin Hu, Lei Xing, Jieun Park, Bonnie Taylor-Blake, James L Krantz, Yun-Chung Hsiao, Chih-Wei Liu, Sophia U Lamberti, Kun Lu, Mark J Zylka","doi":"10.1093/toxsci/kfaf067","DOIUrl":"10.1093/toxsci/kfaf067","url":null,"abstract":"<p><p>Environmental exposures can impact brain development and contribute to neurodevelopmental disorder risk. In this study, we leveraged insights from in vitro high-throughput screening studies that examined the developmental toxicity of environmental chemicals to select 47 chemicals for in vivo testing as complex random mixtures in pregnant female mice. Our objectives were to identify mixtures that impact key neurodevelopmental endpoints-embryonic body, brain, and placenta weight-and subsequently to use mass spectrometry to ascertain which chemicals from each active mixture entered the developing brain following gestational exposure. We identified 3 chemicals that entered the embryonic brain and reduced embryonic brain weight: Perfluorooctanoic acid (PFOA), fenpyroximate, and 4-tert-octylphenol. Given its effect on embryonic brain weight and its widespread presence in environmental samples, we selected PFOA for further study using single-nuclei RNA sequencing. We found that PFOA altered neural progenitor cell proliferation and neuronal differentiation in the developing mouse cerebral cortex. Furthermore, we found that gestational exposure to PFOA disrupted neurodevelopment by altering the cell cycle in neural progenitor cells of males and females. In conclusion, we identified environmental chemicals that impact neurodevelopmental processes in vivo and found that single-nuclei RNA sequencing can provide new insights into the cellular mechanisms of neurotoxicity.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"433-444"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12343035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033674","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}