Toxicological Sciences最新文献

{"title":"Estrogen and glucocorticoid receptors co-regulate acrolein-induced respiratory and systemic homeostatic stress responses.","authors":"Devin I Alewel, Katherine M Rentschler, Mette C Schladweiler, Colette N Miller, Stephen H Gavett, Paul A Evansky, Rachel Grindstaff, Wanda C Williams, Urmila P Kodavanti","doi":"10.1093/toxsci/kfaf084","DOIUrl":"10.1093/toxsci/kfaf084","url":null,"abstract":"<p><p>The contribution of neuroendocrine mechanisms of air pollution health effects in females and the extent to which such effects are related to estrogen signaling are unclear. To examine the interactive roles of estrogen (ER) and glucocorticoid receptors (GR) in acrolein-induced respiratory and systemic effects, female Wistar-Kyoto rats were treated daily for 9 days with corn oil (vehicle, 1 ml/kg), fulvestrant (ER-antagonist/degrader, 20 mg/kg), mifepristone (GR antagonist, 30 mg/kg) or fulvestrant + mifepristone, and on days 8 and 9 post-drug-treatment start, rats were exposed nose-only to 0 or 3.2 ppm acrolein for ∼4 h/day. Glucose-tolerance testing was performed following the first exposure. Nasal and lung lavages and blood samples were collected following the second exposure. Fulvestrant and mifepristone pretreatments decreased serum estrogen and progesterone, respectively, and each drug increased adrenocorticotropic hormone in acrolein-exposed rats. Although acrolein-induced nasal and lung protein leakage was reduced in fulvestrant-treated rats, neutrophilic inflammation and pro-inflammatory cytokine increases were exacerbated. However, acrolein-induced airway inflammation was not observed in mifepristone or co-treated rats. Regarding systemic markers of hypothalamic-pituitary-adrenal (HPA) activity, fulvestrant and mifepristone each increased circulating basal leukocytes regardless of exposure, especially total white blood cells and neutrophils. Fulvestrant-induced neutrophilia was slightly dampened in acrolein-exposed females. Fulvestrant also primed multiple adverse acrolein-induced metabolic alterations. Importantly, systemic markers of acrolein-induced HPA activity were not impacted in mifepristone or fulvestrant + mifepristone co-treated rats. These data demonstrate that neuroendocrine co-regulation by ER and GR might explain acrolein susceptibility differences, contributing novel mechanistic information to the growing recognition of gonadal hormone influence in air pollution health effects susceptibility.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"109-125"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259014","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":"Computationally informed point of departure evaluation for proarrhythmic cardiotoxicity assessment using 3D engineered cardiac microtissues from human iPSC-derived cardiomyocytes.","authors":"Mark C Daley, Peter Bronk, Tae Yun Kim, Arvin H Soepriatna, Cao T Tran, Ulrike Mende, Kareen L K Coulombe, Bum-Rak Choi","doi":"10.1093/toxsci/kfaf094","DOIUrl":"10.1093/toxsci/kfaf094","url":null,"abstract":"<p><p>Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a promising new approach for in vitro proarrhythmic cardiotoxicity assessment. However, variation due to differentiation batch, individual sample variation, and non-linear responses to test drugs complicate the prediction of proarrhythmic drug concentrations. This study combines a computational human action potential (AP) model of hERG channel block with experimental data from three-dimensional hiPSC-CM engineered microtissues to optimize point of departure (POD) estimation of drug-induced prolongation of AP duration (APD). Computer simulations predicted that APD prolongation from hERG block follows a logistic curve and that >81% hERG block induced early afterdepolarizations (EADs), which significantly shifted the APD response curve. Curve fitting of APD response by logistic, bilinear breakpoint, and maximal curvature was more accurate prior to EAD onset. Goodness-of-fit testing indicated that logistic regression with ≥6 test concentrations was sufficient to accurately estimate PODs. Power analysis, based on experimental variations between batches (n = 14), molds (n = 57), and microtissues (n = 1701), predicted that PODs from 2 ∼ 3 batches with 10 microtissues per mold using a 5% threshold for APD prolongation detected proarrhythmic cardiotoxicity with a negligible false positive rate. We then applied this POD analysis to hiPSC-CM microtissue data after treatment with well-characterized drugs (i.e. cisapride, ranolazine, quinidine, and verapamil). Using bootstrapping, we estimated PODs and confidence intervals that matched concentrations known to cause proarrhythmic effects in patients. This study identified a robust method for calculating PODs for proarrhythmic cardiotoxicity risk in vitro and developed a framework for experimental design in this and other in vitro platforms.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"221-237"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683153","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":"A cheminformatics workflow for higher-throughput modeling of chemical exposures from biosolids.","authors":"Paul M Kruse, Caroline L Ring","doi":"10.1093/toxsci/kfaf081","DOIUrl":"10.1093/toxsci/kfaf081","url":null,"abstract":"<p><p>The U.S. Environmental Protection Agency's Biosolids Screening Tool can predict potential human and ecological exposures to chemical contaminants in treated sewage sludge biosolids, but large quantities of chemical-specific physico-chemical data are required to parameterize the model. Here, an R workflow is presented that leverages publicly available databases of chemical information, particularly the U.S. EPA's CompTox Chemicals Dashboard, to prepare data for model simulations using the Biosolids Screening Tool. The workflow is publicly available at https://github.com/USEPA/CompTox-ExpoCast-autoBST. The automated Biosolids Screening Tool workflow (autoBST) reduces the time to gather data necessary to screen hundreds of chemicals from days to just a few minutes. autoBST is a practical example of the utility of leveraging the US EPA CompTox Chemicals Dashboard. autoBST provides transparent and reproducible data retrieval and input into existing models, allowing assessors to defensibly prioritize chemicals in biosolids that may pose a risk to human health or the environment.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"126-138"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259013","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":"Reader comment on: Modeling the developing nervous system: a neuroscience perspective on the use of new approach methodologies in developmental neurotoxicity testing.","authors":"Timothy J Shafer, Monique Perron, Elizabeth Mendez, Yumei Tan, Anna Lowit, Stan Barone","doi":"10.1093/toxsci/kfaf097","DOIUrl":"10.1093/toxsci/kfaf097","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"256-258"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683156","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 reader comment on: Modeling the developing nervous system: a neuroscience perspective on the use of new approach methodologies in developmental neurotoxicity testing.","authors":"Andrew J Newell, Heather B Patisaul","doi":"10.1093/toxsci/kfaf098","DOIUrl":"10.1093/toxsci/kfaf098","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"259-260"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683158","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":"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 remains 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 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. These studies demonstrate that an environmentally relevant mixture of OPEs 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":"148-160"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448188/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging toxicogenomics in a weight of evidence approach to demonstrate a CAR-mediated mode of action for cyclobutrifluram-related mouse liver tumors.","authors":"Fang Zhang, Caleb C Lord, Aniko Kende, David E Cowie, Liam B Doonan, Kathryn A Bailey, Elizabeth F McInnes, Angela Hofstra","doi":"10.1093/toxsci/kfaf085","DOIUrl":"10.1093/toxsci/kfaf085","url":null,"abstract":"<p><p>Toxicogenomics-based approaches are powerful tools for investigating the mode of action and human relevance of chemical-induced effects in animal toxicity studies, thus supporting human risk assessment and regulatory decisions. Here, we incorporated transcriptomics and metabolomics into a mode of action assessment of male mouse liver tumors observed following 80-week dietary exposure to cyclobutrifluram, a novel complex II succinate dehydrogenase inhibitor agrochemical. The assessment was conducted using the framework developed by the International Programme on Chemical Safety (IPCS) and the International Life Sciences Institute (ILSI), based on activation of the nuclear constitutive androstane receptor (CAR) and subsequent downstream events that have been established as human non-relevant. Cyclobutrifluram was shown to activate rat, mouse, and human CAR in in vitro transactivation assays. Dietary administration of cyclobutrifluram in male mice was associated with time- and/or dose-dependent liver weight increases, centrilobular hepatocellular hypertrophy, induction of CAR-related liver enzyme activity, specifically CYP2B and CYP3A, and hepatocellular proliferation. Transcriptomics analysis of mouse liver identified cyclobutrifluram-induced gene expression profiles consistent with CAR activation, based on published signatures and similarity to the reference CAR inducer phenobarbital. Metabolomics analysis of mouse plasma and liver further indicated that cyclobutrifluram induced similar biochemical changes as phenobarbital, with no evidence of any additional activity. Overall, this work demonstrates how toxicogenomics can provide valuable weight of evidence to identify the mode of action for chemical-induced rodent liver tumors and to exclude alternative modes of action.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"238-255"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275958","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":"ToxPoint: Of hammers and nails-understanding academic challenges with \"context of use\" and \"fit for purpose\".","authors":"Ivan Rusyn","doi":"10.1093/toxsci/kfaf058","DOIUrl":"10.1093/toxsci/kfaf058","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"29-30"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The pyrethroid insecticide deltamethrin disrupts neuropeptide and monoamine signaling pathways in the gastrointestinal tract.","authors":"Alexandria C White, Ian N Krout, Sabra Mouhi, Lisa Blackmer-Raynolds, Jianjun Chang, Sean D Kelly, William Michael Caudle, Timothy R Sampson","doi":"10.1093/toxsci/kfaf076","DOIUrl":"10.1093/toxsci/kfaf076","url":null,"abstract":"<p><p>Enteroendocrine cells (EECs) are a rare cell type of the intestinal epithelium. Various subtypes of EECs produce distinct repertoires of monoamines and neuropeptides, which modulate intestinal motility and other physiologies. EECs also possess neuron-like properties, suggesting a potential vulnerability to ingested environmental neurotoxicants. One such group of toxicants is pyrethroids, a class of prevalent insecticides used residentially and agriculturally. Pyrethroids agonize voltage-gated sodium channels (VGSCs), inducing neuronal excitotoxicity, and affect the function of monoamine-producing neurons. Given their anatomical location at the interface with the environment and their expression of VGSCs, EECs likely represent a vulnerable cell type to oral pyrethroid exposure. In this study, we used the EEC cell line, STC-1 cells, to evaluate the effects of the common pyrethroid deltamethrin on the functional status of EECs. We find that deltamethrin impacts both the expression of serotonergic pathways and inhibits the adrenergic-evoked release of an EEC hormone, glucagon-like peptide 1, in vitro. In a mouse model of oral exposure, we found that deltamethrin induced an acute, yet transient, loss of intestinal motility in both fed and fasted conditions. This constipation phenotype was accompanied by a significant decrease in peripheral serotonin production and an inhibition of nutrient-evoked intestinal hormone release. Together, these data demonstrate that deltamethrin alters monoaminergic signaling pathways in EECs and regulates intestinal motility. This work demonstrates a mechanistic link between pyrethroid exposure and intestinal impacts relevant to pyrethroid-associated diseases, including inflammatory bowel disease, neurodegenerative disease, and metabolic disorders.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"208-220"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448213/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144498090","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":"Estimation of Benchmark Dose Ratio Distributions for Subchronic-to-Chronic Extrapolation Using Meta-Analysis.","authors":"Todd Blessinger, John Fox, Jeffry Dean","doi":"10.1093/toxsci/kfaf119","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf119","url":null,"abstract":"<p><p>Recently, the International Programme on Chemical Safety (IPCS) developed a unified probabilistic framework for deriving reference values, and a software tool, Approximate Probabilistic Analysis (APROBA), to help implement this framework. The distributions of multiple sources of uncertainty and variability were estimated, including uncertainty when extrapolating from subchronic to chronic data. The subchronic-to-chronic distribution was estimated using ratios between subchronic and chronic benchmark doses (BMD) and was determined to be approximately lognormal, with parameter values reported by IPCS. These parameters were estimated largely from historical data on body and organ weights from toxicological studies. We estimated the distribution using a larger collection of data, including histopathological and clinical endpoints. Our analysis determined that key assumptions of the method and the default values in APROBA are consistent with the results from the new data. However, the uncertainty of predictions for dichotomous response data was greater than assumed in APROBA, and the reference values derived using our new results were lower than those derived from APROBA (by 25% in an example case). Also, APROBA's default parameter values do not account fully for the uncertainty of predicted chronic BMDs. Most importantly, uncertainty of the prediction can be much greater than assumed in APROBA if BMDs are accepted when they fall well outside the observed dose range or when an upper confidence limit is not quantifiable. Careful evaluation of dose-response model fit, including a number of indicators of model suitability in addition to standard goodness-of-fit statistics, is necessary to improve quantification of uncertainty.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144970516","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}