Toxicological Sciences最新文献

{"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":"https://doi.org/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":"https://doi.org/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}

{"title":"Nicotinamide mononucleotide ameliorates impaired testicular spermatogenesis in uranium-exposed mice by modulating glycolytic pathways.","authors":"Hui Wu, Bingsheng Huang, Ziyu Zhou, Xiaocan Lei, Yu Zhang, Wendian She, Qingwen Peng, Yueze Zhu, Junli Wang, Mingyou Dong","doi":"10.1093/toxsci/kfaf068","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf068","url":null,"abstract":"<p><p>Natural uranium is a ubiquitous element in the environment, and human exposure to low levels of uranium is unavoidable. Several concerns have recently been raised about the reproductive effects of chronic exposure to low levels of uranium. Therefore, the aim of this study was to investigate the protective effect of Nicotinamide mononucleotide（NMN） on uranium exposure-induced testicular sperm function in mice. To this end, a research model was established in which testicular damage and spermatogenic dysfunction were induced in adult male mice by intraperitoneal injection of two different doses of uranyl nitrate. Following a week of intraperitoneal injection, the mice were given oral doses of 500 mg/kg of NMN, a dose that was validated in an in vitro cellular model. The results demonstrated a decline in testicular weight and epididymis weight, along with a reduction in sperm count, in comparison to the control group. Subsequent observation of testicular morphology revealed the presence of disorganized seminiferous tubules, characterized by reduced area and diameter. Concurrently, a downregulation of the anti-apoptotic factor (Bcl-2) and an upregulation of the apoptotic factor (Bax) were observed in the testis. Furthermore, an analysis of testicular genetic expression levels of Sertoli cell (SCs) markers (WT-1, Sox9, PCNA, and Vimentin) revealed a substantial exacerbation of pathological changes, including an augmentation in the severity of tubular degeneration. NMN treatment resulted in a significant enhancement of testicular function, as evidenced by an increase in epididymal and testicular weights, as well as sperm counts, when compared to saline-treated uranium-exposed mice.</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":"144080550","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":"Application of a metabolic network-based graph neural network for the identification of toxicant-induced perturbations.","authors":"Keji Yuan, Rance Nault","doi":"10.1093/toxsci/kfaf065","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf065","url":null,"abstract":"<p><p>Transcriptomic analyses have been an effective approach to investigate the biological responses and metabolic perturbations by environmental contaminants in rodent models. However, it is well recognized that metabolic networks are highly connected and complex, and that traditional gene expression analysis methods, including pathway analyses, have a limited ability to capture these complexities. Given that metabolism can be effectively represented as a graph, this study aims to apply a network-based graph neural network (GNN) to uncover novel or hidden metabolic perturbations in response to a toxicant. A GNN model based on the mouse Reactome pathways was trained and validated on 7,689 transcriptomic samples from 26 mouse tissues curated from Recount3. This model was then used to identify important reactions in publicly available data from livers of mice treated with the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) achieving a performance of 100% when comparing a single dose to a control group. Integrated gradients and centrality analyses identified perturbation of the SUMOylation, cell cycle, P53 signaling, and collagen biosynthesis pathways by TCDD which were not identified using a pathway analysis approach. Collectively, our results demonstrate that GNNs can reveal novel mechanistic insights into toxicant-mediated metabolic disruption, presenting a putative strategy to characterize biological responses to toxicant exposures. Our studies illustrate how the use of a reaction-based graph neural network can support the discovery of toxicant-induced metabolic perturbations, and highlight strengths and challenges in the application of artificial intelligence methods for environmental health research.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187997","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":"Perfluorooctane sulfonate (PFOS) 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":"https://doi.org/10.1093/toxsci/kfaf066","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Exposure to pollutants including the ubiquitous 'forever chemical', Perfluorooctane sulfonate (PFOS) has increasingly been associated with metabolic dysfunction-associated steatotic liver disease (MASLD). 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 plus pollutant) mouse model, enabling testing of this hypothesis. Here, we elucidate the metabolic and disease-modifying effects of PFOS in this model.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Male C57BL/6J mice were fed isocaloric control or 5% Ethanol (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 5-6 hours later.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Approximately 60% of the administered PFOS dose accumulated in liver. PFOS exacerbated EtOH-induced hepatic steatosis and was associated by higher levels of plasma very low-density lipoprotein (vLDL) and alanine aminotransferase (ALT). PFOS upregulated hepatic ethanol-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 (ROS); apoptosis; liver fibrosis; and hepatocellular carcinoma (HCC). GO/KEGG 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 RT-PCR or Western blot, confirming key IPA predictions.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;PFOS is a metabolism disrupting chemical that worsened 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 highlight 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","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/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 three 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 mechanism of neurotoxicity.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}