Toxicology letters最新文献

{"title":"An integrated in vitro and in silico testing strategy applied to PFAS inhibition of antibody production to define a tolerable daily intake","authors":"Martina Iulini ,&nbsp;Aafke W.F. Janssen ,&nbsp;Karsten Beekmann ,&nbsp;Giulia Russo ,&nbsp;Francesco Pappalardo ,&nbsp;Styliani Fragki ,&nbsp;Alicia Paini ,&nbsp;Emanuela Corsini","doi":"10.1016/j.toxlet.2025.111817","DOIUrl":"10.1016/j.toxlet.2025.111817","url":null,"abstract":"<div><div>Per- and polyfluoroalkyl substances (PFAS) are widely used chemicals known for their persistence, bioaccumulation, and adverse health effects, particularly on the immune system. Epidemiological studies link PFAS exposure to immunosuppression, with increased infection susceptibility and reduced vaccine efficacy. In this paper, we describe the workflow we used to establish an integrated testing strategy (ITS) combining <em>in vitro</em> and <em>in silico</em> methods to model PFAS inhibition of antibody production and to define a tolerable daily intake. This strategy was based on data generated within an EFSA-sponsored project. Using human peripheral blood mononuclear cells, the effects of PFAS on antibody production were assessed. Mathematical models were then applied to determine PFAS free concentrations <em>in vitro</em>, while Physiologically Based Kinetics (PBK) modeling enabled quantitative <em>in vitro</em> to <em>in vivo</em> extrapolation (QIVIVE) to translate <em>in vitro</em> effects into external doses. In addition, the Universal Immune System Simulator was used to predict immune-related outcomes and threshold doses for sensitive populations. Following this strategy, we were able to demonstrate that the oral equivalent effect doses derived through QIVIVE were similar to, or lower than, the tolerable weekly intake established by EFSA for PFAS, indicating that our approach is conservative. We demonstrate the possibility of using alternative methods for studying PFAS toxicity, offering insights into their dynamics and kinetics without animal testing. The strategy provides a promising framework for assessing other chemicals, advancing toxicology toward more human-relevant and ethical practices.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111817"},"PeriodicalIF":2.9,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906689","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":"Mechanisms, pathological features, and intervention strategies for nitrogen mustard-induced skin toxicity","authors":"Bing Zhu ,&nbsp;Guanchao Mao ,&nbsp;Qinghe Meng ,&nbsp;Ang Li ,&nbsp;Chaoying Jin ,&nbsp;Yuchong Wang ,&nbsp;Xinwei Wang ,&nbsp;Wenjun Xue ,&nbsp;Fangzhen Hou ,&nbsp;Junjie Yang ,&nbsp;Qingqiang Xu ,&nbsp;Chunyu Xue ,&nbsp;Minliang Wu","doi":"10.1016/j.toxlet.2025.111815","DOIUrl":"10.1016/j.toxlet.2025.111815","url":null,"abstract":"<div><div>Nitrogen mustard (NM) is a representative alkylating vesicant that produces severe and long-lasting damage to the skin. This review summarizes current understanding of its pathological features, molecular mechanisms, and therapeutic approaches, with emphasis on how key signaling pathways interact with one another. Evidence suggests that NM-induced toxicity develops as a cascade of interconnected processes, where genotoxic stress, oxidative imbalance, and innate immune activation mutually reinforce each other. Based on this framework, we outline available intervention strategies and discuss promising directions for future studies.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111815"},"PeriodicalIF":2.9,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906716","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":"Advances in understanding the neurotoxicity of lead, cadmium, arsenic, and therapeutic strategies","authors":"Yi-Ling Li ,&nbsp;Zhi-Xin Huang ,&nbsp;Jian-chao Peng ,&nbsp;Thanh-Tung Ho ,&nbsp;Hai Huang ,&nbsp;Michael Aschner ,&nbsp;Yue-Ming Jiang","doi":"10.1016/j.toxlet.2025.111810","DOIUrl":"10.1016/j.toxlet.2025.111810","url":null,"abstract":"<div><div>The rapid progression of industrialization and urbanization has intensified the public health threat posed by heavy metal pollution. Among these, lead (Pb), cadmium (Cd), and arsenic (As) are pervasive environmental toxicants capable of entering the human body via multiple exposure routes, leading to profound neurotoxic effects. Conventional chelation therapy, when used long-term, can lead to renal and gastrointestinal diseases. This review aims to summarize the neurotoxicity mechanisms of Pb, Cd, and As. Additionally, it focuses on the latest advancements in therapeutic strategies for their neurotoxicity. Particular emphasis is placed on evaluating research progress of nanoparticle-assisted therapeutic approaches. It is expected that this review will offer theoretical and empirical support and research insights for the development of more efficient therapeutic methods in the future.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"415 ","pages":"Article 111810"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844322","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":"Predicting acute developmental toxicity of chemicals in embryos of the African clawed frog (Xenopus laevis): Calibration and validation of regression-based quantitative structure activity relationship models for hazard assessment of chemicals in anuran amphibians","authors":"Christian Novello ,&nbsp;Matteo Riccardo Di Nicola ,&nbsp;Jean Lou CM Dorne ,&nbsp;Erika Colombo ,&nbsp;Edoardo Luca Viganò ,&nbsp;Manuel E. Ortiz-Santaliestra ,&nbsp;Nynke Kramer ,&nbsp;Edoardo Carnesecchi ,&nbsp;Anna Melina Steinbach ,&nbsp;Ivano Eberini ,&nbsp;Antony Williams ,&nbsp;Emilio Benfenati ,&nbsp;Alessandra Roncaglioni","doi":"10.1016/j.toxlet.2025.111813","DOIUrl":"10.1016/j.toxlet.2025.111813","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Global decline of amphibian populations has been correlated with a range of endogenous and exogenous variables including their unique physiology and ecology, exposure to chemicals, habitat reduction, climate change, as well as biological hazards such as emerging infectious diseases. The African clawed frog (&lt;em&gt;Xenopus laevis&lt;/em&gt;) is an OECD test species used in toxicity testing as a specific proxy for humans and environmentally relevant species, for which acute toxicity data for a range of chemicals have been generated historically by industry, a number of public health agencies and academia. Of particular relevance are mechanistic effects of endocrine-active substances on metamorphosis and the thyroid axis, resulting in developmental toxicity. From such toxicity data, no open-source quantitative structure-activity relationships (QSARs) have been developed as in silico tools to predict such toxicity for data-poor chemicals in &lt;em&gt;X&lt;/em&gt;. &lt;em&gt;laevis.&lt;/em&gt; Such QSAR models can provide a quantitative starting point for the hazard assessment of chemicals in other anuran amphibians. This manuscript provides a description of the data collection and curation from the largest historical databases including the US EPA ECOTOX knowledgebase and the Ortiz-Santaliestra databases available for &lt;em&gt;Xenopus&lt;/em&gt; embryos as acute median lethal concentrations (LC&lt;sub&gt;50&lt;/sub&gt;-12 h) for a total of 349 unique structures and 1978 individual entries. After data curation, the database contained 359 individual entries for a total of 175 compounds, and were computed using the negative logarithm of molar concentrations expressed as 12 h log 1/LC50 mmol/L. Subsequently, the database was then split into training set, test set and prediction set with 120, 40 and 13 compounds, respectively. These datasets were then used for the development and validation of two different QSAR models: 1. A k-Nearest Neighbours (k-NN) models using istKNN (in silico tools – KNN). 2. A multiple linear regression model (MLR) using the QSARINS (QSAR-INSUBRIA) software version 2.2.4. Overall, the QSAR models performed well for predicting acute toxicity of chemicals in &lt;em&gt;Xenopus&lt;/em&gt; embryos and the MLR model performed slightly better than the k-NN model with correlation coefficients of 0.76 and 0.75 and root mean square errors of 0.63 and 0.67, respectively. However, underestimation of predictions for highly toxic compounds were observed and these limitations are discussed for both the k-NN and multiple linear regression model in the light of mechanistic interpretation and expert knowledge. Variability in the experimental datasets as well as under-representation of the most toxic compounds in the database are highlighted as major drivers influencing such underpredictions. Future directions from the present work include the modelling of other endpoints and developmental stages as well as other amphibian species using the available, although limited, data. Overall, it can be foreseen in ","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111813"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896940","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":"Effects of cannabidiol on the viability and neuronal differentiation of human iPS cells","authors":"Koushirou Sogawa ,&nbsp;Masahiko Funada","doi":"10.1016/j.toxlet.2025.111812","DOIUrl":"10.1016/j.toxlet.2025.111812","url":null,"abstract":"<div><div>Cannabidiol (CBD) is a non-psychoactive cannabinoid with increasing global use, yet safety data during pregnancy remain limited. Preclinical studies suggest possible developmental neurotoxicity. Here, we examined the effects of CBD (0.001–100 μM) on human induced pluripotent stem cells (hiPSCs) using cell counting, morphology, flow cytometry, and qRT-PCR. Acute exposure to CBD (≥10 μM) markedly reduced hiPSC viability, accompanied by morphological disruptions and upregulation of caspase-3 and −7 within 3–5 h. These effects were significantly attenuated by the pan-caspase inhibitor Z-VAD-FMK, indicating caspase-dependent apoptosis as a key mechanism. Chronic exposure to CBD (0.001–1 μM) for 7 days did not alter transcriptional profiles of <em>Nanog</em>, <em>Pax6</em>, or <em>Map2</em> during neural ectodermal induction, and immunocytochemical analyses further confirmed that early neuroectodermal morphology was preserved, with comparable PAX6- and NESTIN-positive populations in CBD-treated and control cultures. However, higher CBD concentrations caused marked cytotoxicity and impaired colony formation. These findings define a narrow concentration window between safe and toxic levels, highlighting stage-specific vulnerability to CBD during early development. Use of CBD in pregnancy should therefore be approached cautiously, considering potential risks to fetal neural development.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111812"},"PeriodicalIF":2.9,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893162","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":"Organic matter of PM2.5 induces cardiomyocyte toxicity by driving oxidative potential and impairing AMPK/PGC-1α-dependent mitochondrial biogenesis","authors":"Shanshan Chen ,&nbsp;Wenqi Chen ,&nbsp;Hong Geng ,&nbsp;Zhiping Li ,&nbsp;Jianwei Yue ,&nbsp;Ruijin Li","doi":"10.1016/j.toxlet.2025.111814","DOIUrl":"10.1016/j.toxlet.2025.111814","url":null,"abstract":"<div><h3>Introduction</h3><div>While fine particulate matter (PM_2.5) is an established risk factor for cardiovascular disease (CVD), the relative contribution of its specific chemical components to cardiotoxicity remains unclear. This study aimed to systematically compare the cytotoxicity driven by the oxidative potential (OP) of different PM_2.5 components and elucidate the underlying mechanisms.</div></div><div><h3>Methods</h3><div>We conducted a comparative assessment of the water-soluble particle (WSP), non-water-soluble particle (NWSP), and organic matter (OM) of PM_2.5 collected in winter in Taiyuan, China, in H9c2 cardiomyocytes, focusing on OP, cytotoxicity, and mitochondrial biogenesis. OP was measured by the dithiothreitol (DTT) assay, a non-cellular method. The mitochondrial biogenesis-related gene expressions (AMPKα, PGC-1α, Nrf1, Nrf2, TFAM) were quantified by RT-qPCR and western blot. The mitochondrial DNA (mtDNA) copy number was detected. The correlation between the PM_2.5 composition (water-soluble ions, metals, and PAHs, etc.) and OP was analyzed.</div></div><div><h3>Results</h3><div>Among the three components, OM exhibited the highest OP values. Cellular experiments consistently demonstrated that the OM was the most potent inducer of ROS, LDH release, and ATP depletion, and displayed the lowest LD₅₀. Mechanistically, it most severely suppressed mtDNA copy number and the expression of key regulators of mitochondrial biogenesis, including AMPKα, PGC-1α, and its downstream targets Nrf1, Nrf2, and TFAM. Critically, correlation analysis revealed that the OP was strongly associated with the content of PM_2.5-bound PAHs.</div></div><div><h3>Conclusion</h3><div>The OM fraction, particularly the PAHs, is the primary driver of PM_2.5-induced cardiomyocyte toxicity. This effect is mediated through a mechanism involving high oxidative potential, which triggers severe oxidative stress and disrupts mitochondrial biogenesis. This study provides crucial experimental evidence for the increased CVD risk associated with PM_2.5.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111814"},"PeriodicalIF":2.9,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145886411","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":"Comparative transcriptomic analysis reveals STAT3 as a candidate gene involved in aristolochic acid I-induced hepatorenal toxicity","authors":"Gerui Zhu ,&nbsp;Fan Wang ,&nbsp;Siyuan Wang ,&nbsp;Kai Huang ,&nbsp;Gaofeng Chen ,&nbsp;Chenghai Liu ,&nbsp;Yuan Peng ,&nbsp;Yanyan Tao","doi":"10.1016/j.toxlet.2025.111811","DOIUrl":"10.1016/j.toxlet.2025.111811","url":null,"abstract":"<div><div>Aristolochic acids, such as Aristolochic acid I (AAI), are widely recognized for their nephrotoxicity and potential to cause hepatocellular carcinoma. Although previous studies have demonstrated the ability of AAI to induce hepatorenal toxicity, the precise underlying mechanism remains unclear. The objective of this research is to investigate the mechanisms by which AAI induces hepatorenal toxicity. Both in vivo and in vitro studies were conducted, involving the administration of AAI to C57BL/6 mice and the exposure of human hepatocytes (HL-7702/L-02) and proximal kidney tubular epithelial cell (HK-2) to AAI. RNA sequencing analysis of liver and kidney was conducted to ascertain hepatorenal toxicity mechanism, with follow-up experiments for validation. Upon identifying the common target, STAT3, for AAI induced hepatorenal toxicity, we further employed STAT3 inhibitor, Stattic for in vitro validation. The results revealed that elevated expressions of STAT3 caused hepatorenal toxicity, leading to impaired liver and kidney functions, as well as tissue damage. Western Blot demonstrated that AAI increased STAT3 phosphorylation. Furthermore, the application of the STAT3 inhibitor reduced damage to hepatocytes and kidney tubular epithelial cell, confirming the effectiveness of Stattic against AAI-induced harm. These findings provide evidence of the significant hepatorenal toxicity of AAI and indicate that STAT3 may serve as a potential common target.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111811"},"PeriodicalIF":2.9,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889390","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":"Research on the therapeutic effects of recombinant protein PON1Q/R192 intervention on mice poisoned by different categories of organophosphorus compounds","authors":"Shuang Zhou ,&nbsp;Yue Cui ,&nbsp;Lu Li ,&nbsp;Pengsi Zhang ,&nbsp;Zhe Zhu ,&nbsp;Li Yuan ,&nbsp;Min Zhao","doi":"10.1016/j.toxlet.2025.111816","DOIUrl":"10.1016/j.toxlet.2025.111816","url":null,"abstract":"<div><div>Organophosphorus compounds are widely used in agriculture, but their poisoning poses a great threat. This study focuses on exploring the therapeutic effects of rePON1_Q192 and rePON1_R192 on mice poisoned with different types of organophosphorus compounds. These two recombinant proteins are prepared via gene synthesis into the pET - 32a vector and expression in <em>E. coli</em> BL21.Organophosphorus compounds are divided into two groups by structure: one group contained a pyrimidine ring (similar in structure to diazinon), and the other group contained multiple chlorine atoms (similar in structure to chlorpyrifos). Each group included a control group, a rePON1_Q/R192 control group, a poisoned group, and a rePON1_Q/R192 treatment group. Kaplan-Meier survival analysis assessed the 12-h survival proportion of mice per group. Use ELISA to detect IL - 6 expression, HE staining to assess lung and brain injuries, TUNEL staining to observe apoptosis in brain and lung tissues, and electron microscopy to examine mitochondrial structural changes in brain tissues and alterations in lung tissues of each group. The results showed that rePON1_Q/R192 could improve the clinical manifestations of mice with organophosphorus poisoning, increase the survival proportion, reduce the release of the inflammatory factor IL - 6, alleviate the pathological damage of brain and lung tissues, as well as mitochondrial damage. The number of apoptotic cells in the brain and lung tissues of mice in the rePON1_Q/R192 treatment group was significantly reduced. In animal experiments, the therapeutic effects vary: rePON1_Q192 is better for diazinon poisoning, while rePON1_R192 is better for chlorpyrifos-like poisoning. Thus, the therapeutic effects of rePON1_Q192 and rePON1_R192 vary depending on the type of organophosphorus poison, likely due to differences in their molecular structures.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111816"},"PeriodicalIF":2.9,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889420","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":"Association between polycyclic aromatic hydrocarbons (PAHs) and insulin resistance: A comprehensive study utilizing NHANES data and network toxicology","authors":"Longbao Xu ,&nbsp;Lerong Cheng ,&nbsp;Hanqing Wu ,&nbsp;Zelong Pan ,&nbsp;Guoqing Li ,&nbsp;Yanyu Zhao ,&nbsp;Ziqi Li ,&nbsp;Yuxin Ren ,&nbsp;Mengyao Gao ,&nbsp;Yubo Ma ,&nbsp;Faming Pan","doi":"10.1016/j.toxlet.2025.111809","DOIUrl":"10.1016/j.toxlet.2025.111809","url":null,"abstract":"<div><div>Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants with potential endocrine-disrupting effects, yet prior epidemiological research on their association with insulin resistance has yielded inconsistent results. Using data from 3294 participants in the National Health and Nutrition Examination Survey (NHANES) cycles from 2005 to 2016, we applied multivariable linear regression, restricted cubic spline models, weighted quantile sum (WQS) regression, and the g-computation model to examine the relationships between individual and mixed PAH exposures and insulin resistance, with subgroup analyses stratified by sex and age. The analyses revealed that 2-hydroxyfluorene (2-FLU) and 1-hydroxyphenanthrene (1-PHE) were significantly positively associated with the triglyceride–glucose index (TyG), metabolic score for insulin resistance (METS-IR), and triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C) (P &lt; 0.05). Consistently, both weighted quantile sum regression and quantile g-computation demonstrated significant positive associations between PAH mixture exposure and TyG, MEST-IR, triglyceride–glucose–body mass index (TyG-BMI), and TG/HDL-C (P &lt; 0.05), with 2-FLU and 1-PHE identified as dominant contributors. Stratified analyses suggested that women and non-elderly individuals may represent susceptible subpopulations. Network toxicology and molecular docking further indicated that PAHs may disrupt glucose homeostasis by inducing inflammation, promoting oxidative stress, and interfering with insulin signaling pathways. Together, these findings provide both epidemiological and mechanistic evidence for the impact of PAHs on insulin resistance, underscoring the importance of considering PAHs as potential environmental correlates of insulin resistance and related metabolic disorders.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"415 ","pages":"Article 111809"},"PeriodicalIF":2.9,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145840936","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":"Effects of gestational prednisone exposure on long bone development in fetal mice: Role of Sost/Wnt/β-catenin signaling pathways","authors":"Ming Tu ,&nbsp;Hangyuan He ,&nbsp;Liaobin Chen ,&nbsp;Yinxian Wen ,&nbsp;Hui Wang","doi":"10.1016/j.toxlet.2025.111808","DOIUrl":"10.1016/j.toxlet.2025.111808","url":null,"abstract":"<div><div>Prednisone, a synthetic glucocorticoid, is widely used in the treatment of various maternal diseases during pregnancy, such as autoimmune disorders. However, epidemiological studies suggest that prenatal prednisone treatment may lead to fetal growth restriction. Preclinical research has shown that gestational prednisone exposure (PPE) exerts developmental toxicity on multiple organs in offspring. Nevertheless, the impacts of PPE at different doses and time windows on long bone development in offspring remain unclear. This study examined the effects of prednisone (PPE) on fetal long bone development using clinically relevant dosing regimens. pregnant mice received PPE at different doses (0.25, 0.5, or 1.0 mg/kg·d) throughout gestation or at 1.0 mg/kg·d during specific gestational periods: entire gestation (GD0–18), early pregnancy (GD0–9), or mid-to-late pregnancy (GD10–18). Results demonstrated that PPE induced femoral dysplasia in both male and female fetal mice, manifested as reduced femoral length, delayed growth plate differentiation, and impaired primary ossification center formation. These abnormalities were concurrent with suppressed development of osteoblasts, osteoclasts, and endothelial cells. Furthermore, PPE inhibited long bone development in a dose-dependent manner, with the most pronounced effects observed during mid-to-late gestation. In vitro experiments confirmed that prednisone, converted to prednisolone, suppresses the <em>Sost/Wnt/β-catenin</em> signaling pathway. In conclusion, PPE inhibits long bone development in male and female fetal mice, predominantly at high doses and during mid-late pregnancy, without significant sexual dimorphism. Mechanistically, suppression of the <em>Sost/Wnt/β-catenin</em> signaling pathway may mediate the long bone developmental toxicity of PPE. This study enhances our understanding of the risks associated with gestational prednisone exposure and provides theoretical and experimental evidence for guiding rational medication and effectively evaluating the long bone developmental toxicity of prednisone.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"415 ","pages":"Article 111808"},"PeriodicalIF":2.9,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800757","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}