Pub Date : 2026-02-01Epub Date: 2026-01-03DOI: 10.1016/j.toxlet.2025.111815
Bing Zhu , Guanchao Mao , Qinghe Meng , Ang Li , Chaoying Jin , Yuchong Wang , Xinwei Wang , Wenjun Xue , Fangzhen Hou , Junjie Yang , Qingqiang Xu , Chunyu Xue , Minliang Wu
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.
{"title":"Mechanisms, pathological features, and intervention strategies for nitrogen mustard-induced skin toxicity","authors":"Bing Zhu , Guanchao Mao , Qinghe Meng , Ang Li , Chaoying Jin , Yuchong Wang , Xinwei Wang , Wenjun Xue , Fangzhen Hou , Junjie Yang , Qingqiang Xu , Chunyu Xue , 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":"2026-02-01","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}
Pub Date : 2026-02-01Epub Date: 2025-12-30DOI: 10.1016/j.toxlet.2025.111816
Shuang Zhou , Yue Cui , Lu Li , Pengsi Zhang , Zhe Zhu , Li Yuan , Min Zhao
Organophosphorus compounds are widely used in agriculture, but their poisoning poses a great threat. This study focuses on exploring the therapeutic effects of rePON1Q192 and rePON1R192 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 E. coli 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 rePON1Q/R192 control group, a poisoned group, and a rePON1Q/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 rePON1Q/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 rePON1Q/R192 treatment group was significantly reduced. In animal experiments, the therapeutic effects vary: rePON1Q192 is better for diazinon poisoning, while rePON1R192 is better for chlorpyrifos-like poisoning. Thus, the therapeutic effects of rePON1Q192 and rePON1R192 vary depending on the type of organophosphorus poison, likely due to differences in their molecular structures.
{"title":"Research on the therapeutic effects of recombinant protein PON1Q/R192 intervention on mice poisoned by different categories of organophosphorus compounds","authors":"Shuang Zhou , Yue Cui , Lu Li , Pengsi Zhang , Zhe Zhu , Li Yuan , 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<sub>Q192</sub> and rePON1<sub>R192</sub> 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<sub>Q/R192</sub> control group, a poisoned group, and a rePON1<sub>Q/R192</sub> 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<sub>Q/R192</sub> 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<sub>Q/R192</sub> treatment group was significantly reduced. In animal experiments, the therapeutic effects vary: rePON1<sub>Q192</sub> is better for diazinon poisoning, while rePON1<sub>R192</sub> is better for chlorpyrifos-like poisoning. Thus, the therapeutic effects of rePON1<sub>Q192</sub> and rePON1<sub>R192</sub> 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":"2026-02-01","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}
Pub Date : 2026-02-01Epub Date: 2026-01-13DOI: 10.1016/j.toxlet.2026.111830
Xing Liu , Xinyi Wu , Mingzhu Xia, Yi Fan, Yichun Zhao, Junjie Han, Ruobing Chen, Yuting Peng, Man Qu
Sodium p-perfluorous nonenoxybenzenesulfonate (OBS), a widely used substitute for perfluorooctanesulfonic acid, may threaten ocular development, but its mechanisms remain unclear. In this study, zebrafish embryos were exposed to OBS (0, 0.01, 0.1, 1 mg/L) for 120 h. OBS exposure resulted in pronounced ocular developmental abnormalities, including lens deformation, reduced retinal layer thickness, and a significant decrease in eye size. Mechanistic analyses revealed that OBS induced oxidative stress and ferroptosis-associated alterations: the number of early apoptotic cells increased in a dose-dependent manner, accompanied by marked downregulation of key eye development genes (lhx4, pax6, rx1, and vsx1). Additionally, elevated Fe2 + and malondialdehyde levels, abnormally increased superoxide dismutase activity, and reduced catalase activity and glutathione content were observed. Expression levels of ferroptosis-related genes (gpx4, slc7a11, fth, and tfr) were also significantly altered. Notably, treatment with the ferroptosis-specific inhibitor Ferrostatin-1 (Fer-1) effectively alleviated OBS-induced ocular damage, further supporting ferroptosis as a central regulatory mechanism. Collectively, this study provides the first evidence that ferroptosis plays a pivotal role in OBS-induced ocular developmental defects in zebrafish embryos, offering insights into PFOS alternatives' risks and therapeutic targets.
{"title":"The novel PFOS substitute OBS induces visual developmental toxicity in zebrafish embryos via ferroptosis","authors":"Xing Liu , Xinyi Wu , Mingzhu Xia, Yi Fan, Yichun Zhao, Junjie Han, Ruobing Chen, Yuting Peng, Man Qu","doi":"10.1016/j.toxlet.2026.111830","DOIUrl":"10.1016/j.toxlet.2026.111830","url":null,"abstract":"<div><div>Sodium p-perfluorous nonenoxybenzenesulfonate (OBS), a widely used substitute for perfluorooctanesulfonic acid, may threaten ocular development, but its mechanisms remain unclear. In this study, zebrafish embryos were exposed to OBS (0, 0.01, 0.1, 1 mg/L) for 120 h. OBS exposure resulted in pronounced ocular developmental abnormalities, including lens deformation, reduced retinal layer thickness, and a significant decrease in eye size. Mechanistic analyses revealed that OBS induced oxidative stress and ferroptosis-associated alterations: the number of early apoptotic cells increased in a dose-dependent manner, accompanied by marked downregulation of key eye development genes (<em>lhx4, pax6, rx1,</em> and <em>vsx1</em>). Additionally, elevated Fe<sup>2 +</sup> and malondialdehyde levels, abnormally increased superoxide dismutase activity, and reduced catalase activity and glutathione content were observed. Expression levels of ferroptosis-related genes (<em>gpx4, slc7a11, fth,</em> and <em>tfr</em>) were also significantly altered. Notably, treatment with the ferroptosis-specific inhibitor Ferrostatin-1 (Fer-1) effectively alleviated OBS-induced ocular damage, further supporting ferroptosis as a central regulatory mechanism. Collectively, this study provides the first evidence that ferroptosis plays a pivotal role in OBS-induced ocular developmental defects in zebrafish embryos, offering insights into PFOS alternatives' risks and therapeutic targets.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111830"},"PeriodicalIF":2.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990842","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}
Pub Date : 2026-01-01Epub Date: 2025-12-02DOI: 10.1016/j.toxlet.2025.111787
Tao Liu , Xingtong Chen , Yanting Chu , Ruige Zhang , Zhixin Zhao
Phthalates are widespread environmental contaminants, yet their impact on liver function in older adults remains insufficiently understood. This cross-sectional study examined associations between urinary concentrations of 15 phthalate metabolites and serum liver biomarkers in elderly individuals. Metabolite levels were measured using liquid chromatography-tandem mass spectrometry and creatinine-adjusted. Multiple linear regression and Bayesian kernel machine regression (BKMR) models were applied to assess individual and combined effects. Several phthalate metabolites were positively associated with liver enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), and negatively associated with bilirubin (TBIL, DBIL), albumin, and total protein. BKMR analyses confirmed positive mixture effects on ALT, AST, ALP, and gamma-glutamyl transferase (GGT). Body mass index (BMI) modified these associations, suggesting a role of adipose tissue in phthalate accumulation and hepatic effects. These findings highlight potential subclinical liver dysfunction related to phthalate exposure in older adults, warranting further investigation in the context of environmental risk and healthy aging.
{"title":"Relationship between urinary phthalate metabolites and liver function indicators in the elderly in Northeast China","authors":"Tao Liu , Xingtong Chen , Yanting Chu , Ruige Zhang , Zhixin Zhao","doi":"10.1016/j.toxlet.2025.111787","DOIUrl":"10.1016/j.toxlet.2025.111787","url":null,"abstract":"<div><div>Phthalates are widespread environmental contaminants, yet their impact on liver function in older adults remains insufficiently understood. This cross-sectional study examined associations between urinary concentrations of 15 phthalate metabolites and serum liver biomarkers in elderly individuals. Metabolite levels were measured using liquid chromatography-tandem mass spectrometry and creatinine-adjusted. Multiple linear regression and Bayesian kernel machine regression (BKMR) models were applied to assess individual and combined effects. Several phthalate metabolites were positively associated with liver enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), and negatively associated with bilirubin (TBIL, DBIL), albumin, and total protein. BKMR analyses confirmed positive mixture effects on ALT, AST, ALP, and gamma-glutamyl transferase (GGT). Body mass index (BMI) modified these associations, suggesting a role of adipose tissue in phthalate accumulation and hepatic effects. These findings highlight potential subclinical liver dysfunction related to phthalate exposure in older adults, warranting further investigation in the context of environmental risk and healthy aging.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"415 ","pages":"Article 111787"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145678711","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}
Pub Date : 2026-01-01Epub Date: 2025-12-09DOI: 10.1016/j.toxlet.2025.111799
Oksana Gerzen , Daniil A. Kuznetsov , Veronika Votinova , Alyona Tzybina , Alexander Balakin , Ruslan Lisin , Ilzira Minigalieva , Marina Sutunkova , Larisa Nikitina , Yuri L. Protsenko
Lead is a widespread environmental xenobiotic known to adversely affect cardiovascular health. This study is the first to systematically assess the impact of subchronic lead acetate exposure (5.5, 11, and 22.88 mg/kg body weight, administered via intraperitoneal injections three times a week for six weeks) on the contractile properties of the right atrial and right ventricular myocardium in 12-month-old male rats, using both in vitro motility assays and physiological contraction measurements on myocardial strips from the same hearts. Lead exposure produced a dose-dependent decrease in thin filament sliding velocity over right atrial myosin, whereas the effects on right ventricular myosin were nonlinear. Higher doses of lead significantly reduced the fraction of motile filaments in the atrium, while lower doses affected the ventricle. Under physiological loading mode, right atrial myocardial strips generated approximately 20 % of the mechanical work produced by right ventricular strips. Increasing lead doses further reduced mechanical work in both chambers, with a more pronounced reduction in the atrium (≈65 %) than in the ventricle (≈17 %) at the highest dose. Maximum shortening velocity also declined with increasing lead concentration, particularly in the atrium at low afterloads. These findings demonstrate that the right atrial myocardium is more sensitive to subchronic lead intoxication than the right ventricular myocardium. Overall, this study provides the first comprehensive analysis of lead’s differential effects on atrial and ventricular contractility under physiological loading conditions.
{"title":"Dose-response to lead-induced alterations in right atrial and ventricular myocardial contractility in adult rats","authors":"Oksana Gerzen , Daniil A. Kuznetsov , Veronika Votinova , Alyona Tzybina , Alexander Balakin , Ruslan Lisin , Ilzira Minigalieva , Marina Sutunkova , Larisa Nikitina , Yuri L. Protsenko","doi":"10.1016/j.toxlet.2025.111799","DOIUrl":"10.1016/j.toxlet.2025.111799","url":null,"abstract":"<div><div>Lead is a widespread environmental xenobiotic known to adversely affect cardiovascular health. This study is the first to systematically assess the impact of subchronic lead acetate exposure (5.5, 11, and 22.88 mg/kg body weight, administered via intraperitoneal injections three times a week for six weeks) on the contractile properties of the right atrial and right ventricular myocardium in 12-month-old male rats, using both <em>in vitro</em> motility assays and physiological contraction measurements on myocardial strips from the same hearts. Lead exposure produced a dose-dependent decrease in thin filament sliding velocity over right atrial myosin, whereas the effects on right ventricular myosin were nonlinear. Higher doses of lead significantly reduced the fraction of motile filaments in the atrium, while lower doses affected the ventricle. Under physiological loading mode, right atrial myocardial strips generated approximately 20 % of the mechanical work produced by right ventricular strips. Increasing lead doses further reduced mechanical work in both chambers, with a more pronounced reduction in the atrium (≈65 %) than in the ventricle (≈17 %) at the highest dose. Maximum shortening velocity also declined with increasing lead concentration, particularly in the atrium at low afterloads. These findings demonstrate that the right atrial myocardium is more sensitive to subchronic lead intoxication than the right ventricular myocardium. Overall, this study provides the first comprehensive analysis of lead’s differential effects on atrial and ventricular contractility under physiological loading conditions.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"415 ","pages":"Article 111799"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145744674","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}
Pub Date : 2026-01-01Epub Date: 2025-12-16DOI: 10.1016/j.toxlet.2025.111789
Weilin Zhang , Kuize Liu , Boyuan Zhou , Dao Feng , Zhencong Li , Zhiwen Dai , Shengbang Huang , Jinguo Liang , Siyuan Chen , Zhongwei Wang , Weixiong Guo , Chao Mao , Yen Wei , Jinsong Wei
Although plastic products have offered substantial benefits to modern society and daily life, their degradation into microplastics (MPs) has raised significant concerns owing to their adverse effects on ecosystems and human health. This study investigated MP deposition in human skeletal tissues and elucidated their effects on bone metabolism. Comprehensive analysis of human bone tissue using Nile red staining, Raman spectroscopy, and infrared microspectroscopy identified MP particles in 33 out of 40 samples (covering the cervical, thoracic, and lumbar vertebrae, as well as the upper and lower limb bones). These detected MPs exhibited a granular morphology, with particle sizes ranging from 10 to 20 μm, predominantly composed of polyethylene and polypropylene, with 2–3 MPs/2 g bone tissues in each sample. To explore the underlying mechanisms, transcriptomic profiling of femoral tissues from MP-PE-fed mice revealed 870 up-regulated and 930 down-regulated genes, which were enriched in the hematopoietic cell lineage, NF-κB, PPAR, PI3K-Akt, and HIF-1 signaling pathways, and metabolic pathways. In vitro validation further demonstrated that MPs enhanced osteoclast differentiation by modulating the RANKL/OPG axis in bone marrow stromal cells, thereby activating the RANK-NFATc1 signaling pathway in Raw264.7 cells. These findings provide experimental and theoretical evidence of the detrimental impact of MPs on skeletal health, underscoring the urgent need for environmental and public health interventions.
{"title":"RANKL/OPG axis as a therapeutic target for microplastic-induced bone loss: Mechanistic insights from transcriptomic and functional validation","authors":"Weilin Zhang , Kuize Liu , Boyuan Zhou , Dao Feng , Zhencong Li , Zhiwen Dai , Shengbang Huang , Jinguo Liang , Siyuan Chen , Zhongwei Wang , Weixiong Guo , Chao Mao , Yen Wei , Jinsong Wei","doi":"10.1016/j.toxlet.2025.111789","DOIUrl":"10.1016/j.toxlet.2025.111789","url":null,"abstract":"<div><div>Although plastic products have offered substantial benefits to modern society and daily life, their degradation into microplastics (MPs) has raised significant concerns owing to their adverse effects on ecosystems and human health. This study investigated MP deposition in human skeletal tissues and elucidated their effects on bone metabolism. Comprehensive analysis of human bone tissue using Nile red staining, Raman spectroscopy, and infrared microspectroscopy identified MP particles in 33 out of 40 samples (covering the cervical, thoracic, and lumbar vertebrae, as well as the upper and lower limb bones). These detected MPs exhibited a granular morphology, with particle sizes ranging from 10 to 20 μm, predominantly composed of polyethylene and polypropylene, with 2–3 MPs/2 g bone tissues in each sample. To explore the underlying mechanisms, transcriptomic profiling of femoral tissues from MP-PE-fed mice revealed 870 up-regulated and 930 down-regulated genes, which were enriched in the hematopoietic cell lineage, NF-κB, PPAR, PI3K-Akt, and HIF-1 signaling pathways, and metabolic pathways. <em>In vitro</em> validation further demonstrated that MPs enhanced osteoclast differentiation by modulating the RANKL/OPG axis in bone marrow stromal cells, thereby activating the RANK-NFATc1 signaling pathway in Raw264.7 cells. These findings provide experimental and theoretical evidence of the detrimental impact of MPs on skeletal health, underscoring the urgent need for environmental and public health interventions.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"415 ","pages":"Article 111789"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145782981","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}
Pub Date : 2026-01-01Epub Date: 2025-12-18DOI: 10.1016/j.toxlet.2025.111808
Ming Tu , Hangyuan He , Liaobin Chen , Yinxian Wen , Hui Wang
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 Sost/Wnt/β-catenin 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 Sost/Wnt/β-catenin 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.
{"title":"Effects of gestational prednisone exposure on long bone development in fetal mice: Role of Sost/Wnt/β-catenin signaling pathways","authors":"Ming Tu , Hangyuan He , Liaobin Chen , Yinxian Wen , 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":"2026-01-01","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}
Pub Date : 2026-01-01Epub Date: 2025-12-05DOI: 10.1016/j.toxlet.2025.111797
Huo Yingchao , Ma Haoyan , Wang Zengchen , Zhao Haotang , Lu Tong , Qiao Ying , Wu Xiaotong , Zhang Yuezhu
As one of the most prevalently employed herbicides worldwide, atrazine (ATR) is widespread in the environment and is able to enter and impair the human body. Hepatic lipid metabolism disorders can be triggered by exposure to ATR. However, the underlying mechanism remains unclear. We performed a differential gene expression analysis using the NAFLD-related datasets GSE89632 and GSE160016 downloaded from the GEO database, both with the human liver as the samples. Then the GO and KEGG pathway enrichment analyses were performed. It was discovered that the FOXO1/PPARγ pathway might play a crucial role in hepatic lipid metabolism disorders. To confirm the hypothesis, forty 8-week-old male Wistar rats were randomly average exposed to different concentrations of ATR (0, 0.5, 5 and 50 mg/kg/d) by intragastric administration for 90 days. Then the liver tissue were isolated for histopathological observation; the levels of lipids were assessed by colorimetry; the expression of mRNA and protein was identified by Real-Time PCR and western blot. The findings demonstrated that the ATR-treated groups had higher levels of TC and TG in the liver; TC level in the serum was increased but TG level decreased. Besides, the expression of FOXO1, PPARγ, FASN, FABP4 and CD36 was also elevated. A correlation was observed between the lipid metabolism levels and the expression of FOXO1/PPARγ pathway genes. These results suggested that ATR can induce hepatic lipids accumulation by upregulating the expression of FOXO1/PPARγ. This study can offer insightful information for preventing and controlling risks related to agricultural residues.
{"title":"The role of FOXO1/PPARγ in atrazine-induced hepatic lipid metabolism disorders","authors":"Huo Yingchao , Ma Haoyan , Wang Zengchen , Zhao Haotang , Lu Tong , Qiao Ying , Wu Xiaotong , Zhang Yuezhu","doi":"10.1016/j.toxlet.2025.111797","DOIUrl":"10.1016/j.toxlet.2025.111797","url":null,"abstract":"<div><div>As one of the most prevalently employed herbicides worldwide, atrazine (ATR) is widespread in the environment and is able to enter and impair the human body. Hepatic lipid metabolism disorders can be triggered by exposure to ATR. However, the underlying mechanism remains unclear. We performed a differential gene expression analysis using the NAFLD-related datasets GSE89632 and GSE160016 downloaded from the GEO database, both with the human liver as the samples. Then the GO and KEGG pathway enrichment analyses were performed. It was discovered that the FOXO1/PPARγ pathway might play a crucial role in hepatic lipid metabolism disorders. To confirm the hypothesis, forty 8-week-old male Wistar rats were randomly average exposed to different concentrations of ATR (0, 0.5, 5 and 50 mg/kg/d) by intragastric administration for 90 days. Then the liver tissue were isolated for histopathological observation; the levels of lipids were assessed by colorimetry; the expression of mRNA and protein was identified by Real-Time PCR and western blot. The findings demonstrated that the ATR-treated groups had higher levels of TC and TG in the liver; TC level in the serum was increased but TG level decreased. Besides, the expression of FOXO1, PPARγ, FASN, FABP4 and CD36 was also elevated. A correlation was observed between the lipid metabolism levels and the expression of FOXO1/PPARγ pathway genes. These results suggested that ATR can induce hepatic lipids accumulation by upregulating the expression of FOXO1/PPARγ. This study can offer insightful information for preventing and controlling risks related to agricultural residues.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"415 ","pages":"Article 111797"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145701997","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}
Occupational medicamentose-like dermatitis due to trichloroethylene (OMDT) caused by trichloroethylene (TCE) is a systemic allergic disease mainly manifested by acute inflammatory reactions in the skin and mucosa. In addition to fever, skin and mucosal damage, superficial lymph node enlargement and tenderness, OMDT patients often have severe multi-organ damage, with liver function damage being the most common. The degree of liver function injury can seriously affect the cure rate of OMDT, but the mechanism of injury has not been fully elucidated. The aim of our study was to explore the mechanism of mitochondrial DNA (mtDNA) release and the role of mtDNA in trichloroethylene-sensitized liver injury. Previous studies found amounts of tumor necrosis factor TNF- α in the liver of mice sensitized to TCE. Moreover, we found a leakage of mtDNA during TCE sensitization. Mitochondrial DNA Exposure to cytosol can activate innate immune responses and play a key role in immune liver injury induced by TCE, but the mechanism by which mtDNA is released to the cellular cytoplasm is unknown. In this study, we found that TNF-α promotes the upregulation of PUMA (p53 upregulated modulator of apoptosis) pro-apoptotic proteins in the liver of TCE-sensitized mice, and then PUMA promotes mtDNA release by regulating the mitochondrial BAX / BAK apoptotic pore, and subsequently activates the DNA sensor ZBP1 (Z-DNA Binding Protein 1), which ultimately leads to RIPK3 / MLKL-dependent necroptosis in hepatocytes.
{"title":"PUMA upregulation promotes the necroptosis of hepatocytes in trichloroethylene-sensitized mice via mtDNA-mediated ZBP1 pathway","authors":"Xinyu Peng , Lifu Zhu , Chenghuan Wan , Luolun Dong , Weiwei Yang , Qixing Zhu , Haibo Xie , Jiaxiang Zhang","doi":"10.1016/j.toxlet.2025.111807","DOIUrl":"10.1016/j.toxlet.2025.111807","url":null,"abstract":"<div><div>Occupational medicamentose-like dermatitis due to trichloroethylene (OMDT) caused by trichloroethylene (TCE) is a systemic allergic disease mainly manifested by acute inflammatory reactions in the skin and mucosa. In addition to fever, skin and mucosal damage, superficial lymph node enlargement and tenderness, OMDT patients often have severe multi-organ damage, with liver function damage being the most common. The degree of liver function injury can seriously affect the cure rate of OMDT, but the mechanism of injury has not been fully elucidated. The aim of our study was to explore the mechanism of mitochondrial DNA (mtDNA) release and the role of mtDNA in trichloroethylene-sensitized liver injury. Previous studies found amounts of tumor necrosis factor TNF- α in the liver of mice sensitized to TCE. Moreover, we found a leakage of mtDNA during TCE sensitization. Mitochondrial DNA Exposure to cytosol can activate innate immune responses and play a key role in immune liver injury induced by TCE, but the mechanism by which mtDNA is released to the cellular cytoplasm is unknown. In this study, we found that TNF-α promotes the upregulation of PUMA (p53 upregulated modulator of apoptosis) pro-apoptotic proteins in the liver of TCE-sensitized mice, and then PUMA promotes mtDNA release by regulating the mitochondrial BAX / BAK apoptotic pore, and subsequently activates the DNA sensor ZBP1 (Z-DNA Binding Protein 1), which ultimately leads to RIPK3 / MLKL-dependent necroptosis in hepatocytes.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"415 ","pages":"Article 111807"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800816","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}
Pub Date : 2026-01-01Epub Date: 2025-12-24DOI: 10.1016/j.toxlet.2025.111809
Longbao Xu , Lerong Cheng , Hanqing Wu , Zelong Pan , Guoqing Li , Yanyu Zhao , Ziqi Li , Yuxin Ren , Mengyao Gao , Yubo Ma , Faming Pan
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 < 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 < 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.
{"title":"Association between polycyclic aromatic hydrocarbons (PAHs) and insulin resistance: A comprehensive study utilizing NHANES data and network toxicology","authors":"Longbao Xu , Lerong Cheng , Hanqing Wu , Zelong Pan , Guoqing Li , Yanyu Zhao , Ziqi Li , Yuxin Ren , Mengyao Gao , Yubo Ma , 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 < 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 < 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":"2026-01-01","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}
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