Toxicology letters最新文献_第4页

Effects of gestational prednisone exposure on long bone development in fetal mice: Role of Sost/Wnt/β-catenin signaling pathways 妊娠期强的松暴露对胎鼠长骨发育的影响：Sost/Wnt/β-catenin信号通路的作用

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-18 DOI: 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.

强的松是一种合成糖皮质激素，广泛用于治疗妊娠期间的各种母体疾病，如自身免疫性疾病。然而，流行病学研究表明，产前强的松治疗可能导致胎儿生长受限。临床前研究表明，妊娠期强的松暴露（PPE）对后代的多个器官具有发育毒性。然而，不同剂量和时间窗的PPE对后代长骨发育的影响尚不清楚。本研究考察了强的松（PPE）使用临床相关给药方案对胎儿长骨发育的影响。妊娠小鼠在整个妊娠期间或在特定妊娠期(妊娠全期（GD0-18）、妊娠早期（GD0-9）或妊娠中后期（GD10-18）接受不同剂量（0.25、0.5或1.0mg/kg·d）的PPE。结果表明，PPE诱导雄性和雌性胎鼠股骨发育不良，表现为股骨长度缩短，生长板分化延迟，初级骨化中心形成受损。这些异常与成骨细胞、破骨细胞和内皮细胞发育抑制同时发生。此外，PPE以剂量依赖的方式抑制长骨发育，在妊娠中后期观察到最明显的影响。体外实验证实，强的松转化为强的松后，可抑制Sost/Wnt/β-catenin信号通路。总之，PPE抑制雄性和雌性胎鼠的长骨发育，主要是在高剂量和妊娠中后期，没有明显的性别二态性。机制上，Sost/Wnt/β-catenin信号通路的抑制可能介导PPE的长骨发育毒性。本研究增强了我们对妊娠期强的松暴露相关风险的认识，为指导合理用药和有效评价强的松长骨发育毒性提供了理论和实验依据。

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引用次数: 0

PUMA upregulation promotes the necroptosis of hepatocytes in trichloroethylene-sensitized mice via mtDNA-mediated ZBP1 pathway PUMA上调通过mtdna介导的ZBP1途径促进三氯乙烯致敏小鼠肝细胞坏死。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-18 DOI: 10.1016/j.toxlet.2025.111807

Xinyu Peng , Lifu Zhu , Chenghuan Wan , Luolun Dong , Weiwei Yang , Qixing Zhu , Haibo Xie , Jiaxiang Zhang

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.

三氯乙烯致职业性药物样皮炎（OMDT）是由三氯乙烯（TCE）引起的一种全身性过敏性疾病，主要表现为皮肤和粘膜的急性炎症反应。OMDT患者除发热、皮肤粘膜损伤、浅表淋巴结肿大、压痛外，常伴有严重的多脏器损害，以肝功能损害最为常见。肝功能损伤程度严重影响OMDT的治愈率，但其损伤机制尚未完全阐明。本研究旨在探讨线粒体DNA （mtDNA）释放的机制及其在三氯乙烯致敏性肝损伤中的作用。先前的研究发现，对TCE敏感的小鼠肝脏中肿瘤坏死因子TNF- α的含量较高。此外，我们发现在TCE致敏过程中有mtDNA的泄漏。线粒体DNA暴露于细胞质中可激活先天免疫反应，在TCE诱导的免疫性肝损伤中发挥关键作用，但线粒体DNA释放到细胞质中的机制尚不清楚。在本研究中，我们发现TNF-α促进tce致敏小鼠肝脏中PUMA （p53上调的凋亡调节剂）促凋亡蛋白的上调，然后PUMA通过调节线粒体BAX / BAK凋亡孔促进mtDNA释放，进而激活DNA传感器ZBP1 (Z-DNA结合蛋白1)，最终导致肝细胞依赖RIPK3 / mlkl的坏死坏死。

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引用次数: 0

Evaluation of interspecies differences in DS-2087b-induced gastrointestinal toxicity using mouse and monkey intestinal organoids ds -2087b致小鼠和猴肠道类器官胃肠道毒性的种间差异评价

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-17 DOI: 10.1016/j.toxlet.2025.111805

Yuji Shirai, Takuma Iguchi, Kazunori Fujimoto, Masako Imaoka, Yuko Hasegawa, Katsuyoshi Chiba

Gastrointestinal (GI) toxicity is a common adverse event induced by anti-cancer drugs; however, the information of the correlations in vitro to in vivo regarding GI toxicity is limited. The objective of this study was elucidating the usefulness of animal small intestinal organoids using DS-2087b, a novel epidermal growth factor receptor/human epidermal growth factor receptor 2 exon 20 insertion inhibitor. Mice showed no DS-2087b-related GI toxicities up to 100 mg/kg in 28-day repeated oral toxicity studies, while monkeys exhibited diarrhea at 10 mg/kg, along with histopathological changes including intestinal atrophy/erosion at 30 and 100 mg/kg. To clarify the mechanisms involved in interspecies differences, cell viability and transcriptomic analysis were performed using mouse and monkey small intestinal organoids generated from adult stem cells treated with DS-2087b at 0–10,000 nM for 3 days. Cell viability in monkey small intestinal organoids treated with DS-2087b at 1000 and 10,000 nM was significantly decreased compared to that of mice. In the transcriptomic analysis, expression of stem- and Paneth-cell marker genes was markedly decreased in the monkey small intestinal organoids. In conclusion, the intestinal organoids are valuable in vivo–in vitro translation of drug-induced GI toxicity and the changes in specific cell-type composition induced by DS-2087b may be important factors for contributing the interspecies differences.

胃肠道毒性是抗癌药物引起的常见不良事件；然而，关于胃肠道毒性的体内外相关性的信息有限。本研究的目的是阐明DS-2087b（一种新型表皮生长因子受体/人表皮生长因子受体2外显子20插入抑制剂）对动物小肠类器官的作用。在28天的重复口服毒性研究中，当ds -2087b达到100mg/kg时，小鼠未显示出ds -2087b相关的胃肠道毒性，而猴子在10mg/kg时表现出腹泻，同时在30mg /kg和100mg/kg时出现组织病理变化，包括肠道萎缩/侵蚀。为了阐明物种间差异的机制，用DS-2087b在0-10,000nM处理3天的小鼠和猴子成体干细胞产生的小肠类器官进行了细胞活力和转录组学分析。与小鼠相比，DS-2087b在1000和10000 nm下处理的猴小肠类器官细胞活力显著降低。在转录组学分析中，猴小肠类器官中干细胞和泛细胞标记基因的表达明显降低。综上所述，肠道类器官在药物诱导的胃肠道毒性的体内外翻译中具有重要价值，DS-2087b诱导的特定细胞类型组成的变化可能是造成种间差异的重要因素。

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引用次数: 0

RANKL/OPG axis as a therapeutic target for microplastic-induced bone loss: Mechanistic insights from transcriptomic and functional validation RANKL/OPG轴作为微塑性骨丢失的治疗靶点：来自转录组学和功能验证的机制见解。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-16 DOI: 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.

尽管塑料产品为现代社会和日常生活带来了巨大的好处，但由于其对生态系统和人类健康的不利影响，它们降解为微塑料（MPs）引起了重大关注。本研究研究了MP在人体骨组织中的沉积，并阐明了其对骨代谢的影响。利用尼罗红染色、拉曼光谱和红外显微光谱对人体骨组织进行综合分析，在40个样本（包括颈椎、胸椎、腰椎以及上肢和下肢骨骼）中的33个样本中发现了MP颗粒。这些检测到的MPs呈现颗粒状形态，粒径范围为10 ~ 20 μm，主要由聚乙烯和聚丙烯组成，每个样品中含有2-3 MPs/2g骨组织。为了探索其潜在机制，对mp - pe喂养小鼠的股组织进行转录组学分析，发现870个上调基因和930个下调基因，这些基因富集于造血细胞谱系、NF-κB、PPAR、PI3K-Akt和HIF-1信号通路以及代谢通路中。体外验证进一步证明，MPs通过调节骨髓基质细胞的RANKL/OPG轴，从而激活Raw264.7细胞的RANK-NFATc1信号通路，从而促进破骨细胞的分化。这些发现为MPs对骨骼健康的有害影响提供了实验和理论证据，强调了对环境和公共卫生干预的迫切需要。

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引用次数: 0

Diverse impacts of cadmium exposure on adolescent liver health: Suppression of steatosis and promotion of fibrosis 镉暴露对青少年肝脏健康的多种影响：抑制脂肪变性和促进纤维化。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-16 DOI: 10.1016/j.toxlet.2025.111806

Si-Jie Hong , Li-Wei Hong , Xiao-Qin He , Xiao-Qing Yang , Xiao-Hong Zhong , Jin-Zhun Wu

Objectives

Cadmium exposure's impact on adolescent liver health is of concern. This study aimed to explore the association between cadmium exposure and liver health in adolescents.

Methods

A cross-sectional study was conducted using data from NHANES 2017–2020.3. Urinary cadmium concentration was used as an indicator of exposure. Liver ultrasound parameters, controlled attenuation parameter (CAP) and stiffness (E) (STF), were employed to assess the degree of liver steatosis and fibrosis in adolescents. Multivariate linear and logistic regression analyses were performed to examine the correlations between cadmium exposure and liver health. Mediation analysis was utilized to explore the roles of alkaline phosphatase, creatine phosphokinase, cholesterol, triglycerides, C-reactive protein, and creatinine. Additionally, a restricted cubic spline (RCS) analysis was conducted to evaluate the impact of nutritional intake on liver health in high-cadmium exposure groups.

Results

Cadmium exposure levels were associated with ethnicity and family income. Regression analysis showed a negative correlation with CAP and a positive correlation with STF. Mediation analysis demonstrated that creatinine and triglycerides partially mediated cadmium's effect on CAP, while only creatinine mediated the effect on STF. Dietary intake, including eicosadienoic acid and theobromine, significantly impacts liver health in adolescents with high cadmium exposure.

Conclusions

Cadmium exposure affects liver health by inhibiting steatosis and promoting fibrosis, with renal and lipid metabolism factors acting as mediators, and diet influencing the outcomes.

目的：镉暴露对青少年肝脏健康的影响值得关注。本研究旨在探讨镉暴露与青少年肝脏健康之间的关系。方法：采用NHANES 2017 - 2020.3的数据进行横断面研究。尿镉浓度被用作暴露的指标。采用肝脏超声参数，控制衰减参数（CAP）和刚度(E) （STF）评估青少年肝脏脂肪变性和纤维化程度。进行多变量线性和逻辑回归分析以检验镉暴露与肝脏健康之间的相关性。采用中介分析探讨碱性磷酸酶、肌酸磷酸激酶、胆固醇、甘油三酯、c反应蛋白和肌酐的作用。此外，进行了限制性三次样条（RCS）分析，以评估营养摄入对高镉暴露组肝脏健康的影响。结果：镉暴露水平与种族和家庭收入有关。回归分析显示与CAP负相关，与STF正相关。中介分析表明，肌酐和甘油三酯部分介导了镉对CAP的影响，而只有肌酐介导了对STF的影响。饮食摄入，包括二十碳二烯酸和可可碱，显著影响高镉暴露青少年的肝脏健康。结论：镉暴露通过抑制脂肪变性和促进纤维化影响肝脏健康，其中肾脏和脂质代谢因子起中介作用，饮食影响结果。

{"title":"Diverse impacts of cadmium exposure on adolescent liver health: Suppression of steatosis and promotion of fibrosis","authors":"Si-Jie Hong , Li-Wei Hong , Xiao-Qin He , Xiao-Qing Yang , Xiao-Hong Zhong , Jin-Zhun Wu","doi":"10.1016/j.toxlet.2025.111806","DOIUrl":"10.1016/j.toxlet.2025.111806","url":null,"abstract":"<div><h3>Objectives</h3><div>Cadmium exposure's impact on adolescent liver health is of concern. This study aimed to explore the association between cadmium exposure and liver health in adolescents.</div></div><div><h3>Methods</h3><div>A cross-sectional study was conducted using data from NHANES 2017–2020.3. Urinary cadmium concentration was used as an indicator of exposure. Liver ultrasound parameters, controlled attenuation parameter (CAP) and stiffness (E) (STF), were employed to assess the degree of liver steatosis and fibrosis in adolescents. Multivariate linear and logistic regression analyses were performed to examine the correlations between cadmium exposure and liver health. Mediation analysis was utilized to explore the roles of alkaline phosphatase, creatine phosphokinase, cholesterol, triglycerides, C-reactive protein, and creatinine. Additionally, a restricted cubic spline (RCS) analysis was conducted to evaluate the impact of nutritional intake on liver health in high-cadmium exposure groups.</div></div><div><h3>Results</h3><div>Cadmium exposure levels were associated with ethnicity and family income. Regression analysis showed a negative correlation with CAP and a positive correlation with STF. Mediation analysis demonstrated that creatinine and triglycerides partially mediated cadmium's effect on CAP, while only creatinine mediated the effect on STF. Dietary intake, including eicosadienoic acid and theobromine, significantly impacts liver health in adolescents with high cadmium exposure.</div></div><div><h3>Conclusions</h3><div>Cadmium exposure affects liver health by inhibiting steatosis and promoting fibrosis, with renal and lipid metabolism factors acting as mediators, and diet influencing the outcomes.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"415 ","pages":"Article 111806"},"PeriodicalIF":2.9,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145783034","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}

引用次数: 0

Developing a novel in vitro toxicity assay for predicting inhalation toxicity in rats 建立一种预测大鼠吸入毒性的新型体外毒性试验。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-10 DOI: 10.1016/j.toxlet.2025.111803

Arpamas Vachiraarunwong , Masaki Fujioka , David B. Alexander , Shugo Suzuki , Runjie Guo , Guiyu Qiu , Yurina Kawamura , Kana Shibano , Ikue Noura , Kwanchanok Praseatsook , Hirotoshi Akane , Shinji Takasu , Hiroyuki Tsuda , Kumiko Ogawa , Hideki Wanibuchi , Min Gi

The development of alternative in vitro methods for assessing acute inhalation toxicity is essential to reduce animal testing and aligns with the 3Rs principles (replacement, reduction, refinement). In this study, we developed a neutral red uptake (NRU) assay using human lung adenocarcinoma cells (A549) as a predictive model (A549-NRU) for acute inhalation toxicity. The assay incorporates two key features: a 15-minute incubation time to simulate the transient contact of inhaled chemicals with the airway surface under acute inhalation conditions, and the use of both polystyrene plates and glass plates for chemicals reactive with polystyrene. LC₅₀ values were determined for 49 chemicals and compared with reported LC₅₀ values from 4-hour rat inhalation studies. A significant positive correlation was observed between A549-NRU-derived LC₅₀ values and in vivo LC₅₀ values for water-soluble compounds (r = 0.4632, p = 0.0197) as well as chemicals containing aldehyde and ketone (r = 0.9339, p = 0.0007), and alcohol, ether, and epoxide (r = 0.7668, p = 0.0159) functional groups, suggesting that in vivo LC₅₀ values may be predictable using the A549-NRU assay. Importantly, the A549-NRU assay (r = 0.8879, p = 0.1121) demonstrated a stronger correlation with in vivo LC₅₀ values than the conventional NRU assay using mouse 3T3 fibroblast cells (r = 0.4524, p = 0.5476). These findings support the A549-NRU assay as an alternative for predicting acute inhalation toxicity and for estimating starting doses for confirmatory in vivo studies.

开发用于评估急性吸入毒性的替代体外方法对于减少动物试验和符合3Rs原则（替代、减少、改进）至关重要。在这项研究中，我们开发了一种中性红色摄取（NRU）试验，使用人肺腺癌细胞（A549）作为急性吸入毒性的预测模型（A549-NRU）。该试验具有两个关键特征：15分钟的潜伏期，以模拟吸入的化学物质在急性吸入条件下与气道表面的短暂接触，以及使用聚苯乙烯板和玻璃板用于与聚苯乙烯反应的化学物质。测定了49种化学物质的LC50值，并与4小时大鼠吸入研究报告的LC50值进行了比较。A549-NRU衍生的LC50值与体内水溶性化合物（r = 0.4632, p = 0.0197）、含有醛和酮的化学物质（r = 0.9339, p = 0.0007）、醇、醚和环氧化物（r = 0.7668, p = 0.0159）的LC50值呈显著正相关，表明体内LC50值可以通过A549-NRU检测预测。重要的是，A549-NRU实验（r = 0.8879, p = 0.1121）与使用小鼠3T3成纤维细胞的传统NRU实验（r = 0.4524, p = 0.5476）相比，与体内LC50值的相关性更强。这些发现支持A549-NRU测定作为预测急性吸入毒性和估计体内验证性研究起始剂量的替代方法。

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引用次数: 0

Dose-response to lead-induced alterations in right atrial and ventricular myocardial contractility in adult rats 铅致成年大鼠右心房和心室心肌收缩性改变的剂量反应。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-09 DOI: 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.

铅是一种广泛存在的环境外来生物，已知会对心血管健康产生不利影响。本研究首次系统地评估了亚慢性醋酸铅暴露（5.5、11和22.88mg/kg体重，通过腹腔注射，每周3次，持续6周）对12月龄雄性大鼠右心房和右心室心肌收缩特性的影响，采用体外运动测定和同一心脏心肌条的生理收缩测量。铅暴露使右心房肌球蛋白上细丝滑动速度呈剂量依赖性降低，而对右心室肌球蛋白的影响是非线性的。高剂量的铅显著降低心房活动纤维的比例，而低剂量则影响心室。在生理负荷模式下，右心房心肌条带所产生的机械功约为右心室条带所产生的机械功的20%。增加铅剂量进一步减少了两个心室的机械功，在最高剂量时，心房的减少（≈65%）比心室的减少（≈17%）更为明显。最大缩短速度也随着铅浓度的增加而下降，特别是在低后负荷时心房。这些结果表明，右心房心肌比右心室心肌对亚慢性铅中毒更敏感。总的来说，这项研究首次全面分析了铅在生理负荷条件下对心房和心室收缩力的不同影响。

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引用次数: 0

Multi-omics analysis reveals the mechanism of indirect hepatotoxicity of triptolide upon LPS stimulation 多组学分析揭示了雷公藤甲素在LPS刺激下的间接肝毒性机制。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-09 DOI: 10.1016/j.toxlet.2025.111802

Tao Shen , Linrui Fan , Huayu Luo , Yulong Zha , Yu Zhang , Hongzheng Ren

Purpose

Triptolide (TP), an active compound derived from the traditional Chinese herb Tripterygium wilfordii Hook F, is notable for its therapeutic properties. However, hepatotoxicity remains its primary adverse effect. There is a new perspective about TP hepatotoxicity: hepatic hypersensitivity triggered by lipopolysaccharide (LPS) stimulation. However, the global molecular alterations underlying this synergistic effect remain poorly defined.

Methods

We employed an integrated proteomics and metabolomics approach to systematically characterize the molecular landscape in the livers of mice treated with TP and LPS. Liver injury was assessed by serum biochemistry and histopathology.

Results

The TP+LPS combination induced severe liver damage, based upon histopathological and biochemical analyses, which was not observed with either agent alone. Proteomic analysis revealed that TP+LPS co-treatment induced aberrant expression of fatty acid/cholesterol metabolizing enzymes and dysregulation of cytoskeletal proteins, which collectively contributed to hepatocyte steatosis, structural disruption, and impaired regeneration. Metabolomics results showed that TP+LPS co-treatment significantly inhibited glucose metabolic pathways compared to LPS treatment alone, leading to a reduction of critical metabolic intermediates. This inhibition significantly impaired ATP production and triggered energy depletion. Integrated analysis showed that the suppression of these enzymes in the TP+LPS group impaired mitochondria integrity and the electron transport chain, contributing to ROS-mediated oxidative stress and consequent aggravation of inflammatory response. The inflammatory environment further inhibits mitochondrial function, worsening metabolic disorders and promoting ROS accumulation, thereby forming a self-perpetuating cycle of "metabolism-oxidation-inflammation".

Conclusion

Our multi-omics data provide a comprehensive resource and novel insights into the mechanism of TP-potentiated, LPS-induced hepatotoxicity. TP might amplify hepatotoxicity by influencing energy metabolism, activating oxidative stress and inflammation in the context of LPS-induced inflammation.

目的：雷公藤甲素（Triptolide， TP）是一种从中药雷公藤中提取的活性化合物，具有显著的治疗作用。然而，肝毒性仍然是其主要的副作用。TP肝毒性有一个新的观点：脂多糖刺激引起的肝脏超敏反应。然而，这种协同效应背后的全局分子改变仍然不明确。方法：采用综合蛋白质组学和代谢组学方法，系统表征TP和LPS处理小鼠肝脏的分子景观。采用血清生化及组织病理学检测肝损伤程度。结果：经组织病理学和生化分析，TP+LPS联合用药可引起严重的肝损伤，单独使用两种药物均未观察到肝损伤。蛋白质组学分析显示，TP+LPS共处理诱导脂肪酸/胆固醇代谢酶的异常表达和细胞骨架蛋白的失调，这些共同导致肝细胞脂肪变性、结构破坏和再生受损。代谢组学结果显示，与单独LPS处理相比，TP+LPS共处理显著抑制了葡萄糖代谢途径，导致关键代谢中间体减少。这种抑制显著损害ATP的产生并引发能量消耗。综合分析表明，TP+LPS组对这些酶的抑制破坏了线粒体完整性和电子传递链，导致ros介导的氧化应激，从而加重炎症反应。炎症环境进一步抑制线粒体功能，加重代谢紊乱，促进ROS积累，从而形成“代谢-氧化-炎症”的自我延续循环。结论：我们的多组学数据为tp增强、lps诱导的肝毒性机制提供了全面的资源和新的见解。在lps诱导炎症的情况下，TP可能通过影响能量代谢、激活氧化应激和炎症来增强肝毒性。

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引用次数: 0

Rotenone-induced cellular dysfunction in human blood platelets: Unraveling calcium dysregulation, mitochondrial impairment, oxidative stress, and apoptosis 鱼藤酮诱导的人血小板细胞功能障碍：揭示钙失调、线粒体损伤、氧化应激和细胞凋亡。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-09 DOI: 10.1016/j.toxlet.2025.111804

Samir Kumar Beura, Nisha Yadav, Abhishek Kumar Maurya, Nikki Kumari, Sunil Kumar Singh

Rotenone, a naturally occurring pesticide and a well-established mitochondrial complex I inhibitor, disrupts electron transport chain activity, resulting in impaired energy metabolism, oxidative stress, and apoptosis. Our recent findings revealed that rotenone suppresses agonist-induced platelet functional activity; however, the molecular mechanisms underlying this effect remain largely unclear. In this study, we demonstrate that rotenone exposure induces pronounced cytotoxic effects in human platelets, evident from decreased cell viability and phosphatidylserine externalization, a hallmark of apoptosis-like processes. At the mitochondrial level, rotenone markedly compromises organelle integrity by inducing mitochondrial membrane potential depolarization, excessive reactive oxygen species generation, and calcium dysregulation. These mitochondrial perturbations act as key upstream signals that trigger caspase activation and drive apoptosis-like cascades in platelets. Collectively, our findings identify mitochondrial dysfunction, oxidative stress, and calcium imbalance as central mediators of rotenone-induced, caspase-dependent platelet apoptosis. This study demonstrates that rotenone induces cytotoxicity and organelle dysfunction in human blood platelets, thereby providing mechanistic insight into altered platelet functions.

鱼藤酮是一种天然存在的杀虫剂，也是一种公认的线粒体复合物I抑制剂，它会破坏电子传递链活性，导致能量代谢受损、氧化应激和细胞凋亡。我们最近的发现表明鱼藤酮抑制激动剂诱导的血小板功能活性；然而，这种作用背后的分子机制仍不清楚。在这项研究中，我们证明鱼藤酮暴露在人血小板中诱导明显的细胞毒性作用，从细胞活力降低和磷脂酰丝氨酸外化（细胞凋亡样过程的标志）可见。在线粒体水平上，鱼藤酮通过诱导线粒体膜电位去极化、活性氧生成过多和钙失调而显著损害细胞器完整性。这些线粒体扰动作为关键的上游信号，触发半胱天冬酶激活，驱动血小板细胞凋亡样级联反应。总的来说，我们的研究结果确定了线粒体功能障碍、氧化应激和钙失衡是鱼藤酮诱导的caspase依赖性血小板凋亡的中心介质。本研究表明鱼藤酮诱导人血小板细胞毒性和细胞器功能障碍，从而为血小板功能改变提供了机制见解。

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引用次数: 0

The role of FOXO1/PPARγ in atrazine-induced hepatic lipid metabolism disorders FOXO1/PPARγ在阿特拉津诱导的肝脏脂质代谢紊乱中的作用

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-05 DOI: 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.

莠去津（ATR）是世界上使用最广泛的除草剂之一，广泛存在于环境中，能够进入人体并对人体产生危害。暴露于ATR可引发肝脂质代谢紊乱。然而，其潜在机制尚不清楚。我们使用从GEO数据库下载的nafld相关数据集GSE89632和GSE160016进行差异基因表达分析，均以人类肝脏为样本。然后进行GO和KEGG途径富集分析。研究发现FOXO1/PPARγ通路可能在肝脏脂质代谢紊乱中起重要作用。为了证实这一假设，将40只8周龄雄性Wistar大鼠随机平均灌胃不同浓度的ATR(0、0.5、5和50mg/kg/d)，持续90天。然后分离肝组织进行组织病理学观察；用比色法测定脂质水平；Real-Time PCR和western blot检测mRNA和蛋白的表达。结果表明，atr治疗组肝脏中TC和TG水平较高；血清TC升高，TG降低。此外，FOXO1、PPARγ、FASN、FABP4和CD36的表达也升高。脂质代谢水平与FOXO1/PPARγ通路基因表达存在相关性。上述结果提示ATR可通过上调FOXO1/PPARγ的表达诱导肝脏脂质积累。本研究可为农业残留相关风险的防控提供参考。

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引用次数: 0