Toxicology letters最新文献_第4页

Comparative transcriptomic analysis reveals STAT3 as a candidate gene involved in aristolochic acid I-induced hepatorenal toxicity 比较转录组学分析揭示STAT3是参与马兜铃酸i诱导的肝肾毒性的候选基因。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-30 DOI: 10.1016/j.toxlet.2025.111811

Gerui Zhu , Fan Wang , Siyuan Wang , Kai Huang , Gaofeng Chen , Chenghai Liu , Yuan Peng , Yanyan Tao

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.

马兜铃酸，如马兜铃酸I (AAI)，被广泛认为具有肾毒性和引起肝细胞癌的潜力。虽然先前的研究已经证明AAI能够诱导肝肾毒性，但其确切的潜在机制尚不清楚。本研究的目的是探讨AAI诱导肝肾毒性的机制。我们进行了体内和体外研究，包括给C57BL/6小鼠AAI，以及人肝细胞（HL-7702/L-02）和近端肾小管上皮细胞（HK-2）暴露于AAI。通过肝脏和肾脏的RNA测序分析，确定肝肾毒性机制，并进行后续实验验证。在确定AAI诱导的肝肾毒性的共同靶点STAT3后，我们进一步使用STAT3抑制剂Stattic进行体外验证。结果显示，STAT3表达升高可引起肝肾毒性，导致肝肾功能受损和组织损伤。Western Blot显示AAI增加STAT3磷酸化。此外，STAT3抑制剂的应用减少了肝细胞和肾小管上皮细胞的损伤，证实了STAT3对aai诱导的损伤的有效性。这些发现为AAI显著的肝肾毒性提供了证据，并表明STAT3可能是一个潜在的共同靶点。

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引用次数: 0

Research on the therapeutic effects of recombinant protein PON1Q/R192 intervention on mice poisoned by different categories of organophosphorus compounds 重组蛋白PON1Q/R192干预对不同有机磷化合物中毒小鼠的治疗作用研究

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-30 DOI: 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 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 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 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.

有机磷化合物在农业中应用广泛，但其中毒危害极大。本研究主要探讨rePON1Q192和rePON1R192对不同类型有机磷化合物中毒小鼠的治疗作用。通过pET - 32a载体的基因合成制备了这两个重组蛋白，并在大肠杆菌BL21中表达。有机磷化合物按结构分为两类：一类含有嘧啶环（结构类似于二嗪农），另一类含有多个氯原子（结构类似于毒死蜱）。每组分为对照组、rePON1Q/R192对照组、中毒组和rePON1Q/R192治疗组。Kaplan-Meier生存分析评估各组小鼠12小时存活率。采用ELISA法检测各组IL - 6表达，HE染色评估肺、脑损伤，TUNEL染色观察脑、肺组织细胞凋亡，电镜观察各组脑组织线粒体结构变化及肺组织变化。结果显示，rePON1Q/R192能改善有机磷中毒小鼠的临床表现，提高生存率，减少炎症因子IL - 6的释放，减轻脑、肺组织病理损伤及线粒体损伤。rePON1Q/R192处理组小鼠脑和肺组织中凋亡细胞数量明显减少。在动物实验中，rePON1Q192的治疗效果各不相同：rePON1R192对重氮肼中毒效果较好，而对毒死蜱类中毒效果较好。因此，rePON1Q192和rePON1R192的治疗效果因有机磷中毒的类型而异，可能是由于它们的分子结构不同。

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引用次数: 0

Association between polycyclic aromatic hydrocarbons (PAHs) and insulin resistance: A comprehensive study utilizing NHANES data and network toxicology 多环芳烃（PAHs）与胰岛素抵抗之间的关系：利用NHANES数据和网络毒理学的综合研究

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-24 DOI: 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.

多环芳烃（PAHs）是一种广泛存在的环境污染物，具有潜在的内分泌干扰作用，但之前关于其与胰岛素抵抗关系的流行病学研究得出了不一致的结果。利用2005年至2016年全国健康与营养检查调查（NHANES）周期3294名参与者的数据，我们应用多变量线性回归、限制三次样条模型、加权分位数和（WQS）回归和g计算模型来研究个体和混合多环烃暴露与胰岛素抵抗之间的关系，并按性别和年龄分层进行亚组分析。结果显示，2-羟基芴（2-FLU）和1-羟基菲（1-PHE）与甘油三酯-葡萄糖指数（TyG）、胰岛素抵抗代谢评分（METS-IR）和甘油三酯/高密度脂蛋白胆固醇比值（TG/HDL-C）呈显著正相关（P <； 0.05）。同样，加权分位数和回归和分位数g计算均显示，PAH混合物暴露与TyG、MEST-IR、甘油三酯-葡萄糖-体重指数（TyG- bmi）和TG/HDL-C之间存在显著正相关（P <； 0.05），其中2-FLU和1-PHE被确定为主要影响因素。分层分析表明，妇女和非老年人可能代表易感亚群。网络毒理学和分子对接进一步表明，多环芳烃可能通过诱导炎症、促进氧化应激、干扰胰岛素信号通路等途径破坏葡萄糖稳态。总之，这些发现为多环芳烃对胰岛素抵抗的影响提供了流行病学和机制证据，强调了将多环芳烃视为胰岛素抵抗和相关代谢紊乱的潜在环境相关因素的重要性。

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引用次数: 0

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。

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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