Toxicology letters最新文献_第10页

PFOA exposure causes kidney injury via disruption of lipid metabolism mediated by PPARα signaling pathway: An integrated analysis PFOA暴露通过PPARα信号通路介导的脂质代谢破坏导致肾损伤：一项综合分析。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-09-28 DOI: 10.1016/j.toxlet.2025.111736

Yuanyuan Wu , Yuhong Jiang , Zhonghua Fan , Xuan Liu , Weiqiang Sun , Li Wang , Hui Liu

Perfluorooctanoic acid (PFOA) is a persistent organic pollutant (POP) that can accumulate in living organisms and cause damage to multiple organs and systems in the human body. The kidney is viewed as a key organ affected by PFOA, but the exact mechanism by which PFOA exposure causes kidney damage remains unclear. We selected data from 13,804 participants aged > 12 years old from the National Health and Nutrition Examination Survey (NHANES) database from 2003 to 2018 to analyze the relationship between PFOA and kidney injury. In addition, in the animal experiment, twenty adult male SD rats were divided into four groups randomly: one control group and three PFOA-treated groups. The experiment lasted 28 days, during which time water consumption and urine output were recorded daily. Kidney tissue samples were collected at the end of the experiment. Biochemical assays, RT-qPCR and Western blotting techniques were used to investigate the toxic effects of PFOA exposure on the kidney. Analysis of NHANES data shows a positive correlation between serum PFOA and uric acid (UA) with a β-value of 0.23 (95 % CI: 0.18–0.27) in Model 2. In animal studies, PFOA significantly affected rats’ water intake (increased at 5 mg/kg/d, decreased at 20 mg/kg/d) and urine output (5 > 1.25 > 20 mg/kg/d > control). Renal biochemical analyses revealed significantly lower total cholesterol (TC) (1.25, 20 mg/kg/d groups) and triglyceride (TG) (1.25, 5 mg/kg/d groups) in PFOA-exposed rats. The peroxisome proliferator-activated receptors (PPAR) pathway-related gene/protein levels were significantly altered, such as 900 differentially expressed genes (DEGs) in the 20 mg/kg/d group and upregulated ACOT1 in all PFOA groups. In conclusion, the present study confirms that exposure to PFOA leads to increased oxidative catabolism of fatty acids and impaired renal lipid metabolism. These findings provide an important basis for elucidating the potential health hazards of PFOA.

全氟辛酸（PFOA）是一种持久性有机污染物（POP），可在生物体中积累，对人体多个器官和系统造成损害。肾脏被认为是受PFOA影响的关键器官，但PFOA暴露导致肾脏损害的确切机制尚不清楚。我们从2003-2018年国家健康与营养检查调查（NHANES）数据库中选择了13804名年龄在0 - 12岁之间的参与者的数据，分析PFOA与肾损伤之间的关系。另外，在动物实验中，将20只成年雄性SD大鼠随机分为4组：1个对照组和3个pfoa处理组。试验期28 d，每天记录耗水量和排尿量。实验结束时采集肾脏组织样本。采用生化分析、RT-qPCR和Western blotting技术研究PFOA暴露对肾脏的毒性作用。NHANES数据分析显示血清PFOA与尿酸（UA）呈正相关，模型2中β值为0.23 （95% CI: 0.18-0.27）。在动物实验中，PFOA显著影响了大鼠的饮水量（5mg/kg/d时增加，20mg/kg/d时减少）和排尿量（5mg/kg/d、1.25 mg/kg/d、20mg/kg/d、>对照组）。肾脏生化分析显示，pfoa暴露大鼠的总胆固醇（TC）（1.25、20mg/kg/d组）和甘油三酯（TG）（1.25、5mg/kg/d组）显著降低。过氧化物酶体增殖物激活受体（PPAR）通路相关基因/蛋白水平显著改变，如20mg/kg/d组有900个差异表达基因（DEGs），所有PFOA组均上调ACOT1。总之，本研究证实，暴露于PFOA会导致脂肪酸氧化分解代谢增加和肾脏脂质代谢受损。这些发现为阐明PFOA的潜在健康危害提供了重要依据。

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引用次数: 0

Role of inflammatory response in benzo[a]pyrene-induced noradrenergic axon degeneration in mouse brain 炎症反应在苯并芘诱导的小鼠脑去肾上腺素能轴突变性中的作用。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-09-27 DOI: 10.1016/j.toxlet.2025.111737

Yousra Reda , Cai Zong , Akane Ikoma , Alzahraa Fergany , Saleh Ahmed , Walaa Slouma Hamouda Abd El Naby , Sahoko Ichihara , Gaku Ichihara

Environmental pollution is a major contributor to neurotoxicity and could explain various nervous system dysfunctions. The polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (B[a]P) is widely present in the environment, including air polluted with combustion or cigarette smoke, and considered to be involved in the development of neurodegenerative disorders. Our previous study demonstrated that B[a]P decreased noradrenergic axon density and upregulated proinflammatory cytokines in the mouse brain. The aim of this study was to explore the hypothesis that B[a]P induced neurodegeneration through signals related to inflammatory response in the brain and that sulforaphane (SFN), a naturally present antioxidant and anti-inflammatory compound, can protect against B[a]P-induced neurotoxicity. Adult male mice (C57Bl/6JJcl) were exposed to B[a]P at 0, 0.87, 2.74 or 8.67 µg which is approximately equivalent to (0.037,0.117 and 0.37 mg/kg) by pharyngeal aspiration once a week, with subcutaneous injection of SFN at 0 or 25 mg/kg body weight daily for 4 weeks. Neurotoxicity was evaluated by morphological examination of noradrenergic axon density and the positive stained Iba-1 microglia in the hippocampal areas CA1 and CA3. Moreover, we also analyzed the expression of various genes in the same tissues. At 8.67 µg, B[a]P significantly increased brain weight. Sulforaphane protected against B[a]P-induced neurotoxicity, including brain weight gain, decreased noradrenergic axon density, and microglial activation in the hippocampus. Sulforaphane also suppressed B[a]P-induced upregulation of Nf-κB and Il-6. These findings demonstrate that SFN effectively protected against B[a]P-induced neuroinflammation and axonal degeneration and suggest that B[a]P-induced neurodegeneration is mediated through brain inflammatory response.

环境污染是神经毒性的主要因素，可以解释各种神经系统功能障碍。多环芳烃（PAH）苯并[a]芘（B[a]P）广泛存在于环境中，包括被燃烧或香烟烟雾污染的空气，并被认为与神经退行性疾病的发展有关。我们之前的研究表明，B[a]P降低了小鼠大脑中去甲肾上腺素能轴突密度，上调了促炎细胞因子。本研究的目的是探索B[a]P通过与大脑炎症反应相关的信号诱导神经变性的假设，以及萝卜硫素（SFN），一种天然存在的抗氧化和抗炎化合物，可以防止B[a]P诱导的神经毒性。以成年雄性小鼠（C57Bl/6JJcl）为研究对象，每周1次咽部滴入剂量分别为0、0.87、2.74或8.67µg（约等于0.037、0.117和0.37mg/kg）的B[a]P，同时每天皮下注射剂量为0或25mg/kg体重的SFN，持续4周。通过形态学检查去甲肾上腺素能轴突密度和海马CA1和CA3区Iba-1小胶质细胞阳性染色评估神经毒性。此外，我们还分析了不同基因在同一组织中的表达。在8.67µg剂量下，B[a]P显著增加脑重量。萝卜硫素对B[a] p诱导的神经毒性有保护作用，包括脑增重、降低去甲肾上腺素能轴突密度和海马小胶质细胞激活。萝卜硫素还抑制B[a] p诱导的Nf-κB和Il-6的上调。这些发现表明，SFN可有效预防B[a] p诱导的神经炎症和轴突变性，并提示B[a] p诱导的神经变性是通过脑炎症反应介导的。

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引用次数: 0

Pre-clinical safety assessments of gadobutrol in diabetes-induced neuropathy: In vivo, in vitro and in silico studies Gadobutrol治疗糖尿病性神经病变的临床前安全性评估：体内、体外和计算机研究。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-09-27 DOI: 10.1016/j.toxlet.2025.111733

Batuhan Bilgin , Munevver Gizem Hekim , Muhammed Adam , Ferah Bulut , Seval Ulku Orhan , Suat Tekin , Mehmet Tahir Husunet , Mete Ozcan

Due to its vascular complications, patients with diabetes mellitus (DM) are exposed to gadobutrol in imaging. However, the safety concerns of gadobutrol to diabetes-induced neuropathy, a common complication of DM, remain unclear as a scientific gap. This study aimed to investigate the effects of gadobutrol on hypersensitivity in a streptozotocin (STZ)-induced diabetic neuropathy model in mice and its effects on cytotoxicity and genotoxicity in high glucose (HG)-induced neuropathy in dorsal root ganglion (DRG) neurons. Adult (6–8 weeks old) BALB/c male mice were intraperitoneally administered STZ (150 mg/kg) and hot plate, cold plate, von Frey, and rota rod tests were performed 21 days after blood glucose levels rose above 250 mg/dL (N = 40). Gadobutrol was administered intravenously. DRG neurons were isolated from neonatal Sprague-Dawley rats and HG (45 mmol/L) was administered. Subsequently, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and comet assay were performed on gadobutrol-treated and HG-exposed DRG neurons. Furthermore, molecular docking analysis was performed between gadobutrol and catalase (CAT). STZ + gadobutrol showed a statistically significant increase in sensitivity in hot plate, cold plate and von Frey assays compared to STZ (p = 0.0013, p = 0.0019 and p = 0.0189, respectively). HG + gadobutrol showed statistically significant increases in cytotoxicity and genotoxicity compared to HG. The binding affinity of gadobutrol to CAT was determined as − 8.59 kcal/mol. The results of this study suggest for the first time that gadobutrol can exacerbate diabetes-induced neuropathy. Further clinical studies are needed to elucidate these results, which may pose a new safety concern for patients with diabetic neuropathy.

由于其血管并发症，糖尿病（DM）患者在影像学上暴露于加多比特。然而，gadobutrol对糖尿病引起的神经病变（糖尿病的常见并发症）的安全性问题仍不清楚，这是一个科学空白。本研究旨在探讨加多布唑对链脲佐菌素（STZ）诱导的小鼠糖尿病神经病变模型超敏反应的影响及其对高糖（HG）诱导的背根神经节（DRG）神经元细胞毒性和遗传毒性的影响。成年（6-8周龄）BALB/c雄性小鼠腹腔注射STZ (150mg/kg)，在血糖升高至250mg/dL以上21天后（N = 40）进行热板、冷板、von Frey和rota棒试验。Gadobutrol静脉注射。取新生Sprague-Dawley大鼠DRG神经元，给予45mmol/L的HG。随后，3-（4,5-二甲基噻唑-2-酰基）-2,5-二苯基- 2h -溴化四唑（MTT）和彗星测定在加多丁诺处理和hg暴露的DRG神经元上进行。进一步进行了gadobutrol与过氧化氢酶（CAT）的分子对接分析。与STZ相比，STZ + gadobutrol在热板、冷板和von Frey试验中的敏感性有统计学意义（p=0.0013、p=0.0019和p=0.0189）。与HG相比，HG + gadobutrol对CAT的结合亲和力为-8.59kcal/mol，其细胞毒性和遗传毒性均有统计学意义的增加。本研究的结果首次表明，加多布洛可加重糖尿病引起的神经病变。需要进一步的临床研究来阐明这些结果，这可能会对糖尿病神经病变患者的安全性提出新的关注。

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引用次数: 0

Individual and mixed effects of PFAS on osteoporosis: Insights from epidemiological and bioinformatic approaches PFAS对骨质疏松症的个体和混合作用：来自流行病学和生物信息学方法的见解。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-09-27 DOI: 10.1016/j.toxlet.2025.111731

Wei Wei , Hongjin Huo , Xinxi Song , Dongxuan Wang , Hongyu Huang , Fei Jiang

This cross-sectional study investigated the associations between individual and mixed exposure to per- and polyfluoroalkyl substances (PFAS) and osteoporosis, and explored potential biological mechanisms in 2764 U.S. adults. Multivariable logistic regression and weighted quantile sum (WQS) regression were applied to examine associations between individual and mixed PFAS exposure and osteoporosis. Restricted cubic spline (RCS) was used to assess dose-response relationships. Mediation analysis was used to evaluate the mediated effects of neutrophil-to-lymphocyte ratio (NLR). Five PFAS compounds (PFOA, perfluorooctanoic acid; PFOS, perfluorooctane sulfonic acid; PFHxS, perfluorohexane sulfonic acid; PFDeA, perfluorodecanoic acid; PFNA, perfluorononanoic acid) with > 80 % detection rates were selected for investigation in this study. Individual exposure to PFOA, PFOS, PFHxS and PFNA were associated with increased lumbar osteoporosis risk (OR _Ln-PFOA = 1.963, 95 %CI: 1.433, 2.687, OR _Ln-PFOS = 1.422, 95 %CI: 1.061, 1.907, OR _Ln-PFHxS = 1.530, 95 %CI: 1.141, 2.052, OR _Ln-PFNA = 1.597, 95 %CI: 1.218, 2.094). Dose-response relationships were observed for PFOA and PFHxS, particularly in women and young adults. WQS regression demonstrated that mixed PFAS exposure increased osteoporosis risk (OR = 1.198, 1.077–1.318) and decreased bone mineral density (BMD, β = −0.017, −0.026 to −0.008), with PFOA contributing most significantly (41–48 % weight). NLR partially mediated these associations. Bioinformatic analyses further identified osteoporosis-related targets and pathways, with inflammation emerging as a key mechanistic link in these associations. Our findings demonstrated a significant association between PFAS exposure and osteoporosis risk, underscoring the importance of reducing PFAS exposure in mitigating bone disease burden.

这项横断面研究调查了个体和混合暴露于全氟烷基和多氟烷基物质（PFAS）与骨质疏松症之间的关系，并探讨了2764名美国成年人的潜在生物学机制。采用多变量logistic回归和加权分位数和（WQS）回归来检验单个和混合PFAS暴露与骨质疏松症之间的关系。限制三次样条（RCS）用于评估剂量-反应关系。采用中介分析评价中性粒细胞与淋巴细胞比值（NLR）的中介作用。本研究选取检出率为80%的5种PFAS化合物（PFOA、全氟辛酸、PFOS、全氟辛烷磺酸、PFHxS、全氟己烷磺酸、PFDeA、全氟癸酸、PFNA、全氟壬酸）进行研究。个体暴露于PFOA、PFOS、PFHxS和PFNA与腰椎骨质疏松风险增加相关（OR Ln-PFOA = 1.963, 95%CI: 1.433, 2.687, OR Ln-PFOS = 1.422, 95%CI: 1.061, 1.907, OR Ln-PFHxS = 1.530, 95%CI: 1.141, 2.052, OR Ln-PFNA = 1.597, 95%CI: 1.218, 2.094）。观察到PFOA和PFHxS的剂量-反应关系，特别是在女性和年轻人中。WQS回归显示，混合PFAS暴露增加骨质疏松风险（OR = 1.198, 1.077 ~ 1.318），降低骨密度（BMD, β = -0.017, -0.026 ~ -0.008），其中PFOA贡献最大（41 ~ 48%体重）。NLR部分介导了这些关联。生物信息学分析进一步确定了骨质疏松相关的靶点和途径，炎症是这些关联的关键机制环节。我们的研究结果证明了PFAS暴露与骨质疏松风险之间的显著关联，强调了减少PFAS暴露对减轻骨病负担的重要性。

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引用次数: 0

Microplastics as vectors for environmental contaminants in the food chain: Assessing the combined toxicological effects and bioavailability 微塑料作为食物链中环境污染物的载体：评估综合毒理学效应和生物利用度。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-09-26 DOI: 10.1016/j.toxlet.2025.111734

Jia Du, Linlin Qiu, Qingwei Zhou, Meiqing Jin, Weihong Wu

The global proliferation of microplastics (MPs) and nanoplastics (NPs) has raised concerns not only for their persistence in ecosystems but also for their role as transport agents of environmental contaminants through food chains. This review provides a comprehensive analysis of the mechanisms driving the sorption and desorption of diverse pollutants—including hydrophobic organics, metals, additives, and microbial agents—onto plastic particles, emphasizing how polymer composition, particle size, environmental aging, and eco-corona formation influence these interactions. Particular attention is paid to the transfer of MPs/NPs across trophic levels and their documented presence in various food items consumed by humans. The paper evaluates how ingestion may lead to desorption of contaminants in gastrointestinal environments, with in vitro studies demonstrating variable bioaccessibility depending on physicochemical and digestive conditions. Furthermore, the review synthesizes findings on cellular and systemic toxicity, highlighting how exposure to MPs/NPs—alone or in combination with other contaminants—can disrupt oxidative balance, immune responses, metabolic regulation, and reproductive health. Notably, combined exposures often result in synergistic or antagonistic effects, contingent on concentration, particle properties, and biological context. The potential for translocation of smaller particles and their associated chemicals across epithelial barriers introduces an additional vector of concern for internal exposure. Methodological variability in contamination assessment, limited real-world exposure data, and unresolved questions regarding long-term health consequences underscore the need for standardization and further investigation. This review aims to inform future risk assessments by integrating current knowledge of contaminant transport, bioavailability, and co-toxicological effects related to MPs/NPs in environmental and food systems.

微塑料（MPs）和纳米塑料（NPs）的全球扩散不仅引起了人们对它们在生态系统中的持久性的关注，而且引起了人们对它们作为环境污染物通过食物链运输媒介的作用的关注。本文全面分析了各种污染物（包括疏水有机物、金属、添加剂和微生物剂）在塑料颗粒上的吸附和解吸机制，强调了聚合物组成、颗粒大小、环境老化和生态电晕形成如何影响这些相互作用。特别关注MPs/NPs在营养水平上的转移以及它们在人类消费的各种食物中的记录存在。本文评估了摄入如何导致胃肠道环境中污染物的解吸，体外研究显示了不同的生物可及性，这取决于物理化学和消化条件。此外，该综述综合了细胞和全身毒性的研究结果，强调了暴露于MPs/ nps（单独或与其他污染物联合）如何破坏氧化平衡、免疫反应、代谢调节和生殖健康。值得注意的是，联合暴露通常会导致协同或拮抗效应，这取决于浓度、颗粒特性和生物环境。小颗粒及其相关化学物质跨越上皮屏障易位的可能性引入了另一个关注内部暴露的载体。污染评估方法的可变性、有限的实际暴露数据以及有关长期健康后果的未解决问题强调了标准化和进一步调查的必要性。本综述旨在通过整合环境和食品系统中与MPs/NPs相关的污染物运输、生物利用度和共同毒理学效应的现有知识，为未来的风险评估提供信息。

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引用次数: 0

Dysregulation of immune checkpoint LAG3 in mice exposed to silica 二氧化硅暴露小鼠免疫检查点LAG3的失调

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-09-18 DOI: 10.1016/j.toxlet.2025.111729

Meixiu Duan , Youliang Zhao , Yaqian Qu , Changfu Hao , Wu Yao

Silica exposure can cause silicosis, and its pathogenesis is not fully understood. This study investigates the role of immune checkpoint lymphocyte activation gene 3 (LAG3) in silicosis. Mice were intratracheally exposed to silica, and tissues were collected and analyzed after 7 and 28 days. Additionally, peripheral blood samples were also collected from silicosis patients. The mRNA and protein expression levels of LAG3 in various tissues were quantified using qRT-PCR and western blot techniques. The localization of LAG3 in the lung, spleen, thymus and hilar lymph nodes was visualized by immunochemistry. Our data showed that silica exposure induced systemic changes in LAG3 expression in an organ-specific manner. In mouse lungs, LAG3 levels were significantly upregulated after silica exposure. In mouse spleen, LAG3 expression changed only during early stage of silica exposure. In mouse thymus, the level of LAG3 decreased during early stage of silica exposure but reversed to increase during late stage. In mouse hilar lymph nodes, expression of LAG3 increased significantly. A marked increase in the concentration of soluble LAG3 was observed in the plasma of mice exposed to silica. Plasma soluble LAG3 levels in silicosis patients were found to be significantly higher than healthy controls. These findings suggest that LAG3 may be involved in the pathogenesis of silicosis and that immune disorders in lung tissue may further affect systemic immune homeostasis.

二氧化硅暴露可引起矽肺病，其发病机制尚不完全清楚。本研究探讨免疫检查点淋巴细胞激活基因3 （LAG3）在矽肺中的作用。小鼠气管内暴露于二氧化硅，在7天和28天后收集组织并进行分析。此外，还采集了矽肺患者的外周血样本。采用qRT-PCR和western blot技术定量分析LAG3在各组织中的mRNA和蛋白表达水平。免疫化学法观察LAG3在肺、脾、胸腺和肺门淋巴结的定位。我们的数据显示，二氧化硅暴露以器官特异性的方式诱导LAG3表达的系统性变化。在小鼠肺中，二氧化硅暴露后LAG3水平显著上调。在小鼠脾脏中，LAG3的表达仅在二氧化硅暴露的早期发生变化。在小鼠胸腺中，LAG3水平在二氧化硅暴露早期下降，但在暴露后期又反转上升。小鼠肺门淋巴结中LAG3的表达明显升高。在暴露于二氧化硅的小鼠血浆中观察到可溶性LAG3浓度的显著增加。矽肺患者血浆可溶性LAG3水平明显高于健康对照组。这些发现提示LAG3可能参与矽肺的发病机制，肺组织免疫紊乱可能进一步影响全身免疫稳态。

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引用次数: 0

Constitutive androstane receptor activation modulates YAP expression and activity through ubiquitination and sumoylation 组成型雄甾受体激活通过泛素化和聚合化调节YAP的表达和活性。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-09-18 DOI: 10.1016/j.toxlet.2025.111728

Fengting Liang , Shuaishuai Zhang , Wenhong Zhou , Guofang Bi , Xiao Yang , Peng Wang , Shicheng Fan , Shuang Hu , Chenghua Wu , Xiaowen Jiang , Dan Li , Hui Ouyang , Jian-Hong Fang , Huichang Bi

Constitutive Androstane Receptor (CAR) is a member of the nuclear receptor superfamily that significantly contributes to the metabolism of endogenous and exogenous substances and the homeostatic regulation of the body. Yes-associated protein (YAP) is a core component of the Hippo signaling pathway. We have previously demonstrated that CAR activation interacts with YAP and induces the nuclear translocation of YAP, although the specific binding site and regulatory mechanism remain unclear. In this study, we identified the ligand-binding domain (LBD) of CAR as essential for its interaction with YAP, while the WW domain (Tryptophan- Tryptophan domain) of YAP was found to be crucial for CAR binding. We further explored the impact of CAR activation on YAP post-translational modifications. CAR agonism inhibited YAP ubiquitination but promoted its SUMO1 modification, and had no effect on acetylation, glycosylation, and methylation. Notably, CAR activation enhanced the K63-linked ubiquitination of YAP, facilitating its nuclear translocation, and this effect was dependent on the E3 ligase TRAF6. Furthermore, PIAS4 was identified as a key SUMO E3 ligase, promoting YAP SUMO1 modification upon CAR activation. These findings provide new insights into how CAR regulates YAP activity through post-translational modifications, contributing to the understanding of CAR's role in liver regeneration.

组成型雄甾烷受体（Constitutive Androstane Receptor， CAR）是核受体超家族的一员，对内源性和外源性物质的代谢和机体的稳态调节有重要作用。yes相关蛋白（YAP）是Hippo信号通路的核心组成部分。我们之前已经证明，CAR激活与YAP相互作用并诱导YAP的核易位，尽管具体的结合位点和调控机制尚不清楚。在这项研究中，我们发现CAR的配体结合域（LBD）是其与YAP相互作用的关键，而YAP的WW结构域（色氨酸-色氨酸结构域）是CAR结合的关键。我们进一步探讨了CAR激活对YAP翻译后修饰的影响。CAR激动作用抑制YAP泛素化，但促进其SUMO1修饰，对乙酰化、糖基化和甲基化无影响。值得注意的是，CAR激活增强了YAP的k63连锁泛素化，促进了其核易位，这种作用依赖于E3连接酶TRAF6。此外，PIAS4被鉴定为SUMO E3的关键连接酶，在CAR激活时促进YAP SUMO1修饰。这些发现为CAR如何通过翻译后修饰调节YAP活性提供了新的见解，有助于理解CAR在肝脏再生中的作用。

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引用次数: 0

Studying APAP metabolism in a cohort of intoxicated patients using HRMS-based profiling: Detection of catechol and delayed thiomethyl metabolites 在一组醉酒患者中使用基于hrms的分析研究APAP代谢：检测儿茶酚和延迟硫甲基代谢物。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-09-16 DOI: 10.1016/j.toxlet.2025.111727

Thomas Gicquel , Romain Pelletier , Eva Gorrochategui , Margaux Heurté , Diane Le Bouedec , Jade Chaker , Isabelle Morel , Brendan Le Daré , Arthur David

Acetaminophen (APAP) overdose is one of the most important causes of drug-induced liver injury worldwide. Hepatotoxicity induced by APAP is mainly caused by the production of N-acetyl-p-benzoquinone imine (NAPQI), a highly reactive intermediate. Although, the medical management of APAP intoxication is well known, research is still ongoing to identify markers that could help to predict adverse issues after APAP intoxication. In this study, we aimed to study APAP biotransformation pathways in a cohort of patients with proven acute APAP intoxication to identify new biomarkers using state-of-the-art high-resolution mass spectrometry (HRMS) methodologies that could help improve the diagnosis of intoxication as well as patient follow-up. We used a cohort of 37 patients whom blood plasma samples were stratified according to the collection time after APAP intoxication. Our results showed that direct phase II metabolites from glucuronidation and sulfation pathways remain the main markers of APAP consumption. Our study also revealed that several oxidative pathways produce significant metabolites (including catechol ones) that could also help to monitor the intoxication and the elimination of the hepatotoxic NAPQI. In particular, significant levels of thiomethyl metabolites derived from the glutathione-NAPQI conjugates could be detected with a delay in their kinetics of appearance.

对乙酰氨基酚（APAP）过量是世界范围内引起药物性肝损伤的最重要原因之一。APAP引起的肝毒性主要是由n -乙酰-对苯醌亚胺（N-acetyl-p-benzoquinone亚胺，NAPQI）的产生引起的，NAPQI是一种高活性中间体。虽然APAP中毒的医疗管理是众所周知的，但研究仍在进行中，以确定可以帮助预测APAP中毒后不良反应的标志物。在这项研究中，我们旨在研究急性APAP中毒患者队列中的APAP生物转化途径，以使用最先进的高分辨率质谱（HRMS）方法识别新的生物标志物，这有助于提高中毒的诊断和患者随访。我们采用了37例患者的队列，根据APAP中毒后的血浆样本采集时间进行分层。我们的研究结果表明，葡萄糖醛酸化和硫酸化途径的直接II期代谢物仍然是APAP消耗的主要标志。我们的研究还揭示了几种氧化途径产生重要的代谢物（包括儿茶酚类代谢物），这些代谢物也有助于监测中毒和消除肝毒性NAPQI。特别是，由谷胱甘肽- napqi偶联物衍生的硫甲基代谢物的显著水平可以在其外观动力学延迟的情况下被检测到。

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引用次数: 0

Follicular and neural toxic effect of prolonged exposure of synthetic dye fast green FCF (E143)–Insights from zebrafish model 长时间暴露于合成染料耐晒绿FCF （E143）的卵泡和神经毒性效应——来自斑马鱼模型的见解。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-09-15 DOI: 10.1016/j.toxlet.2025.111726

Gokul Sudhakaran , P. Snega Priya , Raghul Murugan , B. Haridevamuthu , Jagan Kannan , Saeedah Musaed Almutairi , Dina S. Hussein , Yasmine Hamdy Eisa , Kathiravan Muthu Kumaradoss , S. Karthick Raja Namasivayam , Jesu Arockiaraj

This study highlights the toxic effects of prolonged exposure of synthetic food dye fast green FCF (E143) in zebrafish and the cumulative consequences of such exposure on multiple biological systems mainly neural and reproductive. Chronic exposure to FCF at concentrations of 0.1 %, 0.3 %, and 0.5 % led to a reduction in acetylcholinesterase (AChE) activity and an increase in malondialdehyde (MDA) levels, indicating impaired neuronal function. The disruption in the production of key antioxidant enzymes, including catalase (CAT), lactate dehydrogenase (LDH), superoxide dismutase (SOD), and nitric oxide (NO), further supported the link between elevated reactive oxygen species (ROS) levels and increased oxidative stress and lipid peroxidation (LPO). Histopathological analysis using H&E, MTS, Toluidine blue, and PAS staining revealed significant changes in the brain, liver, and ovaries of FCF-exposed zebrafish, suggesting potential neurological damage, hepatotoxicity, and reproductive disturbances, particularly arrest of follicular maturation. High-performance liquid chromatography (HPLC) analysis confirmed bioaccumulation of FCF in the ovaries. Gene expression analysis of SOD1, CAT, NF-κB, TNF-α, IL-1β, BCL2, BAX, MBP, and Syn2a provided molecular evidence of disrupted antioxidant defenses, impaired myelin formation, altered synaptic function in the brain, inflammatory responses, and increased apoptosis in the ovaries. This study is crucial for understanding the potential risks to zebrafish and provides insights into the broader implications for consumer health when exposed to similar food dyes in the environment.

本研究强调了斑马鱼长期暴露于合成食用染料快绿FCF （E143）的毒性作用，以及这种暴露对多种生物系统（主要是神经和生殖系统）的累积后果。长期暴露于浓度为0.1%、0.3%和0.5%的FCF会导致乙酰胆碱酯酶（AChE）活性降低，丙二醛（MDA）水平升高，表明神经元功能受损。过氧化氢酶（CAT）、乳酸脱氢酶（LDH）、超氧化物歧化酶（SOD）和一氧化氮（NO）等关键抗氧化酶的产生受到破坏，进一步支持了活性氧（ROS）水平升高与氧化应激和脂质过氧化（LPO）增加之间的联系。H&E、MTS、甲苯胺蓝和PAS染色的组织病理学分析显示，接触fcf的斑马鱼的大脑、肝脏和卵巢发生了显著变化，提示潜在的神经损伤、肝毒性和生殖障碍，特别是卵泡成熟阻滞。高效液相色谱（HPLC）分析证实了FCF在卵巢中的生物蓄积。SOD1、CAT、NF-κB、TNF-α、IL-1β、BCL2、BAX、MBP和Syn2a的基因表达分析提供了抗氧化防御被破坏、髓磷脂形成受损、脑突触功能改变、炎症反应和卵巢细胞凋亡增加的分子证据。这项研究对于了解斑马鱼的潜在风险至关重要，并为消费者在环境中暴露于类似的食用色素时对健康的更广泛影响提供了见解。

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引用次数: 0

Physiologically based toxicokinetic models in aggregate exposure: A review 基于生理的毒性动力学模型在总体暴露：综述。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-09-13 DOI: 10.1016/j.toxlet.2025.111725

L. Lamon , A. Paini , M. Siccardi , J. Doyle , C. McNamara , K.S. Galea , M. Ghosh , H. Louro , M.J. Silva , N. El Yamani , M. Dusinska , R. Moeller , R.C. Duca , F. Cubadda , S. Viegas , C. Martins , P. Price

This literature review explores the application of Physiologically Based Kinetic (PBK) models in aggregate exposure (AE) assessment across different chemical classes. It builds on the screening of 1119 publications and the identification of 40 relevant articles. The most frequently studied chemicals include volatile organic compounds and plant protection products, with metals, personal care products, persistent organic pollutants and plasticisers also represented. Most studies reported in this review are applied to human populations and build on human biomonitoring (HBM) data to enhance model reliability. However, some studies use animal models (primarily rat models) and apply cross-species extrapolation to the human AE scenario. Occupational exposure is taken into consideration as part of the AE scenario in a few studies. Many of the reviewed studies are designed in support of chemical risk assessment (CRA), illustrating the wide applicability of PBK models. The review discusses the joint role of HBM data and PBK model in AE scenarios, highlighting its importance for a reliable risk assessments. The studies identified and discussed in this review suggest a broad interpretation of AE. The diversity across case reported studies is attributed to varying interpretations and existing definitions of AE. Finally, the roles of forward and reverse dosimetry in refining AE assessments are discussed, highlighting their importance for future research. This scoping review provides a comprehensive overview of PBK model applications in addressing AE, serving as a valuable foundation for future research and development aimed at advancing human health protection towards the Next-Generation Risk Assessment (NGRA).

这篇文献综述探讨了生理动力学（PBK）模型在不同化学类别的总暴露（AE）评估中的应用。它以筛选1119种出版物和确定40篇相关文章为基础。最常被研究的化学品包括挥发性有机化合物和植物保护产品，还有金属、个人护理产品、持久性有机污染物和增塑剂。本综述中报道的大多数研究都应用于人群，并建立在人类生物监测（HBM）数据基础上，以提高模型的可靠性。然而，一些研究使用动物模型（主要是大鼠模型），并将跨物种外推应用于人类AE情景。在一些研究中，职业暴露被考虑为AE情景的一部分。许多被回顾的研究都是为了支持化学品风险评估（CRA）而设计的，这说明了PBK模型的广泛适用性。本文讨论了HBM数据和PBK模型在AE情景中的联合作用，强调了其对可靠风险评估的重要性。本综述中确定和讨论的研究建议对AE进行广泛的解释。病例报告研究的多样性归因于对AE的不同解释和现有定义。最后，讨论了正向和反向剂量学在改进声发射评估中的作用，并强调了它们对未来研究的重要性。本综述全面概述了PBK模型在AE研究中的应用，为未来研究和开发旨在推进人类健康保护的下一代风险评估（NGRA）奠定了有价值的基础。

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引用次数: 0