Toxicology letters最新文献_第5页

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

Lopinavir/ritonavir induces hepatotoxicity in HepG2 cells through inhibition of the Nrf2 pathway, resulting in oxidative stress, endoplasmic reticulum stress, and cell cycle arrest 洛匹那韦/利托那韦通过抑制Nrf2通路诱导HepG2细胞肝毒性，导致氧化应激、内质网应激和细胞周期阻滞。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-05 DOI: 10.1016/j.toxlet.2025.111798

Wenhong Zhou , Dan Wang , Jundou Tu , Jun Li , Jiayu Xu , Wenjing Tan , Diwei Mo , Pengying Liang , Yinglin Guo , Ming Hu , Linhu Ye

Lopinavir/ritonavir (LPV/r), a clinically used protease inhibitor for treating human immunodeficiency virus, is associated with liver injury. In this study, we demonstrated that LPV/r significantly suppressed HepG2 cell viability and increased the secretion of ALT, AST and LDH in the cell supernatant. Flow cytometry analysis revealed that LPV/r induced cell cycle arrest at the G0/G1 phase and triggered apoptosis in HepG2 cells. Furthermore, LPV/r significantly induced oxidative stress and endoplasmic reticulum (ER) stress, evidenced by elevated intracellular reactive oxygen species (ROS) levels, ER vesicular dilation, and alterations in the expression of related proteins. Additionally, LPV/r markedly increased the expression of apoptosis-related proteins. Mechanistically, activation of Nrf2 with tBHQ or overexpression of Nrf2 protein can effectively reverse the suppression of Nrf2/HO-1 expression by LPV/r, thereby reducing ROS accumulation and alleviating LPV/r-induced hepatocyte injury. Collectively, our findings demonstrate that LPV/r suppresses Nrf2 and HO-1 protein, promotes ROS accumulation, which induces oxidative stress and ER stress, ultimately leading to cell apoptosis and G0/G1 phase cell cycle arrest. This research provides novel mechanistic insights into the hepatotoxic effects of LPV/r.

洛匹那韦/利托那韦（LPV/r）是临床用于治疗人类免疫缺陷病毒的蛋白酶抑制剂，与肝损伤有关。在本研究中，我们发现LPV/r显著抑制HepG2细胞活力，增加细胞上清中ALT、AST和LDH的分泌。流式细胞术分析显示，LPV/r诱导HepG2细胞周期阻滞于G0/G1期，并引发细胞凋亡。此外，LPV/r显著诱导氧化应激和内质网（ER）应激，表现为细胞内活性氧（ROS）水平升高、内质网囊泡扩张和相关蛋白表达改变。此外，LPV/r显著增加凋亡相关蛋白的表达。机制上，通过tBHQ激活Nrf2或Nrf2蛋白过表达可有效逆转LPV/r对Nrf2/HO-1表达的抑制，从而减少ROS的积累，减轻LPV/r诱导的肝细胞损伤。综上所述，我们的研究结果表明，LPV/r抑制Nrf2和HO-1蛋白，促进ROS积累，诱导氧化应激和内质网应激，最终导致细胞凋亡和G0/G1期细胞周期阻滞。这项研究为LPV/r的肝毒性作用提供了新的机制见解。

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引用次数: 0

Relationship between urinary phthalate metabolites and liver function indicators in the elderly in Northeast China 东北地区老年人尿邻苯二甲酸酯代谢物与肝功能指标的关系

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-02 DOI: 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.

邻苯二甲酸盐是广泛存在的环境污染物，但其对老年人肝功能的影响尚不清楚。这项横断面研究检查了老年人尿液中15种邻苯二甲酸酯代谢物浓度与血清肝脏生物标志物之间的关系。代谢物水平采用液相色谱-串联质谱法测定，肌酐调整。多元线性回归和贝叶斯核机回归（BKMR）模型用于评估个体和联合效应。几种邻苯二甲酸酯代谢物与肝酶，包括丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）和碱性磷酸酶（ALP）呈正相关，与胆红素（TBIL、DBIL）、白蛋白和总蛋白呈负相关。BKMR分析证实了ALT、AST、ALP和γ -谷氨酰转移酶（GGT）的阳性混合作用。体重指数（BMI）改变了这些关联，表明脂肪组织在邻苯二甲酸酯积累和肝脏效应中的作用。这些发现强调了与老年人邻苯二甲酸盐暴露相关的潜在亚临床肝功能障碍，值得在环境风险和健康老龄化的背景下进一步研究。

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引用次数: 0

Subtotal removal of the stratum corneum by brushing as a decontamination strategy after hydrofluoric-acid exposure of human skin 在氢氟酸暴露于人体皮肤后，通过刷牙去除角质层作为一种去污策略

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-02 DOI: 10.1016/j.toxlet.2025.111788

Suvarna Mini Vijayan , Thomas Göen , Andrea Kaifie , Franklin Kiesewetter , Raymund E. Horch , Wibke Müller-Seubert , Hans Drexler , Sonja Kilo , Anna Wolfschmidt

Accidents with hydrofluoric acid (HF) can cause systemic poisoning by transdermal penetration of fluoride ions. Abrasive techniques, like mechanical brushing, are occasionally used as a method of decontamination, but their efficacy in reducing systemic fluoride absorption remains unclear. In a modified Franz diffusion-cell model, human skin samples (0.9 mm thickness, n = 6 per group) were exposed to 30 % HF. After one minute of exposure, the supernatant fluid was removed with cotton swabs. With the exception of untreated controls, the skin was then decontaminated either with a water jet alone or combined with brushing, using an electric toothbrush. Samples were collected from the receptor solution at different timepoints during the 72 h post-exposure timeframe. Both strategies were effective when compared to a lack of decontamination. There was no significant difference in cumulative fluoride absorption between the combination of water jet plus brushing and the water jet alone. However, approximately 4–48 h after exposure, the fluoride flux (absorption per hour) was lower in the skin samples treated with the combination of water jet and brushing. This difference was significant at 12 h and 24 h post-exposure. Overall, our results suggest an additional efficacy of mechanical decontamination during the prolonged follow-up period after hydrofluoric-acid exposure. This might be especially relevant in exposure scenarios with a larger skin depot of fluoride, like exposure to higher HF-concentrations. However, future research is needed to place these findings on a broader data basis and to evaluate the safety and efficacy of mechanical decontamination in practice.

氢氟酸（HF）事故可通过氟离子经皮渗透引起全身中毒。磨料技术，如机械刷，偶尔被用作去污方法，但它们在减少全身氟化物吸收方面的功效尚不清楚。在改进的Franz扩散细胞模型中，人体皮肤样品（0.9 mm厚度，每组 = 6）暴露于30 % HF。暴露1分钟后，用棉签除去上清液。除未经处理的对照组外，研究人员分别用喷水或用电动牙刷对皮肤进行消毒。在暴露后72 h的不同时间点从受体溶液中收集样品。与缺乏净化相比，这两种策略都是有效的。水射流联合刷牙与单独使用水射流刷牙的累积氟化物吸收量无显著差异。然而，在接触后约4-48 h，使用水射流和刷牙组合处理的皮肤样品的氟化物通量（每小时吸收量）较低。这种差异在暴露后12 h和24 h显著。总的来说，我们的研究结果表明，在氢氟酸暴露后的长时间随访期间，机械去污具有额外的功效。这可能与皮肤氟化物储存量较大的暴露情况特别相关，例如暴露于较高的hf浓度。然而，未来的研究需要将这些发现建立在更广泛的数据基础上，并评估机械去污在实践中的安全性和有效性。

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引用次数: 0

Integrated transcriptomic and metabolomic analyses reveal the pathogenesis of 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced liver injury in mice 综合转录组学和代谢组学分析揭示了3,5-二氧羰基-1,4-二氢碰撞碱诱导小鼠肝损伤的发病机制。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-01 DOI: 10.1016/j.toxlet.2025.111786

Zijun Zhang, Rong Ji, Ahua Ku, Ruhan A, Binbin Song

The hepatotoxic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) has been widely utilized to establish various liver disease models. However, the molecular networks and metabolic regulatory mechanisms underlying DDC-induced liver injury remain to be fully elucidated. In this study, an integrated transcriptomic and metabolomic approach was employed to investigate the mechanisms of DDC-induced hepatotoxicity. C57BL/6 J mice were administered a 0.1 % DDC-supplemented diet for two weeks to induce liver injury, followed by collection of serum and liver tissue samples for analysis. The results demonstrated that DDC treatment significantly elevated markers of liver injury, cholestasis, and fibrosis. Histopathological examination revealed hepatocyte damage, inflammatory cell infiltration, and increased collagen deposition in DDC-treated mice. Liver transcriptomic analysis identified 814 differentially expressed genes, while serum metabolomic profiling detected 958 differentially expressed metabolites. Integrated pathway analysis revealed co-enrichment of 14 pathways in both transcriptomic and metabolomic datasets, including steroid hormone biosynthesis, glycerophospholipid metabolism, retrograde endocannabinoid signaling, and primary bile acid biosynthesis. Validation experiments using qRT-PCR and UPLC-MS/MS demonstrated that DDC treatment upregulated hepatic mRNA levels of Cyp27a1, Mrp2, and Mrp3, while downregulating Cyp8b1, Hsd3b7, Scp2, and Hsd17b4. Serum analysis showed significant increases in the concentrations of CA, TCA, GCA, TCDCA, α-MCA, β-MCA, Tβ-MCA, TUDCA, CDCA, UDCA, ω-MCA, and HDCA, along with decreased LCA levels. These findings indicate that DDC-induced liver injury involves multiple pathways and mechanisms, with disruption of bile acid homeostasis representing a central pathological feature.

肝毒性化合物3,5-二氧羰基-1,4-二氢碰撞碱（DDC）已被广泛用于建立各种肝脏疾病模型。然而，ddc诱导的肝损伤的分子网络和代谢调控机制仍未完全阐明。本研究采用综合转录组学和代谢组学方法研究ddc诱导肝毒性的机制。C57BL/6 J小鼠给予添加0.1% % ddc的日粮诱导肝损伤2周，然后采集血清和肝组织样本进行分析。结果表明，DDC治疗显著提高肝损伤、胆汁淤积和纤维化指标。组织病理学检查显示ddc处理小鼠肝细胞损伤，炎症细胞浸润，胶原沉积增加。肝脏转录组学分析鉴定出814个差异表达基因，而血清代谢组学分析检测到958个差异表达代谢物。综合通路分析显示，转录组学和代谢组学数据集中共有14条通路富集，包括类固醇激素生物合成、甘油磷脂代谢、逆行内源性大麻素信号传导和初级胆油酸生物合成。qRT-PCR和UPLC-MS/MS验证实验表明，DDC处理上调了肝脏Cyp27a1、Mrp2和Mrp3 mRNA水平，下调了Cyp8b1、Hsd3b7、Scp2和Hsd17b4 mRNA水平。血清分析显示CA、TCA、GCA、TCDCA、α-MCA、β-MCA、t - mca、TUDCA、CDCA、UDCA、ω-MCA、HDCA浓度显著升高，LCA水平降低。这些发现表明，ddc诱导的肝损伤涉及多种途径和机制，胆汁酸稳态的破坏是一个主要的病理特征。

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引用次数: 0

Comprehensive estrogenicity assessment of 4-methylbenzophenone via in vivo, in vitro, and in silico approaches within an integrated testing strategy framework 在综合测试策略框架内，通过体内、体外和计算机方法对4-甲基二苯甲酮的综合雌激素性进行评估。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-01 DOI: 10.1016/j.toxlet.2025.111784

Darlene Mae D. Ortiz, Ngoc Minh-Hong Hoang, Handule Lee, Kwangsik Park

4-Methylbenzophenone (4-MBP) is extensively used as a photoinitiator in ultraviolet-cured printing inks and food packaging. This study comprehensively evaluated its estrogenic activity using an Integrated Testing Strategy (ITS) incorporating in vivo, in vitro, and in silico methodologies. Repeated oral administration of 4-MBP at 300 mg/kg (lowest observed effect concentration, LOEC) in ovariectomized rats significantly increased relative uterine weight (0.11 ± 0.01 % vs. 0.05 ± 0.00 % in controls) and serum estradiol levels elevated serum estradiol levels (4-fold over vehicle control). Histological analysis confirmed estrogenic alterations, including epithelial thickening, glandular degeneration, and stromal inflammation. Although estrogen receptor α (ERα) expression remained unchanged, aromatase (CYP19) was significantly upregulated in uterine tissue, suggesting that enhanced estrogen biosynthesis plays a key role in the effects elicited by 4-MBP. In vitro assays showed that 4-MBP activated ER transcription in HeLa9903 cells with a maximum relative proliferative capacity (RPCmax) of about 200 % compared with 1 nM 17β-estradiol, and significantly induced MCF-7 cell proliferation at 10⁻⁵ M, coinciding with peak CYP19 mRNA expression. CYP19 expression was also increased at the mRNA and protein levels, and evidence of post-transcriptional regulation was observed at higher concentrations (10 µM). In silico molecular docking and dynamic simulations corroborated these findings demonstrating strong binding affinities of 4-MBP to ERα (docking score as low as −8.7 kcal/mol) and ERβ. Our results indicate that 4-MBP exerts estrogenic effects by elevating estrogen synthesis and inducing direct ER transcriptional activation. These findings highlight the utility of ITS for evaluating endocrine-disrupting chemicals and emphasize the need for regulatory consideration of 4-MBP and structurally related compounds in consumer products.

4-甲基二苯甲酮（4-MBP）作为光引发剂广泛应用于紫外光固化印刷油墨和食品包装中。本研究使用综合测试策略（its）综合体内，体外和计算机方法全面评估其雌激素活性。去卵巢大鼠反复口服4-MBP 300mg/kg（最低观察效应浓度，LOEC）显著增加相对子宫重量（对照组为0.11±0.01%，对照组为0.05±0.00%），血清雌二醇水平升高（比对照提高4倍）。组织学分析证实雌激素改变，包括上皮增厚、腺体变性和间质炎症。虽然雌激素受体α (ERα)表达不变，但子宫组织中芳香化酶（CYP19）显著上调，提示雌激素生物合成增强在4-MBP诱导的作用中起关键作用。体外实验显示，4-MBP激活HeLa9903细胞内质网转录，与1nM 17β-雌二醇相比，最大相对增殖能力（RPCmax）约为200%，并显著诱导MCF-7细胞在10⁻- 35 M时增殖，与CYP19 mRNA表达高峰一致。在mRNA和蛋白水平上CYP19的表达也增加，并且在较高浓度（10µM）下观察到转录后调节的证据。硅分子对接和动态模拟证实了这些发现，表明4-MBP与ERα（对接评分低至-8.7kcal/mol）和ERβ具有很强的结合亲和力。我们的研究结果表明，4-MBP通过提高雌激素合成和诱导内质网直接转录激活来发挥雌激素作用。这些发现强调了ITS在评估内分泌干扰化学物质方面的效用，并强调了在消费品中对4-MBP和结构相关化合物进行监管的必要性。

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引用次数: 0

Corrigendum to “TLR2-ERK signaling pathway regulates expression of galectin-3 in a murine model of OVA-induced allergic airway inflammation” [Toxicol. Lett. 397 (2024) 55–66] “TLR2-ERK信号通路调节ova诱导的小鼠过敏性气道炎症模型中半乳糖凝集素-3的表达”的更正[毒理学杂志]。Lett. 397(2024) 55-66]。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-01 DOI: 10.1016/j.toxlet.2025.111768

Yunxiang Lv , Guiyun Jiang , Yanru Jiang , Caiqiu Peng , Wei Li

引用次数: 0

Metabolic activation, hepatic protein covalent binding, and cytotoxicity of arctigenin 牛蒡子素的代谢激活、肝蛋白共价结合和细胞毒性。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-01 DOI: 10.1016/j.toxlet.2025.111785

Yuqin Chen , Zixia Hu , Guode Zhao , Mei Li , Ziying Jiang , Liangjia Xu , Jiannan Zheng , Weiwei Li , Ying Peng , Jiang Zheng

Arctigenin (ATG) is an important component isolated from the fruit of the medicinal plant Arctium lappa L., with anti-inflammatory, antiviral and anti-tumor properties. Although ATG has been reported to induce hepatotoxicity in beagle dogs and SD rats, and the underlying mechanisms remained unclear. The aim of this study was to investigate the metabolic activation of ATG and to define the potential correlation between the metabolic activation of ATG and its hepatotoxicity. A quinone methide intermediate was identified in vitro and in vivo, and CYP3A dominated the metabolic activation. ATG was found to show significant cytotoxicity at 50 μM in cultured mouse primary hepatocytes. The ATG-derived quinone methide metabolite assaulted cysteine residue of hepatic protein to form protein covalent binding. The observed protein modification was most likely associated with the cytotoxicity of ATG observed.

牛蒡素（Arctigenin， ATG）是从药用植物牛蒡子中分离得到的一种重要成分，具有抗炎、抗病毒和抗肿瘤的作用。虽然有报道称ATG可引起比格犬和SD大鼠的肝毒性，但其潜在机制尚不清楚。本研究的目的是研究ATG的代谢激活，并确定ATG代谢激活与其肝毒性之间的潜在相关性。体外和体内均鉴定出一种醌类中间体，CYP3A主导代谢激活。ATG对培养的小鼠原代肝细胞有明显的50μM细胞毒性。atg衍生的醌类代谢物攻击肝蛋白半胱氨酸残基形成蛋白共价结合。观察到的蛋白质修饰很可能与观察到的ATG的细胞毒性有关。

引用次数: 0