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Thiopurine S‑methyltransferase- and indolethylamine N‑methyltransferase-mediated formation of methylated tellurium compounds from tellurite. 硫代嘌呤 S-甲基转移酶和吲哚乙胺 N-甲基转移酶介导的亚碲酸盐甲基化碲化合物的形成。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-10-17 DOI: 10.1007/s00204-024-03890-4
Yu-Ki Tanaka, Ayuka Takata, Karin Takahashi, Yoshikazu Yamagishi, Yasunori Fukumoto, Noriyuki Suzuki, Yasumitsu Ogra

Tellurium (Te) is a metalloid widely used in various industries. However, its toxicological impact on humans is poorly understood. In this study, we investigated the role of two methyltransferases, thiopurine S‑methyltransferase (TPMT) and indolethylamine N‑methyltransferase (INMT), in the methylation of tellurite, an inorganic Te oxyanion. The products of the reaction of Te compounds catalyzed by recombinant human TPMT and/or INMT were analyzed by liquid chromatography hyphenated to inductively coupled plasma mass spectrometry (LC-ICP-MS) and gas chromatography mass spectrometry (GC-MS). We found that TPMT catalyzes the methylation of non-methylated Te and methanetellurol to generate dimethyltelluride. On the other hand, INMT catalyzes the methylation of methanetellurol and dimethyltelluride to produce trimethyltelluronium ion, a metabolite excreted into animal urine. We conclude that TPMT and INMT are cooperatively responsible for the detoxification of Te oxyanions through methylation to form trimethyltelluronium ions.

碲(Te)是一种广泛应用于各行各业的类金属。然而,人们对其对人体的毒理影响知之甚少。在这项研究中,我们研究了两种甲基转移酶(硫嘌呤 S-甲基转移酶(TPMT)和吲哚乙胺 N-甲基转移酶(INMT))在碲(一种无机碲氧阴离子)甲基化过程中的作用。通过液相色谱-电感耦合等离子体质谱(LC-ICP-MS)和气相色谱-质谱(GC-MS)分析了重组人 TPMT 和/或 INMT 催化的 Te 化合物反应产物。我们发现,TPMT 催化非甲基化碲和甲烷四氢呋喃的甲基化,生成二甲基四氢呋喃。另一方面,INMT 催化甲烷四呋喃和二甲基碲的甲基化,生成三甲基碲离子,这种代谢物排泄到动物尿液中。我们的结论是,TPMT 和 INMT 通过甲基化形成三甲基碲离子,共同负责碲氧阴离子的解毒。
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引用次数: 0
The current state of EVALI research (electronic cigarettes or vaping product use-associated lung injury) EVALI 研究现状(电子香烟或电子烟产品使用相关肺损伤)。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-10-16 DOI: 10.1007/s00204-024-03885-1
Hermann M. Bolt
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引用次数: 0
Innate immune regulation in inflammation resolution and liver regeneration in drug-induced liver injury. 药物性肝损伤中炎症消退和肝脏再生过程中的先天免疫调节。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-10-12 DOI: 10.1007/s00204-024-03886-0
Yihan Qian, Jie Zhao, Hailong Wu, Xiaoni Kong

Drug-induced liver injury (DILI) is an acute liver injury that poses a significant threat to human health. In severe cases, it can progress into chronic DILI or even lead to liver failure. DILI is typically caused by either intrinsic hepatotoxicity or idiosyncratic metabolic or immune responses. In addition to the direct damage drugs inflict on hepatocytes, the immune responses and liver inflammation triggered by hepatocyte death can further exacerbate DILI. Initially, we briefly discussed the differences in immune cell activation based on the type of liver cell death (hepatocytes, cholangiocytes, and LSECs). We then focused on the role of various immune cells (including macrophages, monocytes, neutrophils, dendritic cells, liver sinusoidal endothelial cells, eosinophils, natural killer cells, and natural killer T cells) in both the liver injury and liver regeneration stages of DILI. This article primarily reviews the role of innate immune regulation mediated by these immune cells in resolving inflammation and promoting liver regeneration during DILI, as well as therapeutic approaches targeting these immune cells for the treatment of DILI. Finally, we discussed the activation and function of liver progenitor cells (LPCs) during APAP-induced massive hepatic necrosis and the involvement of chronic inflammation in DILI.

药物性肝损伤(DILI)是一种急性肝损伤,对人类健康构成重大威胁。严重者可发展为慢性 DILI,甚至导致肝功能衰竭。DILI 通常是由内在肝毒性或特异性代谢或免疫反应引起的。除了药物对肝细胞造成的直接损伤外,肝细胞死亡引发的免疫反应和肝脏炎症也会进一步加剧 DILI。首先,我们简要讨论了肝细胞死亡类型(肝细胞、胆管细胞和LSECs)在免疫细胞激活方面的差异。然后,我们重点讨论了各种免疫细胞(包括巨噬细胞、单核细胞、中性粒细胞、树突状细胞、肝窦内皮细胞、嗜酸性粒细胞、自然杀伤细胞和自然杀伤 T 细胞)在 DILI 的肝损伤和肝再生阶段的作用。本文主要综述了这些免疫细胞介导的先天性免疫调节在 DILI 期间消除炎症和促进肝脏再生中的作用,以及针对这些免疫细胞治疗 DILI 的方法。最后,我们讨论了在 APAP 诱导的大量肝坏死过程中肝脏祖细胞(LPCs)的活化和功能,以及慢性炎症在 DILI 中的参与。
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引用次数: 0
Trends in research on advanced glycation end products (AGEs) 高级糖化终产物(AGEs)的研究趋势
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-10-10 DOI: 10.1007/s00204-024-03883-3
Hermann M. Bolt, Jan G. Hengstler
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引用次数: 0
Mechanistic insight of neurodegeneration due to micro/nano-plastic-induced gut dysbiosis. 微/纳米塑料诱导的肠道菌群失调导致神经退行性变的机制研究。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-10-06 DOI: 10.1007/s00204-024-03875-3
Arya Ghosh, Bapi Gorain

Despite offering significant conveniences, plastic materials contribute substantially in developing environmental hazards and pollutants. Plastic trash that has not been adequately managed may eventually break down into fragments caused by human or ecological factors. Arguably, the crucial element for determining the biological toxicities of plastics are micro/nano-forms of plastics (MPs/NPs), which infiltrate the mammalian tissue through different media and routes. Infiltration of MPs/NPs across the intestinal barrier leads to microbial architectural dysfunction, which further modulates the population of gastrointestinal microbes. Thereby, it triggers inflammatory mediators (e.g., IL-1α/β, TNF-α, and IFN-γ) by activating specific receptors located in the gut barrier. Mounting evidence indicates that MPs/NPs disrupt host pathophysiological function through modification of junctional proteins and effector cells. Moreover, the alteration of microbial diversity by MPs/NPs causes the breakdown of the blood-brain barrier and translocation of metabolites (e.g., SCFAs, LPS) through the vagus nerve. Potent penetration affects the neuronal networks, neuronal protein accumulation, acceleration of oxidative stress, and alteration of neurofibrillary tangles, and hinders distinctive communicating pathways. Conclusively, alterations of these neurotoxic factors are possibly responsible for the associated neurodegenerative disorders due to the exposure of MPs/NPs. In this review, the hypothesis on MPs/NPs associated with gut microbial dysbiosis has been interlinked to the distinct neurological impairment through the gut-brain axis.

尽管塑料材料给人们带来了极大的便利,但它也在很大程度上造成了环境危害和污染。未得到适当管理的塑料垃圾最终可能会因人为或生态因素而分解成碎片。可以说,决定塑料生物毒性的关键因素是塑料的微/纳米形态(MPs/NPs),它们通过不同的介质和途径渗入哺乳动物组织。MPs/NPs渗入肠道屏障会导致微生物结构失调,从而进一步改变胃肠道微生物的数量。因此,MPs/NPs 通过激活肠道屏障中的特定受体,引发炎症介质(如 IL-1α/β、TNF-α 和 IFN-γ)。越来越多的证据表明,MPs/NPs 通过改变连接蛋白和效应细胞来破坏宿主的病理生理功能。此外,MPs/NPs 对微生物多样性的改变会导致血脑屏障的破坏和代谢物(如 SCFAs、LPS)通过迷走神经的转运。强力渗透会影响神经元网络、神经元蛋白质积累、加速氧化应激和改变神经纤维缠结,并阻碍独特的沟通途径。总之,这些神经毒性因素的改变可能是接触 MPs/NPs 导致相关神经退行性疾病的原因。在这篇综述中,关于 MPs/NPs 与肠道微生物菌群失调相关的假说通过肠道-大脑轴与不同的神经损伤相互关联。
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引用次数: 0
Arylacetamide deacetylase regulates hepatic iron homeostasis to protect against carbon tetrachloride-induced ferroptosis 芳基乙酰胺去乙酰化酶调节肝脏铁稳态,防止四氯化碳诱导的铁变态反应。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-10-05 DOI: 10.1007/s00204-024-03873-5
Soshi Shinohara, Seijo Uchijima, Keiya Hirosawa, Mai Nagaoka, Masataka Nakano, Miki Nakajima, Tatsuki Fukami

Arylacetamide deacetylase (AADAC) catalyzes the hydrolysis of small molecules containing ester and amide bonds. Recently, it has been reported that AADAC can suppress reactive oxygen species production in cancer cells. This study aimed to elucidate the possibility that AADAC protects against drug-induced liver injury accompanied by oxidative stress and to explore its molecular mechanisms. Intraperitoneal administration of carbon tetrachloride induced significantly more severe liver injury in Aadac knockout (KO) mice (plasma alanine aminotransferase level: 19,381 ± 10,578 U/L) than in wild-type (WT) mice (7219 ± 4729 U/L). More severe liver injury in Aadac KO mice was accompanied by higher hepatic malondialdehyde and antioxidant gene mRNA levels than those in WT mice. The increase in plasma alanine aminotransferase levels in Aadac KO mice was substantially suppressed by pretreatment with the ferroptosis inhibitors deferoxamine or ferrostatin-1, suggesting that Aadac deficiency increases susceptibility to ferroptosis. Immunoprecipitation followed by proteomic analysis revealed that AADAC interacts with ceruloplasmin (CP), which oxidizes ferrous iron to ferric iron. Hepatic CP activity was significantly lower in Aadac KO mice than that in WT mice, resulting in elevated hepatic ferrous iron levels in Aadac KO mice. Overexpression of human AADAC in Huh-7 cells significantly attenuated carbon tetrachloride-induced cytotoxicity by suppressing ferrous iron accumulation, suggesting that AADAC interacts with CP to suppress hepatic ferrous iron accumulation. The hepatoprotective role of Aadac in ferroptosis was also observed in mice with acetaminophen-induced liver injury. This study demonstrates a novel function of AADAC in protecting against ferroptosis induced by hepatotoxicants, carbon tetrachloride and acetaminophen.

芳基乙酰胺脱乙酰酶(AADAC)催化水解含有酯键和酰胺键的小分子。最近有报道称,AADAC 可抑制癌细胞中活性氧的产生。本研究旨在阐明 AADAC 可防止药物诱导的肝损伤(伴有氧化应激)的可能性,并探索其分子机制。腹腔注射四氯化碳诱导的Aadac基因敲除(KO)小鼠肝损伤(血浆丙氨酸氨基转移酶水平:19381 ± 10578 U/L)比野生型(WT)小鼠(7219 ± 4729 U/L)严重得多。与 WT 小鼠相比,Aadac KO 小鼠肝损伤更严重,肝丙二醛和抗氧化基因 mRNA 水平更高。Aadac KO小鼠血浆丙氨酸氨基转移酶水平的升高在使用铁蛋白沉积抑制剂去铁胺或铁前列素-1预处理后被大大抑制,这表明Aadac缺乏会增加对铁蛋白沉积的易感性。免疫沉淀后的蛋白质组分析表明,AADAC 与将亚铁氧化为铁的脑磷脂蛋白(CP)相互作用。Aadac KO小鼠肝脏CP活性明显低于WT小鼠,导致Aadac KO小鼠肝脏亚铁水平升高。在Huh-7细胞中过表达人AADAC可通过抑制亚铁积累而明显减轻四氯化碳诱导的细胞毒性,这表明AADAC与CP相互作用抑制肝脏亚铁积累。在对乙酰氨基酚诱导的肝损伤小鼠中,也观察到了 Aadac 在铁变态反应中的保肝作用。这项研究证明了 AADAC 在保护肝脏免受四氯化碳和对乙酰氨基酚等肝毒性物质诱导的铁中毒作用方面的新功能。
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引用次数: 0
Animal-free safety assessment of chemicals: an innovation system perspective. 不使用动物的化学品安全评估:创新体系视角。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-10-04 DOI: 10.1007/s00204-024-03878-0
Marjolein J Hoogstraaten, Jelle Vriend, Victoria C de Leeuw, Simona O Negro, Ellen H M Moors, Anne S Kienhuis, Jarno Hoekman

This perspective paper, which is the result of a collaborative effort between toxicologists and scholars in innovation and transition studies, presents a heuristic framework based on innovation system literature for understanding and appraising mission achievement to animal-free chemical safety assessment using New Approach Methodologies (NAMs). While scientific and technical challenges in this area are relatively well known, the recent establishment of missions and roadmaps to accelerate the acceptance and effective use of NAMs for chemical safety assessment raises new questions about how we can grasp the systemic nature of all changes needed in this transition. This includes recognising broader societal, institutional, and regulatory shifts necessary for NAM acceptance and uptake. Our paper discusses how the innovation system approach offers insights into key processes and associated activities that include as well as transcend the technical and scientific realm, and can help to accelerate acceptance and uptake of NAMs. Based on these insights, we present a comprehensive framework that, next to scientific and technological developments, recognises the need for coordinated efforts in areas like education, training, funding, policy-making, and public engagement to promote the acceptance and uptake of NAMs. Our framework can be used to perform structural and functional analyses of the innovation system of NAMs and animal-free safety assessment and as such provides handholds to track progress and organise collective efforts of actors to make sure we are moving in the right direction.

这篇视角论文是毒理学家与创新和转型研究学者合作的成果,它以创新系统文献为基础,提出了一个启发式框架,用于理解和评估使用新方法(NAMs)进行无动物化学安全评估的任务完成情况。虽然这一领域的科学和技术挑战相对众所周知,但最近为加速接受和有效使用新方法评估化学品安全而制定的任务和路线图提出了新的问题,即我们如何才能把握这一过渡所需的所有变革的系统性。这包括认识到更广泛的社会、机构和监管转变对于接受和采用非杀伤人员地雷是必要的。我们的论文讨论了创新系统方法如何为关键流程和相关活动提供见解,这些流程和活动既包括技术和科学领域,也超越技术和科学领域,并有助于加速接受和吸收非杀伤人员地雷。基于这些见解,我们提出了一个综合框架,除科学技术发展外,还认识到需要在教育、培训、资金、政策制定和公众参与等领域协调努力,以促进对非物质文化遗产的接受和吸收。我们的框架可用于对非杀伤人员地雷和无动物安全评估的创新体系进行结构和功能分析,从而为跟踪进展和组织参与者的集体努力提供抓手,以确保我们朝着正确的方向前进。
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引用次数: 0
Minimum information for reporting on the TEER (trans-epithelial/endothelial electrical resistance) assay (MIRTA). 报告 TEER(跨上皮/内皮电阻)测定的最低限度信息(MIRTA)。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-10-04 DOI: 10.1007/s00204-024-03879-z
Monita Sharma, Erin Huber, Emma Arnesdotter, Holger P Behrsing, Adam Bettmann, David Brandwein, Samuel Constant, Rahul Date, Abhay Deshpande, Eric Fabian, Amit Gupta, Robert Gutierrez, Arno C Gutleb, Marie M Hargrove, Michael Hollings, Victoria Hutter, Annie M Jarabek, Yulia Kaluzhny, Robert Landsiedel, Lawrence Milchak, Robert A Moyer, Jessica R Murray, Kathryn Page, Manish Patel, Stephanie N Pearson, Elijah J Petersen, Emily Reinke, Nuria Roldan, Clive Roper, Jamie B Scaglione, Raja S Settivari, Andreas O Stucki, Sandra Verstraelen, Joanne L Wallace, Shaun McCullough, Amy J Clippinger

Standard information reporting helps to ensure that assay conditions and data are consistently reported and to facilitate inter-laboratory comparisons. Here, we present recommendations on minimum information for reporting on the TEER (trans-epithelial/endothelial electrical resistance) assay (MIRTA). The TEER assay is extensively used to evaluate the health of an epithelial/endothelial cell culture model and as an indicator of the potential toxicity of a test substance. This publication is the result of an international collaboration─called the RespTox (Respiratory Toxicity) Collaborative─through which twelve laboratories shared their protocols for assessing the barrier function of respiratory epithelial cells using the TEER assay following exposure to substances. The protocols from each laboratory were reviewed to identify general steps for performing the TEER assay, interlaboratory differences between steps, the rationale for differences, whether these differences impact results or cross-laboratory comparisons between TEER measurements. While the MIRTA recommendations are focused on respiratory epithelial cell systems, these recommendations can be adapted for other cell systems that form barriers. The use of these recommendations will support data transparency and reproducibility, reduce challenges in data interpretation, enable cross-laboratory comparisons, help assess study quality, and facilitate the incorporation of the TEER assay into national and international testing guidance.

标准信息报告有助于确保检测条件和数据报告的一致性,并促进实验室之间的比较。在此,我们就 TEER(跨上皮/内皮电阻)测定(MIRTA)的最低报告信息提出建议。TEER 试验被广泛用于评估上皮/内皮细胞培养模型的健康状况,同时也是检测物质潜在毒性的指标。本出版物是一项国际合作(称为 RespTox(呼吸毒性)合作)的成果。通过这项合作,12 家实验室分享了他们在接触物质后使用 TEER 检测法评估呼吸道上皮细胞屏障功能的方案。对每个实验室的方案都进行了审查,以确定进行 TEER 检测的一般步骤、各步骤之间的实验室间差异、产生差异的理由、这些差异是否会影响结果或 TEER 测量之间的跨实验室比较。虽然 MIRTA 建议的重点是呼吸道上皮细胞系统,但这些建议也可适用于其他形成屏障的细胞系统。使用这些建议将有助于提高数据的透明度和可重复性,减少数据解释方面的挑战,实现跨实验室比较,帮助评估研究质量,并促进将 TEER 分析纳入国家和国际测试指南。
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引用次数: 0
Standardization and optimization of the hiPSC-based PluriLum assay for detection of embryonic and developmental toxicants 基于 hiPSC 的 PluriLum 试验的标准化和优化,用于检测胚胎和发育毒物。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-10-04 DOI: 10.1007/s00204-024-03870-8
Andreas Frederik Treschow, Anne Marie Vinggaard, Maria João Valente

New approach methodologies (NAMs) for predicting embryotoxicity and developmental toxicity are urgently needed for generating human relevant data, while reducing turnover time and costs, and alleviating ethical concerns related to the use of animal models. We have previously developed the PluriLum assay, a NKX2.5-reporter gene 3D model using human-induced pluripotent stem cells (hiPSCs) that are genetically modified to enable the assessment of adverse effects of chemicals on the early-stage embryo. Aiming at improving the predictive value of the PluriLum assay for future screening purposes, we sought to introduce standardization steps to the protocol, improving the overall robustness of the PluriLum assay, as well as a shortening of the assay protocol. First, we showed that the initial size of embryoid bodies (EBs) is crucial for a proper differentiation into cardiomyocytes and overall reproducibility of the assay. When the starting diameter of the EBs exceeds 500 µm, robust differentiation can be anticipated. In terms of reproducibility, exposure to the fungicide epoxiconazole at smaller initial diameters resulted in a larger variation of the derived data, compared to more reliable concentration–response curves obtained using spheroids with larger initial diameters. We further investigated the ideal length of the differentiation protocol, resulting in a shortening of the PluriLum assay by 24 h to 7 days. Following exposure to the teratogens all-trans and 13-cis retinoic acid, both cardiomyocyte contraction and measurement of NKX2.5-derived luminescence were recorded with a similar or increased sensitivity after 6 days of differentiation when compared to the original 7 days. Finally, we have introduced an efficient step for enzymatic dissociation of the EBs at assay termination. This allows for an even splitting of the individual EBs and testing of additional endpoints other than the NKX2.5-luciferase reporter, which was demonstrated in this work by the simultaneous assessment of ATP levels. In conclusion, we have introduced standardizations and streamlined the PluriLum assay protocol to improve its suitability as a NAM for screening of a large number of chemicals for developmental toxicity testing.

目前迫切需要用于预测胚胎毒性和发育毒性的新方法(NAMs),以生成与人类相关的数据,同时减少周转时间和成本,并减轻与使用动物模型相关的伦理问题。我们之前开发了 PluriLum 试验,这是一种 NKX2.5 报告基因三维模型,使用的是经过基因修饰的人类诱导多能干细胞(hiPSCs),可以评估化学品对早期胚胎的不良影响。为了提高 PluriLum 检测法在未来筛选中的预测价值,我们试图在检测方案中引入标准化步骤,提高 PluriLum 检测法的整体稳健性,并缩短检测方案。首先,我们发现胚状体(EBs)的初始大小对正确分化成心肌细胞和测定的整体可重复性至关重要。当 EBs 的初始直径超过 500 微米时,就可以预期其分化的稳健性。就可重复性而言,与使用初始直径较大的球形体获得的更可靠的浓度-反应曲线相比,初始直径较小的球形体暴露于杀真菌剂环唑醇会导致得出的数据变化较大。我们进一步研究了分化方案的理想长度,结果是将 PluriLum 试验从 24 小时缩短到 7 天。在暴露于致畸剂全反式和 13 顺式维甲酸后,与原来的 7 天相比,分化 6 天后记录的心肌细胞收缩和 NKX2.5 衍生发光的灵敏度相似或更高。最后,我们还引入了一个高效步骤,用于在检测终止时酶解 EB。这样就可以均匀拆分单个 EB,并测试 NKX2.5-luciferase 报告器以外的其他终点,这项工作通过同时评估 ATP 水平证明了这一点。总之,我们对 PluriLum 检测方案进行了标准化和简化,使其更适合作为一种 NAM 用于筛选大量化学物质以进行发育毒性测试。
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引用次数: 0
Thallium reabsorption via NKCC2 causes severe acute kidney injury with outer medulla-specific calcium crystal casts in rats 通过 NKCC2 重吸收铊会导致大鼠出现严重的急性肾损伤和外髓特异性钙晶体铸型。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00204-024-03868-2
Kana Unuma, Shuheng Wen, Sho Sugahara, Shutaro Nagano, Toshihiko Aki, Tadayuki Ogawa, Shino Takeda-Homma, Masakazu Oikawa, Akihiro Tojo

Thallium (Tl) is one of the most toxic heavy metals, associated with accidental poisoning and homicide. It causes acute and chronic systemic diseases, including gastrointestinal and cardiovascular diseases and kidney failure. However, few studies have investigated the mechanism by which Tl induces acute kidney injury (AKI). This study investigated the toxic effects of Tl on the histology and function of rat kidneys using biochemical and histopathological assays after intraperitoneal thallium sulfate administration (30 mg/kg). Five days post-administration, rats exhibited severely compromised kidney function. Low-vacuum scanning electron microscopy revealed excessive calcium (Ca) deposition in the outer medulla of Tl-loaded rats, particularly in the medullary thick ascending limb (mTAL) of the loop of Henle. Tl accumulated in the mTAL, accompanied by mitochondrial dysfunction in this segment. Tl-loaded rats showed reduced expression of kidney transporters and channels responsible for Ca2+ reabsorption in the mTAL. Pre-administration of the Na–K–Cl cotransporter 2 (NKCC2) inhibitor furosemide alleviated Tl accumulation and mitochondrial abnormalities in the mTAL. These findings suggest that Tl nephrotoxicity is associated with preferential Tl reabsorption in the mTAL via NKCC2, leading to mTAL mitochondrial dysfunction and disrupted Ca2+ reabsorption, culminating in mTAL-predominant Ca crystal deposition and AKI. These findings on the mechanism of Tl nephrotoxicity may contribute to the development of novel therapeutic approaches to counter Tl poisoning. Moreover, the observation of characteristic Ca crystal deposition in the outer medulla provides new insights into diagnostic challenges in Tl intoxication.

铊(Tl)是毒性最强的重金属之一,与意外中毒和凶杀有关。它可导致急性和慢性全身性疾病,包括胃肠道疾病、心血管疾病和肾衰竭。然而,很少有研究探讨铊诱发急性肾损伤(AKI)的机制。本研究采用生化和组织病理学检测方法,研究了腹腔注射硫酸铊(30 毫克/千克)后,铊对大鼠肾脏组织学和功能的毒性影响。给药五天后,大鼠的肾功能严重受损。低真空扫描电子显微镜检查发现,服用铊的大鼠外侧髓质中钙(Ca)沉积过多,尤其是在亨氏环的髓质粗升支(mTAL)中。Tl 在 mTAL 中积累,并伴随着该节段的线粒体功能障碍。Tl 负荷的大鼠表现出肾脏转运体和负责 mTAL 中 Ca2+ 重吸收的通道表达减少。预先服用 Na-K-Cl 共转运体 2(NKCC2)抑制剂呋塞米可减轻 mTAL 中的 Tl 积累和线粒体异常。这些研究结果表明,Tl 肾毒性与 mTAL 通过 NKCC2 优先重吸收 Tl 有关,从而导致 mTAL 线粒体功能障碍和 Ca2+ 重吸收紊乱,最终导致以 mTAL 为主导的 Ca 晶体沉积和 AKI。这些关于碲肾毒性机制的发现可能有助于开发新的治疗方法来对抗碲中毒。此外,在外髓质观察到特征性的钙晶体沉积,也为碲中毒的诊断难题提供了新的见解。
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引用次数: 0
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