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Fecal metabonomics combined with 16S rRNA gene sequencing to study the mechanisms of cantharidin-induced hepatotoxicity 粪便代谢组学结合16S rRNA基因测序研究斑蝥素诱导肝毒性的机制
IF 2.9 3区 医学 Q2 TOXICOLOGY Pub Date : 2025-04-18 DOI: 10.1016/j.toxlet.2025.04.006
Lijuan Xiong , Jialu Zou , Kexin Lin , Xiaohong Zhang , Caiying Yan , Yanmei He , Jianyong Zhang
Cantharidin (CTD) serves as the principal bioactive compound in traditional Chinese medicine Mylabris, commonly employed in cancer treatment. Nevertheless, the clinical application of CTD is partly restricted by hepatotoxicity, and the toxicology mechanism is not fully elucidated. This study aims to explore the potential mechanism of CTD-induced hepatoxicity by targeted metabolomics-based UPLC-QTOF-MS/MS analysis and 16S rRNA sequencing. Studies have shown that the administration of CTD could lead to elevated serum biochemical indices including ALT and AST. Notably, dilatation of the liver central vein, hepatocellular necrosis, and slight vacuoles in rats were observed after CTD intervention. Fecal metabolomics found CTD could up-regulate 10 and down-regulate 33 metabolites, and metabolic pathway enrichment found that CTD could disrupt 2 metabolic pathways, including Arginine biosynthesis metabolism and β-Alanine metabolism. 16S rRNA gene sequencing analysis showed that CTD could increase the abundance of Turicibacter and Clostridium sensu stricto 1, but decrease the amounts of Prevotella 1. Our correlation analyses showed that alterations in the gut microbiota induced by CTD in rats may have impacted changes in the associated hepatic amino acid metabolism pathway. And the mechanism of action of CTD-induced hepatotoxicity may be related to inflammation, oxidative stress, impaired glucose metabolism and reduced hepatic glycogen storage. These findings will offer novel insights for the prevention and treatment of CTD-induced hepatotoxicity.
坎儿井苷(CTD)是传统中药麦饭石中的主要生物活性化合物,常用于治疗癌症。然而,CTD 的临床应用受到肝毒性的部分限制,其毒理机制尚未完全阐明。本研究旨在通过基于代谢组学的UPLC-QTOF-MS/MS分析和16S rRNA测序,探讨CTD诱导肝毒性的潜在机制。研究表明,服用 CTD 可导致 ALT 和 AST 等血清生化指标升高。值得注意的是,大鼠在服用 CTD 后出现肝中心静脉扩张、肝细胞坏死和轻微空泡。粪便代谢组学研究发现,CTD 可上调 10 种代谢物,下调 33 种代谢物;代谢通路富集研究发现,CTD 可破坏 2 条代谢通路,包括精氨酸生物合成代谢和 β-Alanine 代谢。16S rRNA 基因测序分析表明,CTD 会增加 Turicibacter 和梭菌 sensu stricto 1 的数量,但会减少 Prevotella 1 的数量。我们的相关分析表明,CTD 诱导的大鼠肠道微生物群的改变可能会影响相关肝脏氨基酸代谢途径的变化。而 CTD 诱导肝毒性的作用机制可能与炎症、氧化应激、糖代谢受损和肝糖原储存减少有关。这些发现将为预防和治疗 CTD 引起的肝毒性提供新的见解。
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引用次数: 0
The role of the gut microbiome in the associations between lead exposure and child neurodevelopment 肠道微生物组在铅暴露与儿童神经发育之间的关联中的作用
IF 2.9 3区 医学 Q2 TOXICOLOGY Pub Date : 2025-04-16 DOI: 10.1016/j.toxlet.2025.04.004
Amanda C. Wylie , Nicolas Murgueitio , Alexander L. Carlson , Rebecca C. Fry , Cathi B. Propper
Lead is highly toxic to the developing brain. Given its persistence in the environment, new intervention strategies are needed to mitigate the impacts of lead on child neurodevelopment. The gut microbiome, referring to the bacteria and microorganisms residing in the gastrointestinal system, may be a viable target for intervention. This short review summarizes recent evidence linking the gut-brain axis to child developmental outcomes. We explore how lead-induced effects to the gut microbiome could indirectly affect child neurodevelopment, such that disrupting or offsetting this mediating process could buffer the effects of lead on child developmental outcomes. Unexpected findings with respect to child microbiota diversity and child cognitive and behavioral outcomes as well as lead exposure and adult microbiota diversity are discussed. When possible, we draw connections between observed changes to relative bacterial abundance, proposed bacterial functions, and downstream effects to brain development. We also explore how the gut microbiome might modify the toxicity of lead by impeding the uptake of lead across the gastrointestinal tract or through indirect mechanisms in such ways that the gut microbiome does not fit within a mediating pathway. In this case, promoting the buffering capacity of the gut microbiome may reduce the impacts of lead on child neurodevelopment. The goal of this short review is to bring attention to the potential role of the gut microbiome in the associations between lead exposure and child neurodevelopment with an eye towards intervention.
铅对发育中的大脑有剧毒。鉴于其在环境中的持久性,需要新的干预策略来减轻铅对儿童神经发育的影响。肠道微生物组,指的是居住在胃肠道系统中的细菌和微生物,可能是一个可行的干预目标。这篇简短的综述总结了最近将肠脑轴与儿童发育结果联系起来的证据。我们探索铅诱导的肠道微生物组效应如何间接影响儿童神经发育,从而破坏或抵消这一中介过程可以缓冲铅对儿童发育结果的影响。关于儿童微生物群多样性和儿童认知和行为结果以及铅暴露和成人微生物群多样性的意外发现进行了讨论。在可能的情况下,我们在观察到的相对细菌丰度的变化、提出的细菌功能和对大脑发育的下游影响之间建立联系。我们还探讨了肠道微生物群如何通过阻碍铅在胃肠道中的吸收或通过肠道微生物群不适合介导途径的间接机制来改变铅的毒性。在这种情况下,促进肠道微生物群的缓冲能力可能会减少铅对儿童神经发育的影响。这篇简短综述的目的是引起人们对肠道微生物群在铅暴露与儿童神经发育之间关系中的潜在作用的关注,并着眼于干预。
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引用次数: 0
Synergistic cardiotoxic effects of captagon and azithromycin in rat via oxidative stress, apoptosis and upregulation of the PI3K/AKT/NF-kB pathway captagon和阿奇霉素通过氧化应激、细胞凋亡和上调PI3K/AKT/NF-kB通路对大鼠心脏的协同毒性作用
IF 2.9 3区 医学 Q2 TOXICOLOGY Pub Date : 2025-04-15 DOI: 10.1016/j.toxlet.2025.04.002
Shaimaa A. Shehata , Noha M. Abd El-Fadeal , Islam Omar Abdel Fattah , Abeer M. Hagras , Enas M.A. Mostafa , Mohamed M. Abdel-Daim , Mohamed A. Abdelshakour , Eman Kolieb , Asmaa K.K. Abdelmaogood , Youssef M. Rabee , Khadiga M. Abdelrahman
Fenethylline (Captagon) is a blend of amphetamine and theophylline that functions as a stimulant, while azithromycin (AZ) is a commonly prescribed macrolide antibiotic. The co-usage of illicit substances and therapeutic drugs can result in substantial health risk especially cardiotoxicity. This study aimed to assess cardiotoxicity effects of Captagon (Capta) and Azithromycin/Captagon interaction in adult male rats. Forty-two animals were assigned into 6 groups: Group I (Control) and group II (AZ (30 mg/kg/day) starting from the 14th day of the experiment and for 2 weeks. Group III (Capta10 mg/kg/day), group IV (Capta20 mg/kg/day), group V (AZ+Capta10) and group VI (AZ+Capta20) daily 28 days. Electrocardiogram (ECG), cardiac enzymes, oxidative stress markers, inflammatory genes expression, histopathological and immunohistochemical changes were assessed. Administration of AZ and Capta alone or in combination cause cardiotoxicity. This was indicated by elevated LDH and CTNI levels, ECG changes as increased HR, prolonged QT interval and elevated ST segment accompanied by cardiac histopathological changes. There was a significant reduction in antioxidants SOD, GSH, TAC, and catalase, alongside a significant rise in oxidative stress MDA and NO. Significant rise of ERK, TNF-α, NF-ҡB, PI3K/AKT, Il-1β and IL-6, in both the Capta20 and AZ+Capta groups in dose dependent manner. The Coadministration of AZ and Capta20 produced intense immunoexpression of caspase-3 and BAX and wide areas of negative reactivity for Bcl-2. Coadministration of AZ and Capta induced cardiotoxicity through oxidative stress, inflammation, and apoptosis pathways. It is important to educate healthcare providers and patients about the potential harmful interactions.
苯乙胺(Captagon)是一种苯丙胺和茶碱的混合物,具有兴奋剂的作用,而阿奇霉素(AZ)是一种常用的大环内酯类抗生素。非法药物和治疗药物的共同使用可导致严重的健康风险,特别是心脏毒性。本研究旨在评估Captagon (Capta)和阿奇霉素/Captagon相互作用对成年雄性大鼠的心脏毒性作用。42只动物随机分为6组:ⅰ组(对照)和ⅱ组(AZ(30 mg/kg/d)),从试验第14天开始,持续2周。III组(Capta10 mg/kg/天)、IV组(Capta20 mg/kg/天)、V组(AZ+Capta10)、VI组(AZ+Capta20)每日28天。评估心电图(ECG)、心肌酶、氧化应激标志物、炎症基因表达、组织病理学和免疫组织化学变化。阿斯利康和卡普他单独或联合用药可引起心脏毒性。LDH和CTNI水平升高,心电图改变为HR升高,QT间期延长,ST段升高并伴有心脏组织病理学改变。抗氧化剂SOD、GSH、TAC和过氧化氢酶显著降低,同时氧化应激MDA和NO显著升高。Capta20和AZ+Capta组ERK、TNF-α、NF-ҡB、PI3K/AKT、Il-1β和IL-6均呈剂量依赖性升高。AZ和Capta20共给药可产生caspase-3和BAX的强烈免疫表达,并对Bcl-2产生大面积的阴性反应。AZ和Capta共给药通过氧化应激、炎症和凋亡途径诱导心脏毒性。教育医疗保健提供者和患者关于潜在的有害相互作用是很重要的。
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引用次数: 0
A battery of assays for chasing ricin and its activity 追踪蓖麻毒素及其活性的一系列试验
IF 2.9 3区 医学 Q2 TOXICOLOGY Pub Date : 2025-04-15 DOI: 10.1016/j.toxlet.2025.04.003
Shivani Dixit , Ram Kumar Dhaked , Greeshma TS , Anjali Yadav , Jagrati Parashar , Nandita Saxena
Ricin, a type-2 Ribosome-Inactivating Protein (RIP), is a dangerous biotoxin derived from castor plant seeds. It is classified as a Schedule 1 agent by the Chemical Weapon Convention (CWC) and a Category B agent by the Biological and Toxin Weapon Convention (BTWC). Despite their high toxicity, castor seed plants are widely used for the production of castor oil and in folk medicine systems for the treatment of various diseases. Due to the lack of a Food and Drug Administration (FDA) approved medication, early detection of biologically active ricin is critical for implementing suitable countermeasures in time to avert casualties. It is required to employ an integrated approach to distinguish between pure and crude ricin as well as active/inactive ricin. In the present study, a series of bioassays were performed to identify biologically active ricin and its different forms. This assessment included both field and lab-based assays to detect and differentiate different isoforms of ricin. The assays used are the lateral flow assay (LFA), hemagglutination assay (HA), In-vitro translational system (IVTS), cytotoxicity assay (CA), and mouse protection assay (MPA). Considering the ricin-contaminated scenario, the first step was to qualitatively determine the presence of ricin using LFA. Following that, a HA was optimized to differentiate between crude and pure ricin. In addition to this, the assay was also able to differentiate various cultivars and isoforms. IVTS assay was used to identify the enzymatic activity of the ricin A chain that inhibited translational machinery with IC50 (50 % inhibitory concentration) of 11.2 ng/ml. Further neutralization with anti-ricin rabbit polyclonal antibodies (RPAb) confirmed the ricin-mediated translation inhibition and excluded the use of other RIPs (abrin, saproin, and viscumin). Cytotoxicity in HeLa cells was used as a cellular model with an estimated CC50 value (50 % cytotoxic concentration) of 36 ng/ml. The neutralization experiment with RPAb specifically reversed the ricin-induced cytotoxicity. A mouse protection assay was done using 5X LD50 of ricin, which caused mortality within 48 h. RPAb increased the survival, verdict the presence of ricin, and eliminated the presence of related RIPs. All the proposed assays suffice the requirement during ricin exposure scenario from the field to the laboratory. These assays are also capable of distinguishing crude/pure/cultivars, and isoforms of ricin. During an emergency, a combination of these assays will help us to make faster decisions and increase the therapeutic time window for treatment.
蓖麻毒素是一种 2 型核糖体激活蛋白(RIP),是从蓖麻籽中提取的危险生物毒素。它被《化学武器公约》(CWC)列为附表 1 物剂,被《生物和毒素武器公约》(BTWC)列为 B 类物剂。尽管毒性很高,蓖麻籽植物仍被广泛用于生产蓖麻油,并在民间医药系统中用于治疗各种疾病。由于缺乏食品和药物管理局 (FDA) 批准的药物,因此及早发现生物活性蓖麻毒素对于及时采取适当的应对措施以避免人员伤亡至关重要。需要采用综合方法来区分纯蓖麻毒素和粗蓖麻毒素以及活性/非活性蓖麻毒素。本研究进行了一系列生物测定,以确定生物活性蓖麻毒素及其不同形式。评估包括实地和实验室检测,以检测和区分蓖麻毒素的不同异构体。使用的检测方法包括侧流试验(LFA)、血凝试验(HA)、体外转化系统(IVTS)、细胞毒性试验(CA)和小鼠保护试验(MPA)。考虑到蓖麻毒素污染的情况,第一步是使用 LFA 定性地确定蓖麻毒素的存在。随后,对 HA 进行了优化,以区分粗蓖麻毒素和纯蓖麻毒素。除此之外,该检测方法还能区分各种栽培品种和异构体。IVTS 检测法用于确定蓖麻毒素 A 链的酶活性,该酶抑制翻译机制的 IC50(50% 抑制浓度)为 11.2 纳克/毫升。用抗蓖麻毒素兔多克隆抗体(RPAb)进一步中和,证实了蓖麻毒素介导的翻译抑制作用,并排除了使用其他 RIPs(abrin、saproin 和 viscumin)的可能性。HeLa 细胞的细胞毒性被用作细胞模型,估计 CC50 值(50% 细胞毒性浓度)为 36 ng/ml。用 RPAb 进行的中和实验特异性地逆转了蓖麻毒素诱导的细胞毒性。使用 5 倍半数致死剂量的蓖麻毒素进行了小鼠保护试验,结果显示,蓖麻毒素会在 48 小时内导致小鼠死亡。RPAb 提高了存活率,抑制了蓖麻毒素的存在,并消除了相关 RIPs 的存在。从野外到实验室,所有建议的检测方法都能满足蓖麻毒素暴露情况下的要求。这些检测方法还能区分蓖麻毒素的粗品/纯品/栽培品种和异构体。在紧急情况下,结合使用这些检测方法将有助于我们更快地做出决定,并延长治疗时间窗口。
{"title":"A battery of assays for chasing ricin and its activity","authors":"Shivani Dixit ,&nbsp;Ram Kumar Dhaked ,&nbsp;Greeshma TS ,&nbsp;Anjali Yadav ,&nbsp;Jagrati Parashar ,&nbsp;Nandita Saxena","doi":"10.1016/j.toxlet.2025.04.003","DOIUrl":"10.1016/j.toxlet.2025.04.003","url":null,"abstract":"<div><div>Ricin, a type-2 Ribosome-Inactivating Protein (RIP), is a dangerous biotoxin derived from castor plant seeds. It is classified as a Schedule 1 agent by the Chemical Weapon Convention (CWC) and a Category B agent by the Biological and Toxin Weapon Convention (BTWC). Despite their high toxicity, castor seed plants are widely used for the production of castor oil and in folk medicine systems for the treatment of various diseases. Due to the lack of a Food and Drug Administration (FDA) approved medication, early detection of biologically active ricin is critical for implementing suitable countermeasures in time to avert casualties. It is required to employ an integrated approach to distinguish between pure and crude ricin as well as active/inactive ricin. In the present study, a series of bioassays were performed to identify biologically active ricin and its different forms. This assessment included both field and lab-based assays to detect and differentiate different isoforms of ricin. The assays used are the lateral flow assay (LFA), hemagglutination assay (HA), In-vitro translational system (IVTS), cytotoxicity assay (CA), and mouse protection assay (MPA). Considering the ricin-contaminated scenario, the first step was to qualitatively determine the presence of ricin using LFA. Following that, a HA was optimized to differentiate between crude and pure ricin. In addition to this, the assay was also able to differentiate various cultivars and isoforms. IVTS assay was used to identify the enzymatic activity of the ricin A chain that inhibited translational machinery with IC<sub>50</sub> (50 % inhibitory concentration) of 11.2 ng/ml. Further neutralization with anti-ricin rabbit polyclonal antibodies (RPAb) confirmed the ricin-mediated translation inhibition and excluded the use of other RIPs (abrin, saproin, and viscumin). Cytotoxicity in HeLa cells was used as a cellular model with an estimated CC<sub>50</sub> value (50 % cytotoxic concentration) of 36 ng/ml. The neutralization experiment with RPAb specifically reversed the ricin-induced cytotoxicity. A mouse protection assay was done using 5X LD<sub>50</sub> of ricin, which caused mortality within 48 h. RPAb increased the survival, verdict the presence of ricin, and eliminated the presence of related RIPs. All the proposed assays suffice the requirement during ricin exposure scenario from the field to the laboratory. These assays are also capable of distinguishing crude/pure/cultivars, and isoforms of ricin. During an emergency, a combination of these assays will help us to make faster decisions and increase the therapeutic time window for treatment.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"408 ","pages":"Pages 43-53"},"PeriodicalIF":2.9,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143835049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Multi-approach study on diethylhexyl phthalate and monoethylhexyl phthalate binding to lysozyme: In silico, bioactivity and surface plasmon resonance analyses 邻苯二甲酸二乙基己酯和邻苯二甲酸一乙基己酯与溶菌酶结合的多方法研究:硅、生物活性和表面等离子体共振分析
IF 2.9 3区 医学 Q2 TOXICOLOGY Pub Date : 2025-04-15 DOI: 10.1016/j.toxlet.2025.04.005
Müfide Aydoğan Ahbab , Ilgaz Taşteki̇l , Evren Gazel Pınar , Pemra Özbek , Emir Alper Türkoğlu
Diethylhexyl phthalate (DEHP) and its metabolite monoethylhexyl phthalate (MEHP) are recognized as endocrine disruptors with significant toxicological effects on various human physiological systems. While previous research has explored phthalate-protein interactions, there is a notable gap in studies focusing on the interaction between these endocrine disruptors and lysozyme (LZM), a critical component of the immune system. This study aimed to investigate the interactions of DEHP and MEHP with chicken egg white lysozyme (CEWLZM) using molecular docking, molecular dynamics simulations, bioactivity and surface plasmon resonance (SPR) analyses to evaluate the molecular mechanisms, binding affinity, kinetic properties and bioactivity effects of these interactions. Complementary insights from molecular docking and molecular dynamics simulations indicate that DEHP has a stronger binding affinity for CEWLZM than MEHP. This affinity value was corroborated by an intense hydrophobic and van der Waals interaction network especially maintained by the active residue Leu75 and Asp101-Ala107. Although MEHP did not exhibit a significant effect on enzyme activity in lysozyme bioactivity assay, DEHP inhibited lysozyme with an IC50 value of 453 µM. SPR analysis revealed that DEHP exhibits a significantly stronger binding affinity to CEWLZM compared to MEHP.
邻苯二甲酸二乙基己酯(DEHP)及其代谢物邻苯二甲酸单乙基己酯(MEHP)是公认的内分泌干扰物,对人体的各种生理系统具有显著的毒理学影响。虽然以往的研究已经探讨了邻苯二甲酸酯与蛋白质之间的相互作用,但有关这些内分泌干扰物与溶菌酶(LZM)(免疫系统的一个重要组成部分)之间相互作用的研究却明显不足。本研究旨在通过分子对接、分子动力学模拟、生物活性和表面等离子体共振(SPR)分析,研究 DEHP 和 MEHP 与鸡卵白溶菌酶(CEWLZM)的相互作用,以评估这些相互作用的分子机制、结合亲和力、动力学特性和生物活性效应。分子对接和分子动力学模拟得出的互补结论表明,DEHP 与 CEWLZM 的结合亲和力强于 MEHP。活性残基 Leu75 和 Asp101-Ala107 所维持的强烈疏水和范德华相互作用网络证实了这一亲和力值。在溶菌酶生物活性测定中,虽然 MEHP 对酶活性没有明显影响,但 DEHP 可抑制溶菌酶,其 IC50 值为 453 µM。SPR 分析表明,与 MEHP 相比,DEHP 与 CEWLZM 的结合亲和力明显更强。
{"title":"Multi-approach study on diethylhexyl phthalate and monoethylhexyl phthalate binding to lysozyme: In silico, bioactivity and surface plasmon resonance analyses","authors":"Müfide Aydoğan Ahbab ,&nbsp;Ilgaz Taşteki̇l ,&nbsp;Evren Gazel Pınar ,&nbsp;Pemra Özbek ,&nbsp;Emir Alper Türkoğlu","doi":"10.1016/j.toxlet.2025.04.005","DOIUrl":"10.1016/j.toxlet.2025.04.005","url":null,"abstract":"<div><div>Diethylhexyl phthalate (DEHP) and its metabolite monoethylhexyl phthalate (MEHP) are recognized as endocrine disruptors with significant toxicological effects on various human physiological systems. While previous research has explored phthalate-protein interactions, there is a notable gap in studies focusing on the interaction between these endocrine disruptors and lysozyme (L<sub>ZM</sub>), a critical component of the immune system. This study aimed to investigate the interactions of DEHP and MEHP with chicken egg white lysozyme (CEWL<sub>ZM</sub>) using molecular docking, molecular dynamics simulations, bioactivity and surface plasmon resonance (SPR) analyses to evaluate the molecular mechanisms, binding affinity, kinetic properties and bioactivity effects of these interactions. Complementary insights from molecular docking and molecular dynamics simulations indicate that DEHP has a stronger binding affinity for CEWL<sub>ZM</sub> than MEHP. This affinity value was corroborated by an intense hydrophobic and van der Waals interaction network especially maintained by the active residue Leu75 and Asp101-Ala107. Although MEHP did not exhibit a significant effect on enzyme activity in lysozyme bioactivity assay, DEHP inhibited lysozyme with an IC<sub>50</sub> value of 453 µM. SPR analysis revealed that DEHP exhibits a significantly stronger binding affinity to CEWL<sub>ZM</sub> compared to MEHP.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"408 ","pages":"Pages 54-64"},"PeriodicalIF":2.9,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
6PPD impairs immune responses and fin regeneration in zebrafish ppd损害斑马鱼的免疫反应和鳍再生。
IF 2.9 3区 医学 Q2 TOXICOLOGY Pub Date : 2025-04-04 DOI: 10.1016/j.toxlet.2025.04.001
Xiaoyu Mao , Dashuang Mo , Yuqin Cheng , Mengzhu Lv
N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD), a commonly used antioxidant in tire manufacturing, has been widely detected in the environment and shown to exhibit acute toxicity in several organs. However, the effects of 6PPD on immune responses, particularly following injury, remain poorly understood. In this study, we investigated the impact of 6PPD exposure on immune responses using zebrafish as a model. 6PPD exposure disrupted caudal fin regeneration at various stages of the regenerative process. Further analysis revealed that 6PPD impaired immune responses following fin amputation, as evidenced by the reduced number of lyz+/mpx+ neutrophils and the downregulation of key immune-related genes. Besides, the morphology of neutrophils was changed upon 6PPD exposure, indicating the defective migration of immune cells. The incubation of zebrafish larvae with lipopolysaccharide (LPS), which induces global immune responses, also exhibited impaired immune function when combined with 6PPD exposure. Additionally, the injection of LPS into the egg yolk or trunk exacerbated immune responses at the injury site, yet 6PPD exposure significantly reduced neutrophil accumulation and downregulated the expression of immune-related genes, confirming the toxicity of 6PPD in immune responses. These findings provide new insights into the toxic effects of 6PPD on immune responses during injury, highlighting its potential to impair immune function in animals and human.
N-(1,3-二甲基丁基)-N'-苯基-对苯二胺(6PPD)是轮胎制造中常用的抗氧化剂,已在环境中广泛检测到,并显示出对几个器官的急性毒性。然而,6PPD对免疫反应的影响,特别是在损伤后,仍然知之甚少。在本研究中,我们以斑马鱼为模型,研究了6PPD暴露对免疫反应的影响。ppd暴露在再生过程的各个阶段都破坏了尾鳍的再生。进一步分析显示,6PPD损害了断肢后的免疫反应,这可以通过lyz+/mpx+中性粒细胞数量减少和关键免疫相关基因的下调来证明。此外,中性粒细胞的形态在6PPD暴露后发生了变化,表明免疫细胞的迁移存在缺陷。与脂多糖(LPS)孵育的斑马鱼幼虫,诱导全局免疫反应,也表现出免疫功能受损,当联合6PPD暴露。此外,在蛋黄或躯干注射LPS会加剧损伤部位的免疫反应,而6PPD暴露会显著减少中性粒细胞的积累,下调免疫相关基因的表达,证实6PPD在免疫反应中的毒性。这些发现为6PPD在损伤期间对免疫反应的毒性作用提供了新的见解,突出了其损害动物和人类免疫功能的潜力。
{"title":"6PPD impairs immune responses and fin regeneration in zebrafish","authors":"Xiaoyu Mao ,&nbsp;Dashuang Mo ,&nbsp;Yuqin Cheng ,&nbsp;Mengzhu Lv","doi":"10.1016/j.toxlet.2025.04.001","DOIUrl":"10.1016/j.toxlet.2025.04.001","url":null,"abstract":"<div><div><em>N</em>-(1,3-Dimethylbutyl)-<em>N</em>′-phenyl-<em>p</em>-phenylenediamine (6PPD), a commonly used antioxidant in tire manufacturing, has been widely detected in the environment and shown to exhibit acute toxicity in several organs. However, the effects of 6PPD on immune responses, particularly following injury, remain poorly understood. In this study, we investigated the impact of 6PPD exposure on immune responses using zebrafish as a model. 6PPD exposure disrupted caudal fin regeneration at various stages of the regenerative process. Further analysis revealed that 6PPD impaired immune responses following fin amputation, as evidenced by the reduced number of lyz<sup>+</sup>/mpx<sup>+</sup> neutrophils and the downregulation of key immune-related genes. Besides, the morphology of neutrophils was changed upon 6PPD exposure, indicating the defective migration of immune cells. The incubation of zebrafish larvae with lipopolysaccharide (LPS), which induces global immune responses, also exhibited impaired immune function when combined with 6PPD exposure. Additionally, the injection of LPS into the egg yolk or trunk exacerbated immune responses at the injury site, yet 6PPD exposure significantly reduced neutrophil accumulation and downregulated the expression of immune-related genes, confirming the toxicity of 6PPD in immune responses. These findings provide new insights into the toxic effects of 6PPD on immune responses during injury, highlighting its potential to impair immune function in animals and human.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"408 ","pages":"Pages 32-42"},"PeriodicalIF":2.9,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Exploring gadolinium deposition in maternal and offspring mice: Impacts of gestational and lactational exposure 探索母鼠和子鼠钆沉积:妊娠期和哺乳期暴露的影响。
IF 2.9 3区 医学 Q2 TOXICOLOGY Pub Date : 2025-04-02 DOI: 10.1016/j.toxlet.2025.03.010
Ying Kong , Kai Liu , Shi Qiu , Jiali Wang , Shuai Zhang , Kai Xu
To investigate the gadolinium deposition induced by repeated administration of gadolinium-based contrast agents (GBCAs) in multi-organ/tissue of mother and pup mice during pregnancy and lactation, two hundred and seventy ICR mice were divided into three groups (non-pregnant, pregnant, and lactating; n = 90/group) and received gadodiamide, gadoterate meglumine, or saline intravenously (2.5 mmol Gd/kg once every two days for a total of 10 doses) throughout the entire gestation or lactation period. Gadolinium concentration detection, histological analyses, and transmission electron microscopy were performed on mother and pup mice at the completion of the injection, one month later, and three months later. Our results showed that (i)exposure to GBCAs during pregnancy resulted in gadolinium deposition in fetal organs more significantly with gadodiamide, with the greatest deposition observed in the kidneys and the least in the brain, interestingly, the fetal body was found with no detectable gadolinium deposits one month after birth, that (ii) exposure to GBCAs during lactation did not result in detectable gadolinium deposition in the organs/tissues of the unweaned pups, and that (iii)gadolinium deposition decreased more rapidly in the first month in all tissues examined from all maternal and non-pregnant mice, and gadolinium deposition was found to be lower in the kidneys of both pregnant and lactating mice than in non-pregnant mice. Collectively, exposure to GBCAs during pregnancy resulted in gadolinium deposition in their fetuses with no significant organ toxicity found, and breastfeeding continued after exposure to GBCAs during lactation may not pose a risk of gadolinium deposition to the pups.
为了研究钆基造影剂(gadbca)在妊娠和哺乳期多器官/组织中的沉积作用,将270只ICR小鼠分为三组(未妊娠组、妊娠组和哺乳期组);n=90/组),并在整个妊娠或哺乳期静脉滴注加多二胺、加多二胺或生理盐水(2.5mmol Gd/kg,每2天1次,共10次)。注射完成后、1个月后和3个月后分别对母鼠和幼鼠进行钆浓度检测、组织学分析和透射电镜观察。我们的研究结果表明:(1)妊娠期暴露于gbca后,钆在胎儿器官中的沉积与gadodiamide相比更为显著,肾脏中的沉积最大,大脑中的沉积最少,有趣的是,出生一个月后胎儿体内未发现可检测到的钆沉积;(2)哺乳期暴露于gbca后,未断奶幼犬的器官/组织中未发现可检测到的钆沉积。(3)在所有母鼠和未怀孕小鼠的所有组织中,钆沉积在第一个月的下降速度更快,并且发现怀孕和哺乳期小鼠肾脏中的钆沉积比未怀孕小鼠低。总的来说,怀孕期间暴露于gbca会导致胎儿钆沉积,但没有发现明显的器官毒性,哺乳期暴露于gbca后继续母乳喂养可能不会对幼崽造成钆沉积的风险。
{"title":"Exploring gadolinium deposition in maternal and offspring mice: Impacts of gestational and lactational exposure","authors":"Ying Kong ,&nbsp;Kai Liu ,&nbsp;Shi Qiu ,&nbsp;Jiali Wang ,&nbsp;Shuai Zhang ,&nbsp;Kai Xu","doi":"10.1016/j.toxlet.2025.03.010","DOIUrl":"10.1016/j.toxlet.2025.03.010","url":null,"abstract":"<div><div>To investigate the gadolinium deposition induced by repeated administration of gadolinium-based contrast agents (GBCAs) in multi-organ/tissue of mother and pup mice during pregnancy and lactation, two hundred and seventy ICR mice were divided into three groups (non-pregnant, pregnant, and lactating; n = 90/group) and received gadodiamide, gadoterate meglumine, or saline intravenously (2.5 mmol Gd/kg once every two days for a total of 10 doses) throughout the entire gestation or lactation period. Gadolinium concentration detection, histological analyses, and transmission electron microscopy were performed on mother and pup mice at the completion of the injection, one month later, and three months later. Our results showed that (i)exposure to GBCAs during pregnancy resulted in gadolinium deposition in fetal organs more significantly with gadodiamide, with the greatest deposition observed in the kidneys and the least in the brain, interestingly, the fetal body was found with no detectable gadolinium deposits one month after birth, that (ii) exposure to GBCAs during lactation did not result in detectable gadolinium deposition in the organs/tissues of the unweaned pups, and that (iii)gadolinium deposition decreased more rapidly in the first month in all tissues examined from all maternal and non-pregnant mice, and gadolinium deposition was found to be lower in the kidneys of both pregnant and lactating mice than in non-pregnant mice. Collectively, exposure to GBCAs during pregnancy resulted in gadolinium deposition in their fetuses with no significant organ toxicity found, and breastfeeding continued after exposure to GBCAs during lactation may not pose a risk of gadolinium deposition to the pups.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"408 ","pages":"Pages 13-22"},"PeriodicalIF":2.9,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143789029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Do urinary metabolites reflect occupational exposure to organophosphate flame retardants? A case study in electronic waste recycling workers. 尿代谢物是否反映职业性暴露于有机磷阻燃剂?电子废物回收工人个案研究。
IF 2.9 3区 医学 Q2 TOXICOLOGY Pub Date : 2025-04-02 DOI: 10.1016/j.toxlet.2025.03.012
Sabrina Gravel , Inna Tata Traore , Miriam L. Diamond , Liisa Jantunen , Joseph Zayed , France Labrèche , Marc-André Verner
Organophosphate esters (OPEs) are commonly used in electronic devices to meet safety standards, but electronic-waste recycling (e-recycling) workers may face significant exposure to those potentially hazardous compounds in their workplace. We examined the relationship between urinary OPE metabolites and their parent compounds in the air, in Canadian e-recycling facilities. We collected personal air samples and end-of-shift urine samples from workers at six e-recycling facilities. We employed linear and Tobit regression models to assess associations between air concentrations of triphenyl phosphate (TPhP) and three metabolites, of tris (2-chloroethyl) phosphate (TCEP) and two metabolites, of tris (2-chloroisopropyl) phosphate (TCPP) and two metabolites, of tris (1,3-dichloro-2-propyl) phosphate (TDCPP), and of tris (2-butoxyethyl) phosphate (TBOEP) and one metabolite each. The 85 participants, mostly male (78 %) and aged between 25 and 54, had concentrations of OPEs detected in 90–100 % of air samples, with geometric means of TPhP, TCEP, TBOEP and TDCPP, of 351, 404, 261 and 250 picomoles per cubic metre respectively. The proportion of detection of their corresponding metabolites varied between 32 % and 98 %. Regression models including the urinary flow rate as a covariate showed that a doubling of the air concentration of TCEP was associated with a 42–107 % increase in its metabolites, and a doubling of air concentration of TBOEP, with a 77 % increase. The paucity of data on the toxicokinetics of OPEs limits the determination of appropriate urinary metabolites to monitor OPE occupational exposure. Such additional data, in combination with workplace contextual information, may help clarify the major routes of exposure and the corresponding contributing sources.
有机磷酸酯(OPEs)通常用于电子设备,以满足安全标准,但电子废物回收(e-recycling)工人可能会在工作场所大量接触到这些潜在的有害化合物。我们研究了加拿大电子回收设施中尿OPE代谢物与其母体化合物在空气中的关系。我们收集了六个电子回收设施工人的个人空气样本和下班后的尿液样本。我们采用线性和Tobit回归模型来评估三苯基磷酸(TPhP)和三(2-氯乙基)磷酸(TCEP)和两种代谢物,三(2-氯异丙基)磷酸(TCPP)和两种代谢物,三(1,3-二氯-2-丙基)磷酸(TDCPP)和三(2-丁氧乙基)磷酸(TBOEP)和各一种代谢物的空气浓度之间的关系。85名参与者,大多数是男性(78%),年龄在25至54岁之间,在90-100%的空气样本中检测到OPEs浓度,TPhP, TCEP, TBOEP和TDCPP的几何平均值分别为351,404,261和250皮摩尔每立方米。其相应代谢物的检出率在32-98%之间。包括尿流率作为协变量的回归模型显示,TCEP的空气浓度增加一倍,其代谢物增加42-107%,TBOEP的空气浓度增加一倍,其代谢物增加77%。由于缺乏OPEs的毒物动力学数据,因此无法确定适当的尿液代谢物来监测OPEs的职业暴露。这些额外的数据,结合工作场所环境信息,可能有助于澄清主要的接触途径和相应的贡献来源。
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引用次数: 0
Using explainable machine learning to predict the irritation and corrosivity of chemicals on eyes and skin 使用可解释的机器学习来预测化学物质对眼睛和皮肤的刺激性和腐蚀性
IF 2.9 3区 医学 Q2 TOXICOLOGY Pub Date : 2025-04-01 DOI: 10.1016/j.toxlet.2025.03.008
Yingxu Liu , Yang Liu , Simeng Zhang , Chen Zeng , Qing Zhang , Yunya Jiang , Xi Yang , Lidan Zheng , Qian Ge , Yanmin Zhang , Yadong Chen , Mengyi Lu , Haichun Liu
Contact with specific chemicals often results in corrosive and irritative responses in the eyes and skin, playing a pivotal role in assessing the potential hazards of personal care products, cosmetics, and industrial chemicals to human health. While traditional animal testing can provide valuable information, its high costs, ethical controversies, and significant demand for animals limit its extensive use, particularly during preliminary screening stages. To address these issues, we adopted a computational modeling approach, integrating 3316 experimental data points on eye irritation and 3080 data points on skin irritation, to develop various machine learning and deep learning models. Under the evaluation of the external validation set, the best-performing models for the two tasks achieved balanced accuracies (BAC) of 73.0 % and 75.1 %, respectively. Furthermore, interpretability analyses were conducted at the dataset level, molecular level, and atomic level to provide insights into the prediction outcomes. Analysis of substructure frequencies identified structural alert fragments within the datasets. This information serves as a reference for identifying potentially irritating chemicals. Additionally, a user-friendly visualization interface was developed, enabling non-specialists to easily predict eye and skin irritation potential. In summary, our study provides a new avenue for the assessment of irritancy potential in chemicals used in pesticides, cosmetics, and ophthalmic drugs.
与特定化学品的接触通常会导致眼睛和皮肤的腐蚀和刺激反应,在评估个人护理产品、化妆品和工业化学品对人体健康的潜在危害方面起着关键作用。虽然传统的动物试验可以提供有价值的信息,但其高昂的成本、伦理争议和对动物的大量需求限制了其广泛使用,特别是在初步筛选阶段。为了解决这些问题,我们采用了计算建模的方法,整合了3316个眼睛刺激实验数据点和3080个皮肤刺激数据点,开发了各种机器学习和深度学习模型。在外部验证集的评价下,两个任务的最佳模型的平衡准确率(BAC)分别为73.0 %和75.1 %。此外,在数据集水平、分子水平和原子水平上进行了可解释性分析,以提供对预测结果的见解。对子结构频率的分析确定了数据集中的结构警报片段。这些信息可作为识别潜在刺激性化学物质的参考。此外,还开发了一个用户友好的可视化界面,使非专业人员能够轻松预测眼睛和皮肤的刺激潜力。总之,我们的研究为农药、化妆品和眼科药物中使用的化学物质的潜在刺激性评估提供了新的途径。
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引用次数: 0
Environmental pesticide exposure and its association with hematological parameters and inflammation indices among school-aged children in Mexico 墨西哥学龄儿童环境农药暴露及其与血液学参数和炎症指标的关系
IF 2.9 3区 医学 Q2 TOXICOLOGY Pub Date : 2025-03-28 DOI: 10.1016/j.toxlet.2025.03.009
Miguel Alfonso Ruiz-Arias , Yael Yvette Bernal-Hernández , Irma Martha Medina-Díaz , Ana M. Mora , José Francisco Herrera-Moreno , Briscia Socorro Barrón-Vivanco , Cyndia Azucena González-Arias , Francisco Alberto Verdín-Betancourt , José Antonio Aguilar-Bañuelos , Juan Manuel Agraz-Cibrián , José Francisco Zambrano-Zaragoza , Pedro de Jesús Bastidas-Bastidas , Aurora Elizabeth Rojas-García
Few studies have investigated the association between pesticide exposure and immune-inflammatory indices in children. We conducted a cross-sectional study of 369 school-aged children from three Mexican communities with varying levels of agricultural production. Blood samples were collected to calculate immune-inflammatory indices, and pooled hand-washing samples from 30 randomly selected children per community were analyzed for pesticide metabolites. Urinary dialkylphosphates (DAP) were determined in pooled samples per community. Multivariable logistic regression models assessed associations between pesticide exposure and immune-inflammatory indices (>median vs. <median). We detected ten classes of pesticides in hand-washing samples, including benzimidazoles, carbamates, neonicotinoids, organochlorines, organophosphates, and N-(phosphonomethyl)glycine. Total pesticide residue concentrations were 6.6 µg/L and 5.5 µg/L in the two highest production communities, compared to 0.3 µg/L in the reference community. Bifenthrin, chlorpyrifos, malathion, and carbendazim were present across all communities, with AMPA (a glyphosate metabolite) in the highest concentrations in agricultural areas. Urinary DAP were significantly higher in children from agricultural communities. Children in the largest agricultural community had lower hemoglobin and lymphocyte counts but higher neutrophil and eosinophil counts. Regression models showed increased odds of elevated systemic inflammation indices, particularly in children from the two highest production areas. Our adjusted models revealed significant associations between pesticide exposure and platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and eosinophil-to-lymphocyte ratio (ELR), in community B compared to community C, emphasizing the need for targeted interventions in high-exposure communities.
很少有研究调查农药暴露与儿童免疫炎症指数之间的关系。我们对来自三个不同农业生产水平的墨西哥社区的369名学龄儿童进行了横断面研究。采集血液样本计算免疫炎症指数,并对每个社区随机抽取的30名儿童的洗手样本进行农药代谢物分析。测定每个社区汇总样本的尿二烷基磷酸盐(DAP)。多变量logistic回归模型评估了农药暴露与免疫炎症指数(>中位数vs。
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引用次数: 0
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Toxicology letters
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