首页 > 最新文献

Archives of Toxicology最新文献

英文 中文
The food-borne carcinogenic 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) disrupts circadian rhythms and ameliorated by pterostilbene (PSB) in Caenorhabditis elegans 食源性致癌物 2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶(PhIP)会扰乱草履虫的昼夜节律,而紫檀芪(PSB)可改善其昼夜节律
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-10 DOI: 10.1007/s00204-024-03857-5
Chun-Han Chang, Pei-Ling Yen, Min-Hsiung Pan, Vivian Hsiu-Chuan Liao

The food-borne 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a potential human carcinogen abundant in cooked meat. While circadian rhythms are crucial biological oscillations, the negative impact of PhIP on circadian systems and the potential of mitigation remain underexplored. We investigated the effects of PhIP on circadian rhythms and the mitigating effects of the phytochemical antioxidant pterostilbene (PSB) in Caenorhabditis elegans. We show that exposure to 10 μM PhIP disrupts the 24-h circadian rhythms of C. elegans, an effect mitigated by co-exposure to 100 μM PSB. In addition, PhIP-induced circadian disruption can be linked to defective oxidative stress resistance, which is associated with the DAF-16/FOXO pathway and is modulated by PSB. Molecular docking suggested that PhIP and PSB bind similarly to DAF-16. Moreover, 10 μM PhIP abolished the rhythmic expression of the core clock gene prdx-2, which is restored by 100 μM PSB. Findings from this study provide novel insight of how food-borne contaminant like PhIP may contribute to the disruption of circadian rhythms and suggest potential for PSB to mitigate these effects in higher organisms.

食源性 2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶(PhIP)是一种潜在的人类致癌物质,在熟肉中含量丰富。昼夜节律是重要的生物振荡,但 PhIP 对昼夜节律系统的负面影响和缓解潜力仍未得到充分探索。我们研究了 PhIP 对草履虫昼夜节律的影响以及植物化学抗氧化剂紫檀芪(PSB)的缓解作用。我们的研究表明,暴露于 10 μM PhIP 会扰乱秀丽隐杆线虫的 24 小时昼夜节律,而同时暴露于 100 μM PSB 会减轻这种影响。此外,PhIP 诱导的昼夜节律紊乱可能与氧化应激抗性缺陷有关,而氧化应激抗性缺陷与 DAF-16/FOXO 通路有关,并受到 PSB 的调节。分子对接表明,PhIP 和 PSB 与 DAF-16 的结合方式相似。此外,10 μM PhIP 会抑制核心时钟基因 prdx-2 的节律性表达,而 100 μM PSB 则会恢复这种表达。这项研究的结果提供了一个新的视角,揭示了食源性污染物(如 PhIP)可能如何导致昼夜节律紊乱,并提出了 PSB 在高等生物中减轻这些影响的潜力。
{"title":"The food-borne carcinogenic 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) disrupts circadian rhythms and ameliorated by pterostilbene (PSB) in Caenorhabditis elegans","authors":"Chun-Han Chang,&nbsp;Pei-Ling Yen,&nbsp;Min-Hsiung Pan,&nbsp;Vivian Hsiu-Chuan Liao","doi":"10.1007/s00204-024-03857-5","DOIUrl":"10.1007/s00204-024-03857-5","url":null,"abstract":"<div><p>The food-borne 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a potential human carcinogen abundant in cooked meat. While circadian rhythms are crucial biological oscillations, the negative impact of PhIP on circadian systems and the potential of mitigation remain underexplored. We investigated the effects of PhIP on circadian rhythms and the mitigating effects of the phytochemical antioxidant pterostilbene (PSB) in <i>Caenorhabditis elegans</i>. We show that exposure to 10 μM PhIP disrupts the 24-h circadian rhythms of <i>C. elegans</i>, an effect mitigated by co-exposure to 100 μM PSB. In addition, PhIP-induced circadian disruption can be linked to defective oxidative stress resistance, which is associated with the DAF-16/FOXO pathway and is modulated by PSB. Molecular docking suggested that PhIP and PSB bind similarly to DAF-16. Moreover, 10 μM PhIP abolished the rhythmic expression of the core clock gene <i>prdx-2</i>, which is restored by 100 μM PSB. Findings from this study provide novel insight of how food-borne contaminant like PhIP may contribute to the disruption of circadian rhythms and suggest potential for PSB to mitigate these effects in higher organisms.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142181768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Elevated risk of adverse effects from foodborne contaminants and drugs in inflammatory bowel disease: a review 炎症性肠病患者受到食源性污染物和药物不良影响的风险升高:综述。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-09 DOI: 10.1007/s00204-024-03844-w
Tom Walraven, Mathias Busch, Jingxuan Wang, Joanne M. Donkers, Marjolijn Duijvestein, Evita van de Steeg, Nynke I. Kramer, Hans Bouwmeester

The global burden of Inflammatory bowel disease (IBD) has been rising over the last decades. IBD is an intestinal disorder with a complex and largely unknown etiology. The disease is characterized by a chronically inflamed gastrointestinal tract, with intermittent phases of exacerbation and remission. This compromised intestinal barrier can contribute to, enhance, or even enable the toxicity of drugs, food-borne chemicals and particulate matter. This review discusses whether the rising prevalence of IBD in our society warrants the consideration of IBD patients as a specific population group in toxicological safety assessment. Various in vivo, ex vivo and in vitro models are discussed that can simulate hallmarks of IBD and may be used to study the effects of prevalent intestinal inflammation on the hazards of these various toxicants. In conclusion, risk assessments based on healthy individuals may not sufficiently cover IBD patient safety and it is suggested to consider this susceptible subgroup of the population in future toxicological assessments.

过去几十年来,全球炎症性肠病(IBD)的发病率不断上升。IBD 是一种病因复杂且大多不明的肠道疾病。该病的特点是胃肠道长期发炎,间歇性加重和缓解。这种受损的肠道屏障可导致、增强甚至促成药物、食源性化学物质和微粒物质的毒性。本综述讨论了随着 IBD 在社会中发病率的上升,是否有必要在毒理学安全性评估中将 IBD 患者作为一个特殊的人群来考虑。文中讨论了各种体内、体外和体外模型,这些模型可以模拟 IBD 的特征,并可用于研究普遍存在的肠道炎症对各种毒物危害的影响。总之,基于健康人的风险评估可能不足以涵盖 IBD 患者的安全,建议在未来的毒理学评估中考虑到这一易感人群。
{"title":"Elevated risk of adverse effects from foodborne contaminants and drugs in inflammatory bowel disease: a review","authors":"Tom Walraven,&nbsp;Mathias Busch,&nbsp;Jingxuan Wang,&nbsp;Joanne M. Donkers,&nbsp;Marjolijn Duijvestein,&nbsp;Evita van de Steeg,&nbsp;Nynke I. Kramer,&nbsp;Hans Bouwmeester","doi":"10.1007/s00204-024-03844-w","DOIUrl":"10.1007/s00204-024-03844-w","url":null,"abstract":"<div><p>The global burden of Inflammatory bowel disease (IBD) has been rising over the last decades. IBD is an intestinal disorder with a complex and largely unknown etiology. The disease is characterized by a chronically inflamed gastrointestinal tract, with intermittent phases of exacerbation and remission. This compromised intestinal barrier can contribute to, enhance, or even enable the toxicity of drugs, food-borne chemicals and particulate matter. This review discusses whether the rising prevalence of IBD in our society warrants the consideration of IBD patients as a specific population group in toxicological safety assessment. Various in vivo, ex vivo and in vitro models are discussed that can simulate hallmarks of IBD and may be used to study the effects of prevalent intestinal inflammation on the hazards of these various toxicants. In conclusion, risk assessments based on healthy individuals may not sufficiently cover IBD patient safety and it is suggested to consider this susceptible subgroup of the population in future toxicological assessments.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-024-03844-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Predictive biomarkers for embryotoxicity: a machine learning approach to mitigating multicollinearity in RNA-Seq 胚胎毒性的预测性生物标志物:减轻 RNA-Seq 中多重共线性的机器学习方法。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-06 DOI: 10.1007/s00204-024-03852-w
Yixian Quah, Soontag Jung, Jireh Yi-Le Chan, Onju Ham, Ji-Seong Jeong, Sangyun Kim, Woojin Kim, Seung-Chun Park, Seung-Jin Lee, Wook-Joon Yu

Multicollinearity, characterized by significant co-expression patterns among genes, often occurs in high-throughput expression data, potentially impacting the predictive model’s reliability. This study examined multicollinearity among closely related genes, particularly in RNA-Seq data obtained from embryoid bodies (EB) exposed to 5-fluorouracil perturbation to identify genes associated with embryotoxicity. Six genes—Dppa5a, Gdf3, Zfp42, Meis1, Hoxa2, and Hoxb1—emerged as candidates based on domain knowledge and were validated using qPCR in EBs perturbed by 39 test substances. We conducted correlation studies and utilized the variance inflation factor (VIF) to examine the existence of multicollinearity among the genes. Recursive feature elimination with cross-validation (RFECV) ranked Zfp42 and Hoxb1 as the top two among the seven features considered, identifying them as potential early embryotoxicity assessment biomarkers. As a result, a t test assessing the statistical significance of this two-feature prediction model yielded a p value of 0.0044, confirming the successful reduction of redundancies and multicollinearity through RFECV. Our study presents a systematic methodology for using machine learning techniques in transcriptomics data analysis, enhancing the discovery of potential reporter gene candidates for embryotoxicity screening research, and improving the predictive model's predictive accuracy and feasibility while reducing financial and time constraints.

高通量表达数据中经常会出现多共线性现象,其特征是基因之间存在显著的共表达模式,这可能会影响预测模型的可靠性。本研究研究了密切相关基因之间的多重共线性,特别是暴露于5-氟尿嘧啶扰动的类胚体(EB)的RNA-Seq数据,以确定与胚胎毒性相关的基因。基于领域知识,六个基因-Dppa5a、Gdf3、Zfp42、Meis1、Hoxa2 和 Hoxb1 成为候选基因,并在受到 39 种测试物质干扰的 EB 中使用 qPCR 进行了验证。我们进行了相关性研究,并利用方差膨胀因子(VIF)检查了基因之间是否存在多重共线性。通过交叉验证的递归特征消除法(RFECV),Zfp42 和 Hoxb1 在所考虑的七个特征中排名前两位,被确定为潜在的早期胚胎毒性评估生物标记物。结果,评估该双特征预测模型统计意义的 t 检验得出的 p 值为 0.0044,证实通过 RFECV 成功地减少了冗余和多重共线性。我们的研究提出了一种在转录组学数据分析中使用机器学习技术的系统方法,有助于发现胚胎毒性筛选研究中潜在的候选报告基因,提高预测模型的预测准确性和可行性,同时减少资金和时间限制。
{"title":"Predictive biomarkers for embryotoxicity: a machine learning approach to mitigating multicollinearity in RNA-Seq","authors":"Yixian Quah,&nbsp;Soontag Jung,&nbsp;Jireh Yi-Le Chan,&nbsp;Onju Ham,&nbsp;Ji-Seong Jeong,&nbsp;Sangyun Kim,&nbsp;Woojin Kim,&nbsp;Seung-Chun Park,&nbsp;Seung-Jin Lee,&nbsp;Wook-Joon Yu","doi":"10.1007/s00204-024-03852-w","DOIUrl":"10.1007/s00204-024-03852-w","url":null,"abstract":"<div><p>Multicollinearity, characterized by significant co-expression patterns among genes, often occurs in high-throughput expression data, potentially impacting the predictive model’s reliability. This study examined multicollinearity among closely related genes, particularly in RNA-Seq data obtained from embryoid bodies (EB) exposed to 5-fluorouracil perturbation to identify genes associated with embryotoxicity. Six genes—<i>Dppa5a</i>, <i>Gdf3</i>, <i>Zfp42</i>, <i>Meis1</i>, <i>Hoxa2</i>, and <i>Hoxb1</i>—emerged as candidates based on domain knowledge and were validated using qPCR in EBs perturbed by 39 test substances. We conducted correlation studies and utilized the variance inflation factor (VIF) to examine the existence of multicollinearity among the genes. Recursive feature elimination with cross-validation (RFECV) ranked <i>Zfp42</i> and <i>Hoxb1</i> as the top two among the seven features considered, identifying them as potential early embryotoxicity assessment biomarkers. As a result, a <i>t</i> test assessing the statistical significance of this two-feature prediction model yielded a <i>p</i> value of 0.0044, confirming the successful reduction of redundancies and multicollinearity through RFECV. Our study presents a systematic methodology for using machine learning techniques in transcriptomics data analysis, enhancing the discovery of potential reporter gene candidates for embryotoxicity screening research, and improving the predictive model's predictive accuracy and feasibility while reducing financial and time constraints.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Rapid quantitative high-throughput mouse embryoid body model for embryotoxicity assessment 用于胚胎毒性评估的快速定量高通量小鼠胚状体模型。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-05 DOI: 10.1007/s00204-024-03845-9
Yixian Quah, Soontag Jung, Onju Ham, Ji-Seong Jeong, Sangyun Kim, Woojin Kim, Jireh Yi-Le Chan, Seung-Chun Park, Seung-Jin Lee, Wook-Joon Yu

Individuals are exposed to a wide arrays of hazardous chemicals on a daily basis through various routes, many of which have not undergone comprehensive toxicity assessments. While traditional developmental toxicity tests involving pregnant animals are known for their reliability, they are also associated with high costs and time requirements. Consequently, there is an urgent demand for alternative, cost-efficient, and rapid in vitro testing methods. This study aims to address the challenges related to automating and streamlining the screening of early developmental toxicity of chemicals by introducing a mouse embryoid body test (EBT) model in a 384-ultra low attachment well format. Embryoid bodies (EBs) generated in this format were characterized by a spontaneous differentiation trajectory into cardiac mesoderm by as analyzed by RNA-seq. Assessing prediction accuracy using reference compounds suggested in the ICH S5(R3) guideline and prior studies resulted in the establishment of the acceptance criteria and applicability domain of the EBT model. The results indicated an 84.38% accuracy in predicting the developmental toxicity of 23 positive and 9 negative reference compounds, with an optimized cutoff threshold of 750 µM. Overall, the developed EBT model presents a promising approach for more rapid, high-throughput chemical screening, thereby facilitating well-informed decision-making in environmental management and safety assessments.

人们每天都会通过各种途径接触到各种各样的危险化学品,其中许多化学品都没有经过全面的毒性评估。虽然涉及怀孕动物的传统发育毒性测试以其可靠性而著称,但它们的成本和时间要求也很高。因此,对替代性、成本效益高且快速的体外测试方法的需求十分迫切。本研究旨在通过在 384 超低附着孔格式中引入小鼠类胚体试验(EBT)模型,解决与自动化和简化化学品早期发育毒性筛选有关的挑战。用这种格式生成的类胚体(EB)通过 RNA-seq 分析,具有自发分化为心脏中胚层的特征。利用 ICH S5(R3) 指南中建议的参考化合物和先前的研究评估预测准确性,最终确定了 EBT 模型的接受标准和适用范围。结果表明,在预测 23 种阳性参考化合物和 9 种阴性参考化合物的发育毒性时,准确率为 84.38%,优化的截止阈值为 750 µM。总之,所开发的 EBT 模型为更快速、高通量的化学筛选提供了一种可行的方法,从而有助于在环境管理和安全评估中做出明智的决策。
{"title":"Rapid quantitative high-throughput mouse embryoid body model for embryotoxicity assessment","authors":"Yixian Quah,&nbsp;Soontag Jung,&nbsp;Onju Ham,&nbsp;Ji-Seong Jeong,&nbsp;Sangyun Kim,&nbsp;Woojin Kim,&nbsp;Jireh Yi-Le Chan,&nbsp;Seung-Chun Park,&nbsp;Seung-Jin Lee,&nbsp;Wook-Joon Yu","doi":"10.1007/s00204-024-03845-9","DOIUrl":"10.1007/s00204-024-03845-9","url":null,"abstract":"<div><p>Individuals are exposed to a wide arrays of hazardous chemicals on a daily basis through various routes, many of which have not undergone comprehensive toxicity assessments. While traditional developmental toxicity tests involving pregnant animals are known for their reliability, they are also associated with high costs and time requirements. Consequently, there is an urgent demand for alternative, cost-efficient, and rapid in vitro testing methods. This study aims to address the challenges related to automating and streamlining the screening of early developmental toxicity of chemicals by introducing a mouse embryoid body test (EBT) model in a 384-ultra low attachment well format. Embryoid bodies (EBs) generated in this format were characterized by a spontaneous differentiation trajectory into cardiac mesoderm by as analyzed by RNA-seq. Assessing prediction accuracy using reference compounds suggested in the ICH S5(R3) guideline and prior studies resulted in the establishment of the acceptance criteria and applicability domain of the EBT model. The results indicated an 84.38% accuracy in predicting the developmental toxicity of 23 positive and 9 negative reference compounds, with an optimized cutoff threshold of 750 µM. Overall, the developed EBT model presents a promising approach for more rapid, high-throughput chemical screening, thereby facilitating well-informed decision-making in environmental management and safety assessments.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
A review of the scientific literature on experimental toxicity studies of COVID-19 vaccines, with special attention to publications in toxicology journals 有关 COVID-19 疫苗实验毒性研究的科学文献综述,特别关注在毒理学期刊上发表的文章。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-03 DOI: 10.1007/s00204-024-03854-8
Jose L. Domingo

Since the reports of the first cases of COVID-19, in less than 5 years, a huge number of documents regarding that disease and the coronavirus (SARS-CoV-2), responsible for the infection, have been published. The tremendous number of scientific documents covers many topics on different issues directly related to COVID-19/SARS-CoV-2. The number of articles—including reviews—reporting adverse/side effects of the approved COVID-19 vaccines is considerable. A wide range of adverse/side effects have been reported in humans after COVID-19 vaccination: thrombotic events/thrombocytopenia, myocarditis/pericarditis, cutaneous reactions, immune-mediated effects, psychiatric adverse events, systemic lupus erythematosus, reproductive toxicity, and other miscellaneous adverse effects. In contrast, information on nonclinical studies conducted to assess the potential toxicity/adverse effects of the COVID-19 vaccines in laboratory animals, is comparatively very scarce. The present review was aimed at revising the scientific literature regarding the studies in laboratory animals on the toxic/adverse effects of COVID-19 vaccines. In addition, the investigations reported in those specific toxicology journals with the highest impact factors have been examined one by one. The results of the present review indicate that most nonclinical/experimental studies on the adverse/toxic effects of the COVID-19 vaccines and/or potential candidates showed—in general terms—a good safety profile. Only in some animal studies were certain adverse effects found. However, a rather surprising result has been the limited number of available (in the databases PubMed and Scopus) nonclinical studies performed by the companies that have been the largest manufacturers of mRNA vaccines in the world. It is assumed that these studies have been conducted. However, they have not been published in scientific journals, which does not allow the judgment of the international scientific community, including toxicologists.

自报告第一例 COVID-19 病例以来,在不到 5 年的时间里,有关该疾病和造成感染的冠状病毒(SARS-CoV-2)的大量文件已经出版。大量科学文献涵盖了与 COVID-19/SARS-CoV-2 直接相关的不同问题的许多专题。报告已批准的 COVID-19 疫苗的不良/副作用的文章(包括综述)数量可观。据报道,人类接种 COVID-19 疫苗后出现了多种不良/副作用:血栓事件/血小板减少症、心肌炎/心包炎、皮肤反应、免疫介导效应、精神不良事件、系统性红斑狼疮、生殖毒性以及其他各种不良反应。相比之下,为评估 COVID-19 疫苗在实验动物中的潜在毒性/不良反应而进行的非临床研究的信息则非常稀少。本综述旨在修订有关 COVID-19 疫苗在实验动物中毒性/不良反应研究的科学文献。此外,还对影响因子最高的特定毒理学期刊上的研究报告进行了逐一审查。本综述的结果表明,大多数关于 COVID-19 疫苗和/或潜在候选疫苗不良/毒性作用的非临床/实验研究总体上显示出良好的安全性。只有在一些动物实验中发现了某些不良反应。然而,一个令人惊讶的结果是,世界上最大的 mRNA 疫苗生产商所进行的非临床研究数量有限(在 PubMed 和 Scopus 数据库中)。这些研究应该已经进行过。然而,这些研究并未在科学杂志上发表,这就无法让包括毒理学专家在内的国际科学界作出判断。
{"title":"A review of the scientific literature on experimental toxicity studies of COVID-19 vaccines, with special attention to publications in toxicology journals","authors":"Jose L. Domingo","doi":"10.1007/s00204-024-03854-8","DOIUrl":"10.1007/s00204-024-03854-8","url":null,"abstract":"<div><p>Since the reports of the first cases of COVID-19, in less than 5 years, a huge number of documents regarding that disease and the coronavirus (SARS-CoV-2), responsible for the infection, have been published. The tremendous number of scientific documents covers many topics on different issues directly related to COVID-19/SARS-CoV-2. The number of articles—including reviews—reporting adverse/side effects of the approved COVID-19 vaccines is considerable. A wide range of adverse/side effects have been reported in humans after COVID-19 vaccination: thrombotic events/thrombocytopenia, myocarditis/pericarditis, cutaneous reactions, immune-mediated effects, psychiatric adverse events, systemic lupus erythematosus, reproductive toxicity, and other miscellaneous adverse effects. In contrast, information on nonclinical studies conducted to assess the potential toxicity/adverse effects of the COVID-19 vaccines in laboratory animals, is comparatively very scarce. The present review was aimed at revising the scientific literature regarding the studies in laboratory animals on the toxic/adverse effects of COVID-19 vaccines. In addition, the investigations reported in those specific toxicology journals with the highest impact factors have been examined one by one. The results of the present review indicate that most nonclinical/experimental studies on the adverse/toxic effects of the COVID-19 vaccines and/or potential candidates showed—in general terms—a good safety profile. Only in some animal studies were certain adverse effects found. However, a rather surprising result has been the limited number of available (in the databases PubMed and Scopus) nonclinical studies performed by the companies that have been the largest manufacturers of mRNA vaccines in the world. It is assumed that these studies have been conducted. However, they have not been published in scientific journals, which does not allow the judgment of the international scientific community, including toxicologists.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-024-03854-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Elevated blood-ethanol concentration promotes reduction of aliphatic ketones (acetone and ethyl methyl ketone) to secondary alcohols along with slower oxidation to aliphatic diols 血液中乙醇浓度的升高会促进脂肪族酮类(丙酮和乙基甲基酮)还原成仲醇,同时减慢脂肪族二元醇的氧化速度。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-03 DOI: 10.1007/s00204-024-03860-w
A. W. Jones

Many people convicted for drunken driving suffer from an alcohol use disorder and some traffic offenders consume denatured alcohol for intoxication purposes. Venous blood samples from people arrested for driving under the influence of alcohol were analyzed in triplicate by headspace gas chromatography (HS-GC) using three different stationary phases. The gas chromatograms from this analysis sometimes showed peaks with retention times corresponding to acetone, ethyl methyl ketone (2-butanone), 2-propanol, and 2-butanol in addition to ethanol and the internal standard (1-propanol). Further investigations showed that these drink-driving suspects had consumed an industrial alcohol (T-Red) for intoxication purposes, which contained > 90% w/v ethanol, acetone (~ 2% w/v), 2-butanone (~ 5% w/v) as well as Bitrex to impart a bitter taste. In n = 75 blood samples from drinkers of T-Red, median concentrations of ethanol, acetone, 2-butanone, 2-propanol and 2-butanol were 2050 mg/L (2.05 g/L), 97 mg/L, 48 mg/L, 26 mg/L and 20 mg/L, respectively. In a separate GC analysis, 2,3-butanediol (median concentration 87 mg/L) was identified in blood samples containing 2-butanone. When the redox state of the liver is shifted to a more reduced potential (excess NADH), which occurs during metabolism of ethanol, this favors the reduction of low molecular ketones into secondary alcohols via the alcohol dehydrogenase (ADH) pathway. Routine toxicological analysis of blood samples from apprehended drivers gave the opportunity to study metabolism of acetone and 2-butanone without having to administer these substances to human volunteers.

许多因醉酒驾驶而被定罪的人都患有酒精使用障碍,一些交通违法者会饮用变性酒精来达到醉酒的目的。对因酒后驾车而被捕的人的静脉血样本进行了顶空气相色谱分析(HS-GC),一式三份,使用三种不同的固定相。分析得出的气相色谱图有时会出现保留时间与丙酮、乙基甲基酮(2-丁酮)、2-丙醇和 2-丁醇相对应的峰值,此外还有乙醇和内标物(1-丙醇)。进一步的调查显示,这些酒驾嫌疑人饮用了一种工业酒精(T-Red)来达到醉酒的目的,其中含有大于 90% w/v 的乙醇、丙酮(约 2% w/v)、2-丁酮(约 5% w/v)以及苦味的 Bitrex。在 n = 75 份 T-Red 饮用者的血液样本中,乙醇、丙酮、2-丁酮、2-丙醇和 2-丁醇的中位浓度分别为 2050 毫克/升(2.05 克/升)、97 毫克/升、48 毫克/升、26 毫克/升和 20 毫克/升。在另一项气相色谱分析中,在含有 2-丁酮的血液样本中发现了 2,3-丁二醇(中位数浓度为 87 毫克/升)。在乙醇代谢过程中,肝脏的氧化还原状态会转变为更高的还原电位(过量的 NADH),这有利于低分子酮通过乙醇脱氢酶(ADH)途径还原成仲醇。对被捕司机的血液样本进行常规毒理学分析,为研究丙酮和 2-丁酮的新陈代谢提供了机会,而无需对人体志愿者施用这些物质。
{"title":"Elevated blood-ethanol concentration promotes reduction of aliphatic ketones (acetone and ethyl methyl ketone) to secondary alcohols along with slower oxidation to aliphatic diols","authors":"A. W. Jones","doi":"10.1007/s00204-024-03860-w","DOIUrl":"10.1007/s00204-024-03860-w","url":null,"abstract":"<div><p>Many people convicted for drunken driving suffer from an alcohol use disorder and some traffic offenders consume denatured alcohol for intoxication purposes. Venous blood samples from people arrested for driving under the influence of alcohol were analyzed in triplicate by headspace gas chromatography (HS-GC) using three different stationary phases. The gas chromatograms from this analysis sometimes showed peaks with retention times corresponding to acetone, ethyl methyl ketone (2-butanone), 2-propanol, and 2-butanol in addition to ethanol and the internal standard (1-propanol). Further investigations showed that these drink-driving suspects had consumed an industrial alcohol (T-Red) for intoxication purposes, which contained &gt; 90% w/v ethanol, acetone (~ 2% w/v), 2-butanone (~ 5% w/v) as well as Bitrex to impart a bitter taste. In <i>n</i> = 75 blood samples from drinkers of T-Red, median concentrations of ethanol, acetone, 2-butanone, 2-propanol and 2-butanol were 2050 mg/L (2.05 g/L), 97 mg/L, 48 mg/L, 26 mg/L and 20 mg/L, respectively. In a separate GC analysis, 2,3-butanediol (median concentration 87 mg/L) was identified in blood samples containing 2-butanone. When the redox state of the liver is shifted to a more reduced potential (excess NADH), which occurs during metabolism of ethanol, this favors the reduction of low molecular ketones into secondary alcohols via the alcohol dehydrogenase (ADH) pathway. Routine toxicological analysis of blood samples from apprehended drivers gave the opportunity to study metabolism of acetone and 2-butanone without having to administer these substances to human volunteers.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Unrevealing the mechanisms behind the cardioprotective effect of wheat polyphenolics 揭示小麦多酚保护心脏作用的机制。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-08-31 DOI: 10.1007/s00204-024-03850-y
Pratik Chakraborty, Saikat Dewanjee

Cardiovascular diseases pose a major threat to both life expectancy and quality of life worldwide, and a concerning level of disease burden has been attained, particularly in middle- and low-income nations. Several drugs presently in use lead to multiple adverse events. Thus, it is urgently needed to develop safe, affordable, and effective management of cardiovascular diseases. Emerging evidence reveals a positive association between polyphenol consumption and cardioprotection. Whole wheat grain and allied products are good sources of polyphenolic compounds bearing enormous cardioprotective potential. Polyphenolic extract of the entire wheat grain contains different phenolic compounds viz. ferulic acid, caffeic acid, chlorogenic acid, p-coumaric acid, sinapic acid, syringic acid, vanillic acid, apigenin, quercetin, luteolin, etc. which exert cardioprotection by reducing oxidative stress and interfering with different toxicological processes. The antioxidant capacity has been thought to exert the cardioprotective mechanism of wheat grain polyphenolics, which predominantly suppresses oxidative stress, inflammation and fibrosis by downregulating several pathogenic signaling events. However, the combined effect of polyphenolics appears to be more prominent than that of a single molecule, which might be attained due to the synergy resulting in multimodal cardioprotective benefits from multiple phenolics. The current article covers the bioaccessibility and possible effects of wheat-derived polyphenolics in protecting against several cardiovascular disorders. This review discusses the mechanistic pharmacology of individual wheat polyphenols on the cardiovascular system. It also highlights the comparative superiority of polyphenolic extracts over a single phenolic.

心血管疾病对全世界人民的预期寿命和生活质量都构成了重大威胁,尤其是在中低收入国家,疾病负担已达到令人担忧的程度。目前使用的几种药物会导致多种不良反应。因此,迫切需要开发安全、经济、有效的心血管疾病治疗药物。新的证据显示,多酚消费与心血管保护之间存在正相关。全麦谷物和相关产品是多酚化合物的良好来源,具有巨大的心脏保护潜力。全麦粒的多酚提取物含有不同的酚类化合物,即阿魏酸、咖啡酸、绿原酸、对香豆酸、山奈酸、丁香酸、香草酸、芹菜素、槲皮素、木犀草素等,它们通过减少氧化应激和干扰不同的毒性过程来发挥保护心脏的作用。抗氧化能力一直被认为是小麦多酚保护心脏的机制,它主要通过下调几种致病信号事件来抑制氧化应激、炎症和纤维化。然而,多酚的综合效应似乎比单一分子的效应更为突出,这可能是由于多种酚类物质的协同作用产生了多模式的心脏保护益处。本文论述了小麦多酚的生物可及性和可能对多种心血管疾病产生的保护作用。这篇综述讨论了单个小麦多酚对心血管系统的机理药理学。文章还强调了多酚提取物相对于单一酚类的优越性。
{"title":"Unrevealing the mechanisms behind the cardioprotective effect of wheat polyphenolics","authors":"Pratik Chakraborty,&nbsp;Saikat Dewanjee","doi":"10.1007/s00204-024-03850-y","DOIUrl":"10.1007/s00204-024-03850-y","url":null,"abstract":"<div><p>Cardiovascular diseases pose a major threat to both life expectancy and quality of life worldwide, and a concerning level of disease burden has been attained, particularly in middle- and low-income nations. Several drugs presently in use lead to multiple adverse events. Thus, it is urgently needed to develop safe, affordable, and effective management of cardiovascular diseases. Emerging evidence reveals a positive association between polyphenol consumption and cardioprotection. Whole wheat grain and allied products are good sources of polyphenolic compounds bearing enormous cardioprotective potential. Polyphenolic extract of the entire wheat grain contains different phenolic compounds viz. ferulic acid, caffeic acid, chlorogenic acid, p-coumaric acid, sinapic acid, syringic acid, vanillic acid, apigenin, quercetin, luteolin, etc. which exert cardioprotection by reducing oxidative stress and interfering with different toxicological processes. The antioxidant capacity has been thought to exert the cardioprotective mechanism of wheat grain polyphenolics, which predominantly suppresses oxidative stress, inflammation and fibrosis by downregulating several pathogenic signaling events. However, the combined effect of polyphenolics appears to be more prominent than that of a single molecule, which might be attained due to the synergy resulting in multimodal cardioprotective benefits from multiple phenolics. The current article covers the bioaccessibility and possible effects of wheat-derived polyphenolics in protecting against several cardiovascular disorders. This review discusses the mechanistic pharmacology of individual wheat polyphenols on the cardiovascular system. It also highlights the comparative superiority of polyphenolic extracts over a single phenolic.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Transport of perfluoroalkyl substances across human induced pluripotent stem cell-derived intestinal epithelial cells in comparison with primary human intestinal epithelial cells and Caco-2 cells 全氟烷基物质在人诱导多能干细胞衍生的肠上皮细胞与原代人肠上皮细胞和 Caco-2 细胞之间的转运比较。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-08-31 DOI: 10.1007/s00204-024-03851-x
Aafke W. F. Janssen, Loes P. M. Duivenvoorde, Karsten Beekmann, Nicole Pinckaers, Bart van der Hee, Annelies Noorlander, Liz L. Leenders, Jochem Louisse, Meike van der Zande

Humans can be exposed to per- and polyfluoroalkyl substances (PFASs) via many exposure routes, including diet, which may lead to several adverse health effects. So far, little is known about PFAS transport across the human intestinal barrier. In the current study, we aimed to assess the transport of 5 PFASs (PFOS, PFOA, PFNA, PFHxS and HFPO-DA) in a human induced pluripotent stem cell (hiPSC)-derived intestinal epithelial cell (IEC) model. This model was extensively characterized and compared with the widely applied human colonic adenocarcinoma cell line Caco-2 and a human primary IEC-based model, described to most closely resemble in vivo tissue. The hiPSC-derived IEC layers demonstrated polarized monolayers with tight junctions and a mucus layer. The monolayers consisted of enterocytes, stem cells, goblet cells, enteroendocrine cells, and Paneth cells that are also present in native tissue. Transcriptomics analysis revealed distinct differences in gene expression profiles, where the hiPSC-derived IECs showed the highest expression of intestinal tissue-specific genes relative to the primary IEC-based model and the Caco-2 cells clustered closer to the primary IEC-based model than the hiPSC-derived IECs. The order of PFAS transport was largely similar between the models and the apparent permeability (Papp) values of PFAS in apical to basolateral direction in the hiPSC-derived IEC model were in the following order: PFHxS > PFOA > HFPO-DA > PFNA > PFOS. In conclusion, the hiPSC-derived IEC model highly resembles human intestinal physiology and is therefore a promising novel in vitro model to study transport of chemicals across the intestinal barrier for risk assessment of chemicals.

人类可通过饮食等多种途径接触到全氟烷基和多氟烷基物质(PFAS),这可能会对健康造成多种不利影响。迄今为止,人们对 PFAS 通过人体肠道屏障的转运知之甚少。在本研究中,我们旨在评估 5 种 PFAS(PFOS、PFOA、PFNA、PFHxS 和 HFPO-DA)在人类诱导多能干细胞(hiPSC)衍生的肠上皮细胞(IEC)模型中的转运情况。该模型具有广泛的特征,并与广泛应用的人类结肠腺癌细胞系 Caco-2 和基于人类原代 IEC 的模型进行了比较,后者被描述为最接近体内组织。hiPSC 衍生的 IEC 层显示出具有紧密连接和粘液层的极化单层。单层包括肠细胞、干细胞、鹅口疮细胞、肠内分泌细胞和Paneth细胞,这些细胞也存在于原生组织中。转录组学分析揭示了基因表达谱的明显差异,与基于原生 IEC 的模型相比,源于 hiPSC 的 IEC 显示出最高的肠组织特异性基因表达量,而 Caco-2 细胞比源于 hiPSC 的 IEC 更接近于基于原生 IEC 的模型。两种模型的 PFAS 转运顺序基本相似,在 hiPSC 衍生 IEC 模型中,PFAS 的表观渗透性(Papp)值从顶端到基底侧的顺序如下:PFHxS > PFOA > HFPO-DA > PFNA > PFOS。总之,源于 hiPSC 的 IEC 模型与人类肠道生理结构高度相似,因此是研究化学品通过肠道屏障转运以进行化学品风险评估的一种很有前途的新型体外模型。
{"title":"Transport of perfluoroalkyl substances across human induced pluripotent stem cell-derived intestinal epithelial cells in comparison with primary human intestinal epithelial cells and Caco-2 cells","authors":"Aafke W. F. Janssen,&nbsp;Loes P. M. Duivenvoorde,&nbsp;Karsten Beekmann,&nbsp;Nicole Pinckaers,&nbsp;Bart van der Hee,&nbsp;Annelies Noorlander,&nbsp;Liz L. Leenders,&nbsp;Jochem Louisse,&nbsp;Meike van der Zande","doi":"10.1007/s00204-024-03851-x","DOIUrl":"10.1007/s00204-024-03851-x","url":null,"abstract":"<div><p>Humans can be exposed to per- and polyfluoroalkyl substances (PFASs) via many exposure routes, including diet, which may lead to several adverse health effects. So far, little is known about PFAS transport across the human intestinal barrier. In the current study, we aimed to assess the transport of 5 PFASs (PFOS, PFOA, PFNA, PFHxS and HFPO-DA) in a human induced pluripotent stem cell (hiPSC)-derived intestinal epithelial cell (IEC) model. This model was extensively characterized and compared with the widely applied human colonic adenocarcinoma cell line Caco-2 and a human primary IEC-based model, described to most closely resemble in vivo tissue. The hiPSC-derived IEC layers demonstrated polarized monolayers with tight junctions and a mucus layer. The monolayers consisted of enterocytes, stem cells, goblet cells, enteroendocrine cells, and Paneth cells that are also present in native tissue. Transcriptomics analysis revealed distinct differences in gene expression profiles, where the hiPSC-derived IECs showed the highest expression of intestinal tissue-specific genes relative to the primary IEC-based model and the Caco-2 cells clustered closer to the primary IEC-based model than the hiPSC-derived IECs. The order of PFAS transport was largely similar between the models and the apparent permeability (<i>P</i><sub>app</sub>) values of PFAS in apical to basolateral direction in the hiPSC-derived IEC model were in the following order: PFHxS &gt; PFOA &gt; HFPO-DA &gt; PFNA &gt; PFOS. In conclusion, the hiPSC-derived IEC model highly resembles human intestinal physiology and is therefore a promising novel in vitro model to study transport of chemicals across the intestinal barrier for risk assessment of chemicals.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-024-03851-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Comparative case study on NAMs: towards enhancing specific target organ toxicity analysis 非杀伤人员地雷比较案例研究:加强特定靶器官毒性分析。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-08-29 DOI: 10.1007/s00204-024-03839-7
Kristina Jochum, Andrea Miccoli, Cornelia Sommersdorf, Oliver Poetz, Albert Braeuning, Tewes Tralau, Philip Marx-Stoelting

Traditional risk assessment methodologies in toxicology have relied upon animal testing, despite concerns regarding interspecies consistency, reproducibility, costs, and ethics. New Approach Methodologies (NAMs), including cell culture and multi-level omics analyses, hold promise by providing mechanistic information rather than assessing organ pathology. However, NAMs face limitations, like lacking a whole organism and restricted toxicokinetic interactions. This is an inherent challenge when it comes to the use of omics data from in vitro studies for the prediction of organ toxicity in vivo. One solution in this context are comparative in vitro–in vivo studies as they allow for a more detailed assessment of the transferability of the respective NAM data. Hence, hepatotoxic and nephrotoxic pesticide active substances were tested in human cell lines and the results subsequently related to the biology underlying established effects in vivo. To this end, substances were tested in HepaRG and RPTEC/tERT1 cells at non-cytotoxic concentrations and analyzed for effects on the transcriptome and parts of the proteome using quantitative real-time PCR arrays and multiplexed microsphere-based sandwich immunoassays, respectively. Transcriptomics data were analyzed using three bioinformatics tools. Where possible, in vitro endpoints were connected to in vivo observations. Targeted protein analysis revealed various affected pathways, with generally fewer effects present in RPTEC/tERT1. The strongest transcriptional impact was observed for Chlorotoluron in HepaRG cells (increased CYP1A1 and CYP1A2 expression). A comprehensive comparison of early cellular responses with data from in vivo studies revealed that transcriptomics outperformed targeted protein analysis, correctly predicting up to 50% of in vivo effects.

传统的毒理学风险评估方法依赖于动物试验,尽管动物试验在物种间一致性、可重复性、成本和伦理方面存在问题。新方法(NAMs),包括细胞培养和多层次全息分析,通过提供机理信息而非评估器官病理学,带来了希望。然而,NAMs 也有其局限性,如缺乏整个生物体和有限的毒物动力学相互作用。在使用体外研究的全息数据预测体内器官毒性时,这是一个固有的挑战。在这种情况下,一种解决方案是进行体外-体内对比研究,因为这样可以更详细地评估相关 NAM 数据的可转移性。因此,在人体细胞系中对肝毒性和肾毒性农药活性物质进行了测试,随后将测试结果与体内既定效应的生物学基础联系起来。为此,在 HepaRG 和 RPTEC/tERT1 细胞中以非毒性浓度测试了这些物质,并分别使用定量实时 PCR 阵列和基于微球的多重夹心免疫分析法分析了这些物质对转录组和部分蛋白质组的影响。转录组学数据使用三种生物信息学工具进行分析。在可能的情况下,将体外终点与体内观察结果联系起来。靶向蛋白质分析表明了各种受影响的通路,一般来说,RPTEC/tERT1 的影响较小。在 HepaRG 细胞中观察到的氯酯脲转录影响最大(CYP1A1 和 CYP1A2 表达增加)。将早期细胞反应与体内研究数据进行综合比较后发现,转录组学的效果优于靶向蛋白质分析,能正确预测高达 50% 的体内效应。
{"title":"Comparative case study on NAMs: towards enhancing specific target organ toxicity analysis","authors":"Kristina Jochum,&nbsp;Andrea Miccoli,&nbsp;Cornelia Sommersdorf,&nbsp;Oliver Poetz,&nbsp;Albert Braeuning,&nbsp;Tewes Tralau,&nbsp;Philip Marx-Stoelting","doi":"10.1007/s00204-024-03839-7","DOIUrl":"10.1007/s00204-024-03839-7","url":null,"abstract":"<div><p>Traditional risk assessment methodologies in toxicology have relied upon animal testing, despite concerns regarding interspecies consistency, reproducibility, costs, and ethics. New Approach Methodologies (NAMs), including cell culture and multi-level omics analyses, hold promise by providing mechanistic information rather than assessing organ pathology. However, NAMs face limitations, like lacking a whole organism and restricted toxicokinetic interactions. This is an inherent challenge when it comes to the use of omics data from in vitro studies for the prediction of organ toxicity in vivo. One solution in this context are comparative in vitro–in vivo studies as they allow for a more detailed assessment of the transferability of the respective NAM data. Hence, hepatotoxic and nephrotoxic pesticide active substances were tested in human cell lines and the results subsequently related to the biology underlying established effects in vivo. To this end, substances were tested in HepaRG and RPTEC/tERT1 cells at non-cytotoxic concentrations and analyzed for effects on the transcriptome and parts of the proteome using quantitative real-time PCR arrays and multiplexed microsphere-based sandwich immunoassays, respectively. Transcriptomics data were analyzed using three bioinformatics tools. Where possible, in vitro endpoints were connected to in vivo observations. Targeted protein analysis revealed various affected pathways, with generally fewer effects present in RPTEC/tERT1. The strongest transcriptional impact was observed for Chlorotoluron in HepaRG cells (increased <i>CYP1A1</i> and <i>CYP1A2</i> expression). A comprehensive comparison of early cellular responses with data from in vivo studies revealed that transcriptomics outperformed targeted protein analysis, correctly predicting up to 50% of in vivo effects.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-024-03839-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Toxicokinetics, in vivo metabolic profiling and tissue distribution of chlorfenapyr in mice 氯虫苯甲酰胺在小鼠体内的毒代动力学、体内代谢分析和组织分布。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-08-28 DOI: 10.1007/s00204-024-03846-8
Shunjie Zhang, Xin wang, Xia yang, Ziyang Ma, Peng Liu, Shiyuan Tang, Min Zhao, Haijun Chen, Qiang Qiu, Minghai Tang, Aihua Peng, Yu Cao

Chlorfenapyr is a novel broad-spectrum insecticide derived from natural pyrrole derivatives produced by Streptomyces spp. It acts as a pro-insecticide and is metabolically converted to the active metabolite, tralopyril. Chlorfenapyr poisoning is known for its delayed neurological symptoms and high mortality. Unfortunately, information on the toxicokinetics, metabolism and tissue distribution of chlorfenapyr and tralopyril is still lacking. In this study, the metabolic profile, toxicokinetics and tissue distribution of chlorfenapyr and tralopyril after oral administration at a toxic dose in mice were investigated. Twenty metabolites were identified in plasma, urine and feces, which were mainly formed by dealkylation, oxidative dechlorination and reductive dechlorination. Toxicokinetic results showed that chlorfenapyr was rapidly converted to tralopyril after administration, and the in vivo half-life (t1/2), area under the curve (AUC) and peak concentration (Cmax) values of tralopyril were significantly higher than those of chlorfenapyr (P < 0.05). Tissue distribution experiments confirmed that the metabolite tralopyril had a longer half-life, a lower clearance and a wide distribution in different organs and tissues compared to chlorfenapyr. It was also able to cross the blood–brain barrier, suggesting a potential association with brain lesions. In addition, a sensitive and rapid LC–MS/MS analytical method was established for the detection of chlorfenapyr and tralopyril. In conclusion, this study provided valuable metabolic, toxicokinetic and tissue distribution information, contributing to future risk assessment and forensic identification in cases of chlorfenapyr poisoning. We recommend considering the assessment of tralopyril levels, which may be of greater therapeutic importance in the management of chlorfenapyr poisoning.

Chlorfenapyr 是一种新型广谱杀虫剂,源自链霉菌属(Streptomyces spp)产生的天然吡咯衍生物。氯虫苯甲酰胺中毒以其迟发性神经症状和高死亡率而闻名。遗憾的是,有关氯虫苯甲酰胺和 tralopyril 的毒代动力学、新陈代谢和组织分布的信息仍然缺乏。本研究调查了小鼠口服毒性剂量的氯虫苯甲酰胺和 tralopyril 的代谢概况、毒物动力学和组织分布。在血浆、尿液和粪便中发现了 20 种代谢物,主要由脱烷基、氧化脱氯和还原脱氯形成。毒代动力学结果表明,氯虫苯甲酰胺在给药后会迅速转化为曲唑草胺,曲唑草胺的体内半衰期(t1/2)、曲线下面积(AUC)和峰浓度(Cmax)值明显高于氯虫苯甲酰胺(P<0.05)。
{"title":"Toxicokinetics, in vivo metabolic profiling and tissue distribution of chlorfenapyr in mice","authors":"Shunjie Zhang,&nbsp;Xin wang,&nbsp;Xia yang,&nbsp;Ziyang Ma,&nbsp;Peng Liu,&nbsp;Shiyuan Tang,&nbsp;Min Zhao,&nbsp;Haijun Chen,&nbsp;Qiang Qiu,&nbsp;Minghai Tang,&nbsp;Aihua Peng,&nbsp;Yu Cao","doi":"10.1007/s00204-024-03846-8","DOIUrl":"10.1007/s00204-024-03846-8","url":null,"abstract":"<div><p>Chlorfenapyr is a novel broad-spectrum insecticide derived from natural pyrrole derivatives produced by <i>Streptomyces</i> spp. It acts as a pro-insecticide and is metabolically converted to the active metabolite, tralopyril. Chlorfenapyr poisoning is known for its delayed neurological symptoms and high mortality. Unfortunately, information on the toxicokinetics, metabolism and tissue distribution of chlorfenapyr and tralopyril is still lacking. In this study, the metabolic profile, toxicokinetics and tissue distribution of chlorfenapyr and tralopyril after oral administration at a toxic dose in mice were investigated. Twenty metabolites were identified in plasma, urine and feces, which were mainly formed by dealkylation, oxidative dechlorination and reductive dechlorination. Toxicokinetic results showed that chlorfenapyr was rapidly converted to tralopyril after administration, and the in vivo half-life (<i>t</i><sub>1/2</sub>), area under the curve (AUC) and peak concentration (<i>C</i><sub>max</sub>) values of tralopyril were significantly higher than those of chlorfenapyr (<i>P</i> &lt; 0.05). Tissue distribution experiments confirmed that the metabolite tralopyril had a longer half-life, a lower clearance and a wide distribution in different organs and tissues compared to chlorfenapyr. It was also able to cross the blood–brain barrier, suggesting a potential association with brain lesions. In addition, a sensitive and rapid LC–MS/MS analytical method was established for the detection of chlorfenapyr and tralopyril. In conclusion, this study provided valuable metabolic, toxicokinetic and tissue distribution information, contributing to future risk assessment and forensic identification in cases of chlorfenapyr poisoning. We recommend considering the assessment of tralopyril levels, which may be of greater therapeutic importance in the management of chlorfenapyr poisoning.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142079009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
期刊
Archives of Toxicology
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1