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 Archives of 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
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引用次数: 0

摘要

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。
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Comparative case study on NAMs: towards enhancing specific target organ toxicity analysis

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.

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来源期刊
Archives of Toxicology
Archives of Toxicology 医学-毒理学
CiteScore
11.60
自引率
4.90%
发文量
218
审稿时长
1.5 months
期刊介绍: Archives of Toxicology provides up-to-date information on the latest advances in toxicology. The journal places particular emphasis on studies relating to defined effects of chemicals and mechanisms of toxicity, including toxic activities at the molecular level, in humans and experimental animals. Coverage includes new insights into analysis and toxicokinetics and into forensic toxicology. Review articles of general interest to toxicologists are an additional important feature of the journal.
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