替代性整体机体模型中的神经行为和大脑发育如何有助于预测发育期神经毒性。

IF 3.4 3区 医学 Q2 NEUROSCIENCES Neurotoxicology Pub Date : 2024-03-28 DOI:10.1016/j.neuro.2024.03.005
Eva-Maria S. Collins , Ellen V.S. Hessel , Samantha Hughes
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引用次数: 0

摘要

在化学品风险评估中,发育神经毒性(DNT)并不是常规评估项目,因为目前的 DNT 测试范例需要使用哺乳动物模型,而这些模型在伦理道德上存在争议,而且成本高昂,需要大量资源。因此,人们致力于通过经济实惠的新型风险评估替代方法来彻底改变 DNT 测试。我们的目标是开发出适用于高通量筛选(HTS)的 DNT 体外测试电池。目前,DNT 体外测试主要包括基于人体细胞的检测,因为这些检测与人类健康密切相关。然而,仅靠这种基于细胞的检测方法无法捕捉发育中神经系统的复杂性。目前迫切需要符合 3R(替换、减少和完善)模型的整个生物体系统来补充基于细胞的 DNT 检测。这些模型可以提供必要的生物背景,并通过将分子和/或细胞变化与行为读数联系起来,用于探索化学物质对大脑功能的影响。线虫(Caenorhabditis elegans)、刨食者(Dugesia japonica)和斑马鱼(Danio rerio)的胚胎都适用于低成本 HTS,而且在 DNT 测试方面各有千秋。在此,我们以一种新颖、综合的方式回顾了这些生物的优势和互补性,并重点介绍了它们如何能增强目前基于细胞的检测方法,从而对化学品进行更全面、更稳健的 DNT 筛选。考虑到所有体外测试系统的局限性,我们将讨论如何巧妙地结合使用这些系统,以更好地考虑大脑发育的复杂性,对化学品进行与人类相关的风险评估。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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How neurobehavior and brain development in alternative whole-organism models can contribute to prediction of developmental neurotoxicity

Developmental neurotoxicity (DNT) is not routinely evaluated in chemical risk assessment because current test paradigms for DNT require the use of mammalian models which are ethically controversial, expensive, and resource demanding. Consequently, efforts have focused on revolutionizing DNT testing through affordable novel alternative methods for risk assessment. The goal is to develop a DNT in vitro test battery amenable to high-throughput screening (HTS). Currently, the DNT in vitro test battery consists primarily of human cell-based assays because of their immediate relevance to human health. However, such cell-based assays alone are unable to capture the complexity of a developing nervous system. Whole organismal systems that qualify as 3 R (Replace, Reduce and Refine) models are urgently needed to complement cell-based DNT testing. These models can provide the necessary organismal context and be used to explore the impact of chemicals on brain function by linking molecular and/or cellular changes to behavioural readouts. The nematode Caenorhabditis elegans, the planarian Dugesia japonica, and embryos of the zebrafish Danio rerio are all suited to low-cost HTS and each has unique strengths for DNT testing. Here, we review the strengths and the complementarity of these organisms in a novel, integrative context and highlight how they can augment current cell-based assays for more comprehensive and robust DNT screening of chemicals. Considering the limitations of all in vitro test systems, we discuss how a smart combinatory use of these systems will contribute to a better human relevant risk assessment of chemicals that considers the complexity of the developing brain.

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来源期刊
Neurotoxicology
Neurotoxicology 医学-毒理学
CiteScore
6.80
自引率
5.90%
发文量
161
审稿时长
70 days
期刊介绍: NeuroToxicology specializes in publishing the best peer-reviewed original research papers dealing with the effects of toxic substances on the nervous system of humans and experimental animals of all ages. The Journal emphasizes papers dealing with the neurotoxic effects of environmentally significant chemical hazards, manufactured drugs and naturally occurring compounds.
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