U.S. Environmental Protection Agency, Office of Research and Development, Center for Computational Toxicology and Exposure, United States.
Leidos, United States.
Reprod Toxicol. 2020 Sep;96:300-315. doi: 10.1016/j.reprotox.2020.06.010. Epub 2020 Jun 24.
Development of the neurovascular unit (NVU) is a complex, multistage process that requires orchestrated cell signaling mechanisms across several cell types and ultimately results in formation of the blood-brain barrier. Typical high-throughput screening (HTS) assays investigate single biochemical or single cell responses following chemical insult. As the NVU comprises multiple cell types interacting at various stages of development, a methodology combining high-throughput results across pertinent cell-based assays is needed to investigate potential chemical-induced disruption to the development of this complex cell system. To this end, we implemented a novel method for screening putative NVU disruptors across diverse assay platforms to predict chemical perturbation of the developing NVU. HTS assay results measuring chemical-induced perturbations to cellular key events across angiogenic and neurogenic outcomes in vitro were combined to create a cell-based prioritization of NVU hazard. Chemicals were grouped according to similar modes of action to train a logistic regression literature model on a training set of 38 chemicals. This model utilizes the chemical-specific pairwise mutual information score for PubMed MeSH annotations to represent a quantitative measure of previously published results. Taken together, this study presents a methodology to investigate NVU developmental hazard using cell-based HTS assays and literature evidence to prioritize screening of putative NVU disruptors towards a knowledge-driven characterization of neurovascular developmental toxicity. The results from these screening efforts demonstrate that chemicals representing a range of putative vascular disrupting compound (pVDC) scores can also produce effects on neurogenic outcomes and characterizes possible modes of action for disrupting the developing NVU.
神经血管单元 (NVU) 的发育是一个复杂的多阶段过程，需要协调几种细胞类型的细胞信号机制，最终导致血脑屏障的形成。典型的高通量筛选 (HTS) 检测方法研究化学损伤后单个生化或单个细胞的反应。由于 NVU 由多种细胞类型组成，这些细胞在不同的发育阶段相互作用，因此需要一种将高通量结果与相关基于细胞的检测相结合的方法，以研究潜在的化学物质对这个复杂细胞系统发育的干扰。为此，我们实施了一种新的方法，在多种检测平台上筛选潜在的 NVU 破坏剂，以预测化学物质对发育中的 NVU 的干扰。测量化学物质对体外血管生成和神经发生结果中细胞关键事件的诱导干扰的 HTS 检测结果被组合在一起，以基于细胞的方式对 NVU 危害进行优先级排序。根据类似的作用模式对化学品进行分组，以便在 38 种化学品的训练集上训练逻辑回归文献模型。该模型利用化学特异性两两互信息得分来表示 Pubmed MeSH 注释的定量度量，以表示先前发表结果的定量度量。总的来说，这项研究提出了一种使用基于细胞的 HTS 检测和文献证据来研究 NVU 发育危害的方法，以优先筛选潜在的 NVU 破坏剂，从而实现对神经血管发育毒性的知识驱动特征描述。这些筛选工作的结果表明，代表一系列潜在血管破坏化合物 (pVDC) 评分的化学品也可能对神经发生结果产生影响，并描述了破坏发育中的 NVU 的可能作用模式。
