Cell Biology and Toxicology ( IF 5.3 ) Pub Date : 2022-06-15 , DOI: 10.1007/s10565-022-09730-4 Jördis Klose 1 , Lu Li 2, 3, 4, 5 , Melanie Pahl 1 , Farina Bendt 1 , Ulrike Hübenthal 1 , Christian Jüngst 6 , Patrick Petzsch 7 , Astrid Schauss 6 , Karl Köhrer 7 , Ping Chung Leung 4 , Chi Chiu Wang 3, 8, 9 , Katharina Koch 1 , Julia Tigges 1 , Xiaohui Fan 2, 5 , Ellen Fritsche 1, 9, 10
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Adverse outcome pathways (AOPs) are organized sequences of key events (KEs) that are triggered by a xenobiotic-induced molecular initiating event (MIE) and summit in an adverse outcome (AO) relevant to human or ecological health. The AOP framework causally connects toxicological mechanistic information with apical endpoints for application in regulatory sciences. AOPs are very useful to link endophenotypic, cellular endpoints in vitro to adverse health effects in vivo. In the field of in vitro developmental neurotoxicity (DNT), such cellular endpoints can be assessed using the human “Neurosphere Assay,” which depicts different endophenotypes for a broad variety of neurodevelopmental KEs. Combining this model with large-scale transcriptomics, we evaluated DNT hazards of two selected Chinese herbal medicines (CHMs) Lei Gong Teng (LGT) and Tian Ma (TM), and provided further insight into their modes-of-action (MoA). LGT disrupted hNPC migration eliciting an exceptional migration endophenotype. Time-lapse microscopy and intervention studies indicated that LGT disturbs laminin-dependent cell adhesion. TM impaired oligodendrocyte differentiation in human but not rat NPCs and activated a gene expression network related to oxidative stress. The LGT results supported a previously published AOP on radial glia cell adhesion due to interference with integrin-laminin binding, while the results of TM exposure were incorporated into a novel putative, stressor-based AOP. This study demonstrates that the combination of phenotypic and transcriptomic analyses is a powerful tool to elucidate compounds’ MoA and incorporate the results into novel or existing AOPs for a better perception of the DNT hazard in a regulatory context.
Graphical abstract
中文翻译：
不良后果通路概念在体外人神经祖细胞研究中草药发育神经毒性潜力中的应用
不良结果途径 (AOP) 是由异源物诱导的分子引发事件 (MIE) 触发的关键事件 (KE) 的有组织序列，并在与人类或生态健康相关的不良结果 (AO) 中达到顶峰。AOP 框架将毒理学机制信息与顶端终点因果联系起来，用于监管科学。AOP 对于将体外的内表型细胞终点与体内的不良健康影响联系起来非常有用。在体外发育神经毒性 (DNT) 领域，可以使用人类“神经球分析”评估此类细胞终点，该方法描述了各种神经发育 KE 的不同内表型。将该模型与大规模转录组学相结合，我们评估了两种选定的中草药 (CHM) 雷公藤 (LGT) 和天麻 (TM) 的 DNT 危害，并进一步了解了它们的作用方式 (MoA)。LGT 扰乱了 hNPC 迁移，引发了异常的迁移内表型。延时显微镜和干预研究表明，LGT 会干扰层粘连蛋白依赖性细胞粘附。TM 损害了人类而非大鼠 NPC 的少突胶质细胞分化，并激活了与氧化应激相关的基因表达网络。LGT 结果支持先前发表的关于由于干扰整合素-层粘连蛋白结合而导致的放射状神经胶质细胞粘附的 AOP，而 TM 暴露的结果被纳入一个新的推定的、基于应激源的 AOP。
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