Department of Biomedical Sciences, University of Lausanne, Rue du Bugnon 7, 1005 Lausanne, Switzerland; Swiss Centre for Applied Human Toxicology (SCAHT), University of Basel, Missionsstrasse 64, 4055 Basel, Switzerland.
Edelweiss Connect GmbH, Technology Park Basel, Hochbergerstrasse 60C, 4057 Basel, Switzerland; Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Toxicol In Vitro. 2022 Jun;81:105333. doi: 10.1016/j.tiv.2022.105333. Epub 2022 Feb 16.
Most OECD guidelines for chemical risk assessment include tests performed on animals, raising financial, ethical and scientific concerns. Thus, the development of human-based models for toxicity testing is highly encouraged. Here, we propose an in vitro multi-organ strategy to assess the toxicity of chemicals. Human induced pluripotent stem cells (hiPSCs)-derived models of the brain, blood-brain barrier, kidney, liver and vasculature were generated and exposed to paraquat (PQ), a widely employed herbicide with known toxic effects in kidneys and brain. The models showed differential cytotoxic sensitivity to PQ after acute exposure. TempO-Seq analysis with a set of 3565 probes revealed the deregulation of oxidative stress, unfolded protein response and estrogen receptor-mediated signaling pathways, in line with the existing knowledge on PQ mechanisms of action. The main advantages of this strategy are to assess chemical toxicity on multiple tissues/organs in parallel, exclusively in human cells, eliminating the interspecies bias, allowing a better evaluation of the differential sensitivity of the models representing the diverse organs, and increasing the chance to identify toxic compounds. Furthermore, although we focused on the mechanisms of action of PQ shared by the different models, this strategy would also allow for organ-specific toxicity testing, by including more cell type-specific probes for TempO-Seq analyses. In conclusion, we believe this strategy will participate in the further improvement of chemical risk assessment for human health.
大多数经合组织化学风险评估指南都包括在动物身上进行的测试，这引发了财务、伦理和科学方面的担忧。因此，人们强烈鼓励开发基于人体的毒性测试模型。在这里，我们提出了一种体外多器官策略来评估化学品的毒性。我们生成了源自人诱导多能干细胞（hiPSC）的大脑、血脑屏障、肾脏、肝脏和血管模型，并将其暴露于百草枯（PQ）中，PQ 是一种广泛使用的除草剂，已知对肾脏和大脑有毒性作用。这些模型在急性暴露后对 PQ 的细胞毒性敏感性表现出差异。使用一组 3565 个探针的 TempO-Seq 分析显示，氧化应激、未折叠蛋白反应和雌激素受体介导的信号通路失调，与 PQ 作用机制的现有知识一致。该策略的主要优势在于能够并行评估多种组织/器官的化学毒性，仅使用人类细胞，消除种间偏差，更好地评估代表不同器官的模型的差异敏感性，并增加识别有毒化合物的机会。此外，尽管我们专注于不同模型共有的 PQ 作用机制，但通过在 TempO-Seq 分析中包含更多针对特定细胞类型的探针，该策略还可以允许进行针对特定器官的毒性测试。总之，我们相信该策略将有助于进一步改善人类健康的化学风险评估。
