Systems modeling of developmental vascular toxicity

More than 80,000 chemicals in commerce present a challenge for hazard assessments that toxicity testing in the 21st century strives to address through high-throughput screening (HTS) assays. Assessing chemical effects on human development adds an additional layer of complexity to the screening, with a need to capture complex and dynamic events essential for proper embryo-fetal development. HTS data from ToxCast/Tox21 informs systems toxicology models, which incorporate molecular targets and biological pathways into mechanistic models describing the effects of chemicals on human cells, 3D organotypic culture models, and small model organisms. Adverse Outcome Pathways (AOPs) provide a useful framework for integrating the evidence derived from these in silico and in vitro systems to inform chemical hazard characterization. To illustrate this formulation, we have built an AOP for developmental toxicity through a mode of action linked to embryonic vascular disruption (Aop43). Here, we review the model for quantitative prediction of developmental vascular toxicity from ToxCast HTS data and compare the HTS results to functional vascular development assays in complex cell systems, virtual tissues, and small model organisms. ToxCast HTS predictions from several published and unpublished assays covering different aspects of the angiogenic cycle were generated for a test set of 38 chemicals representing a range of putative vascular disrupting compounds (pVDCs). Results boost confidence in the capacity to predict adverse developmental outcomes from HTS in vitro data and model computational dynamics for in silico reconstruction of developmental systems biology. Finally, we demonstrate the integration of the AOP and developmental systems toxicology to investigate the unique modes of action of two angiogenesis inhibitors.当前商用化学品已超80000种，给危险评估工作带来了极大挑战，而21世纪的毒性检测正通过高通量筛选 (high-throughput screening, HTS) 实验致力解决这一难题。评估化学品对人类发育的影响则为该筛选流程平添了额外复杂度，因需捕捉保障胚胎-胎儿正常发育所必需的复杂动态事件。ToxCast/Tox21产生的HTS数据可为系统毒理学模型提供支撑，这类模型将分子靶点与生物通路整合入机制模型，用以刻画化学品对人类细胞、3D器官型培养模型及小型模式生物的影响。不良结局途径 (Adverse Outcome Pathways, AOPs) 为整合上述计算机模拟 (in silico) 与体外系统所得证据、支撑化学品危险表征工作提供了实用框架。为阐明该构建思路，我们针对与胚胎血管破坏相关的作用模式，构建了发育毒性相关的AOP (Aop43)。本文综述了基于ToxCast HTS数据定量预测发育性血管毒性的模型，并将HTS结果与复杂细胞系统、虚拟组织及小型模式生物中的功能性血管发育实验结果进行了对比。我们针对涵盖血管生成周期不同维度的38种推定血管破坏化合物 (putative vascular disrupting compounds, pVDCs) 测试集，生成了来自多项已发表及未发表实验的ToxCast HTS预测结果。该研究结果增强了我们依托HTS体外数据预测不良发育结局的信心，同时也为发育系统生物学的计算机模拟重建提供了动力学模型参考。最后，我们展示了如何整合AOP与发育系统毒理学，以探究两种血管生成抑制剂的独特作用模式。