Duke University, Durham, NC, USA.
Division of Translational Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
ALTEX. 2024;41(4):617-632. doi: 10.14573/altex.2403211. Epub 2024 Jul 8.
Dysregulation of vascular endothelial growth factor (VEGF) and its receptor (VEGFR) contributes to atherosclerosis and cardiovascular disease (CVD), making it a potential target for CVD risk assessment. High-throughput screening (HTS) approaches have resulted in large-scale in vitro data, providing mechanistic information that can help assess chemical toxicity and identify molecular initiating events (MIEs) of adverse outcome pathways (AOPs). AOPs represent a logical sequence of biological responses contributing to toxicity and are valuable tools to inform chemical risk assessment. Here, we used HTS data to formulate an AOP relating VEGF signaling perturbation to atherosclerosis. ToxCast, Tox21, and PubChem data were evaluated to obtain bioprofiles of 4165 compounds active in assays targeting VEGFR. Cheminformatics analysis identified 109 enriched structural fingerprints. Applying a subspace clustering approach based on chemical structure bioactivity yielded 12 primary targets, whose relevance to CVD was confirmed by an AI-assisted literature review. An AOP was hypothesized by coupling mechanistic relationships highlighted by HTS data with literature review findings, linking serotonin receptor (HTR), estrogen receptor alpha (ERα), and vasopressin receptor (AVPR) targets with VEGFR activity, angiogenic signaling, and atherosclerosis. Several endocrine disrupting chemicals (EDCs), e.g., bisphenols, triclosan, dichlorodiphenyltrichloroethane (DDT), and polychlorinated biphenyls (PCBs), were identified as relevant chemical stressors. Subspace clustering of these chemicals evaluated potential MIEs and highlighted associations with use case classes. By applying computational methods to profile HTS data and hypothesize a mechanistic AOP, this study proposes a data-driven approach to evaluating environmental cardiotoxicity, which could eventually supplement and reduce the need for animal testing in toxicological assessments.
血管内皮生长因子 (VEGF)及其受体 (VEGFR) 的失调导致动脉粥样硬化和心血管疾病 (CVD)，使其成为 CVD 风险评估的潜在靶点。高通量筛选 (HTS) 方法产生了大量的体外数据，提供了有助于评估化学毒性和识别不良结局途径 (AOP)分子起始事件 (MIE)的机制信息。AOP 代表了导致毒性的一系列逻辑生物反应，是告知化学风险评估的有价值工具。在这里，我们使用 HTS 数据来制定一个与 VEGF 信号转导扰动相关的动脉粥样硬化 AOP。评估了 ToxCast、Tox21 和 PubChem 数据，以获得 4165 种针对 VEGFR 的活性化合物的生物谱。计算化学分析确定了 109 个富集的结构指纹。应用基于化学结构生物活性的子空间聚类方法得到 12 个主要靶点，通过 AI 辅助文献综述证实了这些靶点与 CVD 的相关性。通过将 HTS 数据突出显示的机制关系与文献综述结果相结合，假设了一个 AOP，将 5-羟色胺受体 (HTR)、雌激素受体 alpha (ERα)和血管加压素受体 (AVPR) 与 VEGFR 活性、血管生成信号和动脉粥样硬化联系起来。几种内分泌干扰化学物质 (EDCs)，如双酚类、三氯生、滴滴涕 (DDT)和多氯联苯 (PCBs)，被确定为相关的化学应激物。这些化学物质的子空间聚类评估了潜在的 MIE，并强调了与用例类别的关联。通过应用计算方法对 HTS 数据进行分析并假设一个机制 AOP，本研究提出了一种基于数据的评估环境心脏毒性的方法，这最终可能会补充和减少毒理学评估中对动物测试的需求。
