典型有机磷酸酯阻燃剂的血管发育毒性及细胞毒作用机制研究

有机磷酸酯阻燃剂（OPFRs）的环境负荷逐年加重。发育毒性是OPFRs的主要健康危害，但其靶效应特征和细胞内毒作用过程尚未阐明，仍缺乏表征早期暴露的敏感生物标志物。本研究将从血管系统角度探讨环境中典型OPFRs的发育毒性。采用特异性标记斑马鱼模型观察OPFRs暴露对血管发育的影响，分析不同类型血管对OPFRs毒作用反应的相似性和异质性,建立血管发育毒性的剂量（时间）-效应关系。通过高内涵分析技术在单一细胞水平同时观测OPFRs对血管细胞的形态、功能、亚细胞结构、内平衡稳态等损害效应特征，解析效应关联性，建立多参数细胞毒作用剂量-效应关系；结合siRNA文库筛选和转基因斑马鱼模型深入研究OPFRs对血管的直接损伤和小胶质细胞介导的炎症机制，确认关键分子事件、毒性通路及主要毒作用靶点。为阐明典型OPFRs的发育毒性机制、识别敏感生物标志物以及开展环境风险评价提供重要依据和崭新思路。

The growing production and extensive use of organophosphate flame retardants (OPFRs) have led to an increase in their environmental distribution and human exposure. Developmental toxicity is a major concern of OPFRs' adverse health effects. However, the target effect of OPFRs on development and its intracellular modes of action are poorly understood. The sensitive biomarkers for early exposure are still needed for the environmental risk assessment. The project is to investigate the developmental toxicity of typical OPFRs in environment, based on the adverse effect on vascular system. Vascular development will be observed in an flk1-specific transgenic zebrafish, focusing on the similarity and hereogeneity of vascular response to OPFRs exposure. As a result, the dose- or time-effect relationship will be established. Using a high-content analysis approach, we will simultaneously observe the cellular effects of OPFRs, including the morphological and functional changes, disruption of subcellular structure, and disturbance of homeostasis. In addition, the correlation of effects will be analyzed and a multiple-parameter dos-effect relationship will be established using the in vitro data. To identify the key molecular events, toxicity pathways and the major targets, we will apply a siRNA screening in combined with the transgenic zebrafish model to demonstrate the direct and inflammation-mediating mechanisms underlying the vascular damage. This project will help to elucidate the mode of action and identify the biomarkers, which will provide new insight into the environmental risk assessment of OPFRs.