双酚类化合物(BPs)的毒性效应及分子机制是毒理学的研究热点。BPA暴露显著促进动脉粥样硬化，然而其新型替代品BPS和BPAF对动脉粥样硬化的毒性效应不明确，BPs促进动脉粥样硬化早期形成的分子机制不清楚。申请人前期发现BPs暴露内皮细胞导致表达谱发生较大变化，其中重要核转录因子egr3显著上调，染色质开放性增强并预测受到雌激素受体(ER)调控。已知BPs可与ER结合调控靶基因转录，因此提出BPs通过ER/EGR3通路导致内皮细胞功能紊乱并促进动脉粥样硬化早期形成的假说。本项目拟利用小鼠和离体内皮细胞模型，研究环境剂量的BPs对动脉粥样硬化的长期暴露风险，识别BPs通过ER对egr3的转录调控网络，从而揭示BPs影响内皮细胞功能并导致动脉粥样硬化早期形成的分子致毒机制。该项目的实施不仅可为BPS/BPAF的健康风险评价提供毒理数据，同时也为认识BPs导致动脉粥样硬化的机制研究提供理论依据。

The toxicity and the underlying molecular mechanism of bisphenols (BPs) has been a researching focus in toxicology of environment. Studies showed that bisphenol A (BPA) exposure could accelerate atherosclerosis (ATH), however, it is unclear that the potential risk of the new alternatives BPS and BPAF to ATH, and the underlying early pathogenic mechanism of BPs in the process of ATH. Our preliminary data showed that BPs exposure resulted in significant changes of gene expression profile, among which an important nuclear transcription factor egr3 was obviously increased, and chromatin openness was promoted and was predicted to be regulated by estrogen receptor (ER). It is known that BPs could bind to ER and regulate the target gene transcription. Therefore, we proposed that BPs could lead to endothelial cell dysfunction by regulating egr3 signaling via biding to ER and then accelerate the early process of ATH. This project will use ATH mole mice and in vitro endothelial cell, to study the chronic exposure risk of environmental concentrations of BPA and BPS/BPAF on ATH, to explore the transcriptional mechanism of egr3 regulated by BPs via ER, and then to reveal the molecular mechanism of endothelial cell dysfunction and ATH early process induced by BPs. These findings will provide toxicological data for BPS/BPAF health risk assessment, as well as theory basis for the molecular mechanism of ATH induced by BPs.