文献类型：期刊文献

英文题名：From Exposome-Scale Screening to Foam Cell Formation: Identifying Environmental Chemicals with Atherogenic Potential via Nuclear Receptor Perturbation

作者：Shen, Xinming[1,2];Zhen, Huajun[2,3];Xu, Cheng[2];Li, Yatai[1];Deng, Qihong[1]

机构：[1]Zhengzhou Univ, Coll Publ Hlth, Zhengzhou 450001, Peoples R China;[2]Peking Univ, Coll Urban & Environm Sci, Lab Earth Surface Proc, Beijing 100871, Peoples R China;[3]East China Univ Sci & Technol, Sch Resources & Environm Engn, State Environm Protect Key Lab Environm Risk Asses, Shanghai 200237, Peoples R China

年份：2026

卷号：60

期号：31

起止页码：21596

外文期刊名：ENVIRONMENTAL SCIENCE & TECHNOLOGY

收录：;EI(收录号：20263321310353);Scopus(收录号：2-s2.0-105046868968);WOS:【SCI-EXPANDED(收录号:WOS:001834472600001)】；

基金：The authors gratefully acknowledge financial support from the National Natural Science Foundation of China (Grants 22406173 and 42407574) and the Startup Fund of Zhengzhou University (Grant 35220725). This work was also supported by the Open Fund of the Laboratory for Earth Surface Processes, Ministry of Education, Peking University.

语种：英文

外文关键词：priority screening; nuclear receptor; foamcell; atherosclerosis

摘要：Cardiovascular diseases driven by atherosclerosis are a leading global cause of mortality. However, currently identified risk chemicals account for only a small fraction of the environmental chemical burden contributing to atherosclerosis. To address this gap, we established a multi-source prioritization framework to identify pro-atherogenic chemicals among 6346 exogenous compounds predicted in human blood. The framework integrates bioactivity data for atherosclerosis-relevant nuclear receptors, including peroxisome proliferator-activated receptor gamma (PPAR gamma), liver X receptor alpha (LXR alpha), farnesoid X receptor (FXR), and pregnane X receptor (PXR), with physicochemical properties and predicted blood concentrations of the compounds. Experimental validation identified eight chemicals with specific nuclear receptor modulating activity. Notably, six of these chemicals significantly promoted macrophage foam cell formation, a hallmark and initiating event in atherosclerosis. Mechanistic investigations demonstrated that antagonists of PPAR gamma and/or LXR alpha, including tetrabromobisphenol A bis(2-hydroxyethyl) ether (TBBPA-BHEE), 3,5-dichlorosalicyl-3,4-dichloroanilide (TCSA), 4,4 ',4 ''-ethane-1,1,1-triyltriphenol (THPE), and lopinavir, disrupted cholesterol homeostasis, potentially through inhibition of LXR alpha-mediated efflux. In parallel, PXR agonists, 2,2 ',6,6 '-tetrachlorobisphenol A (TCBPA) and 4,4 '-methylenebis(2,6-diethylaniline) (MDEA), promoted lipid accumulation by enhancing cholesterol uptake. This study provides a mechanistically anchored, high-throughput strategy for identifying potential environmental contributors to cardiovascular disease, revealing previously unrecognized pro-atherogenic chemicals and their molecular mechanisms.