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

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 γ (PPARγ), liver X receptor α (LXRα), 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 PPARγ and/or LXRα, 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 LXRα-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.