State Key Laboratory of Environmental Chemistry and Eco-Toxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China.
Chem Res Toxicol. 2022 Jun 20;35(6):1023-1035. doi: 10.1021/acs.chemrestox.2c00043. Epub 2022 May 16.
2,2',4,4'-Tetrabromodiphenyl ether (PBDE 47) is one of the most prominent PBDE congeners detected in the human body, suggesting that the potential health risks of PBDE 47 should be thoroughly considered. However, the cardiovascular toxicity of PBDE 47 remains poorly understood. Here, toxic outcomes of PBDE 47 in human THP-1 macrophages concerning foam cell formation, which play crucial roles in the occurrence and development of atherosclerosis, were elucidated. First, our results indicated that PBDE 47 affected the PPARγ pathway most efficiently in THP-1 macrophages by transcriptomic analysis. Second, the PPARγ target genes and , responsible for lipid uptake and accumulation in macrophages, were consistently upregulated both at transcriptional and translational levels in THP-1 macrophages upon PBDE 47. Unexpectedly, PBDE 47 failed to activate the PPARγ target gene and PPARγ-LXRα-ABCA1/G1 cascade, which is activated by the PPARγ full agonist rosiglitazone and enables cholesterol efflux in macrophages. Thus, coincident with the selective upregulation of the PPARγ target genes and , PBDE 47, distinct from rosiglitazone, functionally resulted in more lipid accumulation and oxLDL uptake in THP-1 macrophages through high-content analysis (HCA). Moreover, these effects were markedly abrogated by the addition of the PPARγ antagonist T0070907. Mechanistically, the structural basis of selective activation of PPARγ by PBDE 47 was explored by molecular docking and dynamics simulation, which indicated that PBDE 47 interacted with the PPARγ ligand binding domain (PPARγ-LBD) distinctively from that of rosiglitazone. PBDE 47 was revealed to interact with helix 3 and helix 5 but not helix 12 in the PPARγ-LBD. Collectively, these results unraveled the potential cardiovascular toxicity of PBDE 47 by selective activation of PPARγ to facilitate foam cell formation for the first time.
2,2',4,4'-四溴二苯醚 (PBDE 47) 是人体内检测到的最主要的多溴二苯醚同系物之一，这表明 PBDE 47 可能存在健康风险，需要进行深入研究。然而，目前人们对 PBDE 47 的心血管毒性知之甚少。本研究旨在探讨 PBDE 47 对人类 THP-1 巨噬细胞泡沫细胞形成的毒性作用，因为泡沫细胞在动脉粥样硬化的发生和发展中起着关键作用。首先，通过转录组分析，我们的研究结果表明 PBDE 47 对 THP-1 巨噬细胞中的过氧化物酶体增殖物激活受体γ (PPARγ) 途径影响最大。其次，PPARγ 靶基因 和 ，负责巨噬细胞中的脂质摄取和积累，在 PBDE 47 作用下，无论是在转录水平还是翻译水平，在 THP-1 巨噬细胞中均持续上调。出乎意料的是，PBDE 47 未能激活 PPARγ 靶基因 和 PPARγ-LXRα-ABCA1/G1 级联反应，而该级联反应由 PPARγ 完全激动剂罗格列酮激活，并使巨噬细胞中的胆固醇流出。因此，与 PPARγ 靶基因 和 的选择性上调一致，PBDE 47 与罗格列酮不同，通过高内涵分析 (HCA) ，在 THP-1 巨噬细胞中导致更多的脂质积累和 oxLDL 摄取。此外，这些作用通过添加 PPARγ 拮抗剂 T0070907 明显被阻断。在机制上，通过分子对接和动力学模拟探索了 PBDE 47 选择性激活 PPARγ 的结构基础，结果表明 PBDE 47 与罗格列酮在 PPARγ 配体结合域 (PPARγ-LBD) 上的结合方式明显不同。PBDE 47 与 PPARγ-LBD 中的螺旋 3 和螺旋 5 相互作用，但不与螺旋 12 相互作用。综上所述，本研究首次揭示了 PBDE 47 通过选择性激活 PPARγ 促进泡沫细胞形成，从而产生潜在的心血管毒性。
