Chen Yiran, Lv Jiayun, Fu Lei, Wu Yan, Zhou Si, Liu Shiwei, Zheng Linjie, Feng Wenru, Zhang Lin
Guangzhou Center for Disease Control and Prevention, Guangzhou 510440, China; Institute of Public Health, Guangzhou Medical University & Guangzhou Center for Disease Control and Prevention, Guangzhou 510440, China.
School of Public Health, China Medical University, Shenyang 110122, China.
Environ Int. 2023 Mar;173:107817. doi: 10.1016/j.envint.2023.107817. Epub 2023 Feb 13.
Environmental exposure increases the risk of dyslipidemia, which affects human health. Research has shown that persistent organic pollutants (POPs), including per- and polyfluoroalkyl substances (PFASs), polychlorinated biphenyls, polybrominated diphenyl ethers, and phthalate metabolites, are associated with a higher risk of abnormal blood lipid levels in humans. However, the key molecules involved in dyslipidemia and the mechanisms are not fully understood. This study aims to investigate the biomarkers that mediate the relationships between blood lipids and four groups of POPs and revealed their potential mechanisms. Specifically, in 278 male blood samples, blood lipid and POPs levels were measured and metabolites were detected using untargeted metabolomics. Spearman's correlation analysis and binary logistic regression were employed to assess the relationship between POPs and lipid indexes. We observed that PFASs were associated with a higher risk of abnormal total cholesterol (TC) and low-density lipoprotein (LDL), while other POPs displayed little association with abnormal lipid indexes. Among all the PFASs, 6:2Cl-PFESA was associated with the fewest metabolites. A metabolome-wide association study combined with a meet-in-the-middle approach was used to identify potential biomarkers that mediate the association between POPs and abnormal blood lipids. The mediation analysis pointed to 105 significant mediators as potential biomarkers mediating the association between PFASs and TC, and 82 significant mediators were potential biomarkers that mediated the association between PFASs and LDL. 24-Hydroxycholesterol, 3alpha,7alpha-dihydroxy-5beta-cholestan-26-al, PC(18:0/0:0), PC(22:5/0:0), GPCho(18:1/18:1), LysoPC(22:2(13Z,16Z)), LysoPC(16:0), 9(S)-HODE, 9,10-DHOME, l-glutamate, 4-hydroxybutyric acid, cytosine, PC(14:1(9Z)/18:0), sphinganine, and (S)-beta-aminoisobutyrate were identified as important biomarkers. The mechanism may mainly involves glycerophospholipid metabolism, primary bile acid biosynthesis, and linoleic acid metabolism. PPARγ likely plays a role in the associations between PFASs and abnormal cholesterol metabolism. Overall, our study provides clues for the early detection of PFAS-induced dyslipidemia and brings forth a theoretical framework for further research into this mechanism.
环境暴露会增加血脂异常的风险，而血脂异常会影响人类健康。研究表明，持久性有机污染物（POPs），包括全氟和多氟烷基物质（PFASs）、多氯联苯、多溴二苯醚和邻苯二甲酸酯代谢物，与人类血脂异常水平较高的风险相关。然而，参与血脂异常的关键分子及其机制尚未完全明确。本研究旨在探究介导血脂与四类POPs之间关系的生物标志物，并揭示其潜在机制。具体而言，在278份男性血液样本中，检测血脂和POPs水平，并使用非靶向代谢组学检测代谢物。采用Spearman相关性分析和二元逻辑回归评估POPs与血脂指标之间的关系。我们观察到，PFASs与总胆固醇（TC）和低密度脂蛋白（LDL）异常风险较高相关，而其他POPs与血脂异常指标几乎没有关联。在所有PFASs中，6:2Cl-PFESA与最少的代谢物相关。采用全代谢组关联研究结合中间相遇法来识别介导POPs与血脂异常之间关联的潜在生物标志物。中介分析指出，105种显著的中介物是介导PFASs与TC之间关联的潜在生物标志物，82种显著的中介物是介导PFASs与LDL之间关联的潜在生物标志物。24-羟基胆固醇、3α,7α-二羟基-5β-胆甾烷-26-醛、PC(18:0/0:0)、PC(22:5/0:0)、GPCho(18:1/18:1)、LysoPC(22:2(13Z,16Z))、LysoPC(16:0)、9(S)-羟基十八碳二烯酸、9,10-二羟基十八碳二烯酸、L-谷氨酸、4-羟基丁酸、胞嘧啶、PC(14:1(9Z)/18:0)、鞘氨醇和(S)-β-氨基异丁酸被确定为重要的生物标志物。其机制可能主要涉及甘油磷脂代谢、初级胆汁酸生物合成和亚油酸代谢。PPARγ可能在PFASs与异常胆固醇代谢之间的关联中起作用。总体而言，我们的研究为早期检测PFASs诱导的血脂异常提供了线索，并为进一步研究该机制提出了理论框架。
