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，从而影响人类健康。研究表明，持久性有机污染物 (POP)，包括全氟烷基物质和多氟烷基物质 (PFAS)、多氯联苯、多溴联苯醚和邻苯二甲酸酯代谢物，与人类血脂水平异常的较高风险有关。然而，参与血脂异常的关键分子及其机制尚不完全清楚。本研究旨在探讨介导血脂与四组持久性有机污染物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，测量了血脂和持久性有机污染物水平，并使用非靶向代谢组学检测了代谢物。采用 Spearman 相关分析和二元 logistic 回归评估 POPs 与脂质指标之间的关系。我们观察到，PFAS 与总胆固醇 (TC) 和低密度脂蛋白 (LDL) 异常的风险较高有关，而其他持久性有机污染物与脂质指数异常几乎没有关联。在所有 PFAS 中，6:2Cl-PFESA 与最少的代谢物相关。代谢组范围的关联研究与中间相遇方法相结合，用于鉴定介导持久性有机污染物与异常血脂之间关联的潜在生物标志物。中介分析指出 105 种重要介质作为潜在生物标志物介导 PFAS 和 TC 之间的关联，82 种重要介质是潜在生物标志物介导 PFAS 和 LDL 之间的关联。l-谷氨酸、4-羟基丁酸、胞嘧啶、PC(14:1(9Z)/18:0)、二氢鞘氨醇和 (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 PFAS 与异常胆固醇代谢之间的关联中发挥作用。总的来说，我们的研究为早期发现 PFAS 引起的血脂异常提供了线索，并为进一步研究该机制提供了理论框架。