Guan Haibin, Chen Jia, Kaur Kirtan, Amreen Bushra, Lesseur Corina, Dolios Georgia, Andra Syam S, Narasimhan Srinivasan, Pulivarthi Divya, Midya Vishal, De Witte Lotje D, Bergink Veerle, Rommel Anna-Sophie, Petrick Lauren M
bioRxiv. 2024 Dec 17:2024.12.16.628663. doi: 10.1101/2024.12.16.628663.
We previously found that per- and polyfluoroalkyl substances (PFAS) mixture exposure is inversely associated with SARS-CoV-2 IgG (IgG) antibody levels in pregnant individuals. Here, we aim to identify metabolites mediating this relationship to elucidate the underlying biological pathways.
We included 59 pregnant participants from a US-based pregnancy cohort. Untargeted metabolomic profiling was performed using Liquid Chromatography-High Resolution Sass spectrometry (LC-HRMS), and weighted Quantile Sum (WQS) regression was applied to assess the PFAS and metabolites mixture effects on IgG. Metabolite indices positively or negatively associated with IgG levels were constructed separately and their mediation effects were examined independently and jointly.
The PFAS-index was negatively associated with IgG levels (beta=-0.273, p=0.002), with PFHpS and PFHxS as major contributors. Two metabolite-indices were constructed, one positively (beta=1.260, p<0.001) and one negatively (beta=-0.997, p<0.001) associated with IgG. Key contributors for these indices included protoporphyrin, 5-hydroxytryptophan, n-acetylproline, and tyrosine. Analysis of single mediator showed that 48.9% (95%CI: 21.9%,125.0%) and 50.1% (95% CI: 8.1%, 90.1%) of the PFAS index-IgG total effect were mediated by the negative and positive metabolite-indices, respectively. Joint analysis of the metabolite-indices indicated a cumulative mediation effect of 73.6% (95%CI: 44.9%, 116.4%). Enriched pathways associated with these metabolites indices were phenylalanine, tyrosine, and tryptophan biosynthesis and arginine metabolism.
We observed significant mediation effects of plasma metabolites on the PFAS-IgG relationship, suggesting that PFAS disrupts the balance of plasma metabolites that contributes to reduced plasma IgG production.
我们之前发现，全氟和多氟烷基物质（PFAS）混合物暴露与孕妇体内的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）IgG抗体水平呈负相关。在此，我们旨在确定介导这种关系的代谢物，以阐明潜在的生物学途径。
我们纳入了来自美国一个妊娠队列的59名孕妇参与者。使用液相色谱-高分辨率质谱（LC-HRMS）进行非靶向代谢组学分析，并应用加权分位数和（WQS）回归来评估PFAS和代谢物混合物对IgG的影响。分别构建与IgG水平呈正相关或负相关的代谢物指数，并独立和联合检验它们的中介效应。
PFAS指数与IgG水平呈负相关（β=-0.273，p=0.002），主要贡献者为全氟庚烷磺酸（PFHpS）和全氟己烷磺酸（PFHxS）。构建了两个代谢物指数，一个与IgG呈正相关（β=1.260，p<0.001），另一个与IgG呈负相关（β=-0.997，p<0.001）。这些指数的关键贡献者包括原卟啉、5-羟色氨酸、N-乙酰脯氨酸和酪氨酸。单一中介分析表明，PFAS指数与IgG的总效应中，分别有48.9%（95%CI：21.9%，125.0%）和50.1%（95%CI：8.1%，90.1%）由负性和正性代谢物指数介导。代谢物指数的联合分析表明累积中介效应为73.6%（95%CI：44.9%，116.4%）。与这些代谢物指数相关的富集途径是苯丙氨酸、酪氨酸和色氨酸的生物合成以及精氨酸代谢。
我们观察到血浆代谢物对PFAS与IgG关系有显著的中介作用，这表明PFAS破坏了血浆代谢物的平衡，导致血浆IgG产生减少。
