Background

Per- and polyfluoroalkyl substances (PFASs) exposure is ubiquitous among the US population and has been linked to adverse health outcomes including cardiometabolic diseases, immune dysregulation and endocrine disruption. However, the metabolic mechanism underlying the adverse health effect of PFASs exposure is unknown.

Objective

The aim of this project is to investigate the association between PFASs exposure and altered metabolic pathways linked to increased cardiometabolic risk in young adults.

Methods

A total of 102 young adults with 82% overweight or obese participants were enrolled from Southern California between 2014 and 2017. Cardiometabolic outcomes were assessed including oral glucose tolerance test (OGTT) measures, body fat and lipid profiles. High-resolution metabolomics was used to quantify plasma exposure levels of three PFAS congeners and intensity profiles of the untargeted metabolome. Fasting concentrations of 45 targeted metabolites involved in fatty acid and lipid metabolism were used to verify untargeted metabolomics findings. Bayesian Kernel Machine Regression (BKMR) was used to examine the associations between PFAS exposure mixture and cardiometabolic outcomes adjusting for covariates. Mummichog pathway enrichment analysis was used to explore PFAS-associated metabolic pathways. Moreover, the effect of PFAS exposure on the metabolic network, including metabolomic profiles and cardiometabolic outcomes, was investigated.

Results

Higher exposure to perfluorooctanoic acid (PFOA) was associated with higher 30-minute glucose levels and glucose area under the curve (AUC) during the OGTT (p < 0.001). PFAS exposure was also associated with altered lipid pathways, which contributed to the metabolic network connecting PFOA and higher glucose levels following the OGTT. Targeted metabolomics analysis indicated that higher PFOA exposure was associated with higher levels of glycerol (p = 0.006), which itself was associated with higher 30-minute glucose (p = 0.006).

Conclusions

Increased lipolysis and fatty acid oxidation could contribute to the biological mechanisms linking PFAS exposure and impaired glucose metabolism among young adults. Findings of this study warrants future experimental studies and epidemiological studies with larger sample size to replicate.

中文翻译：

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脂质和脂肪酸代谢失调与年轻人的全氟烷基物质暴露和葡萄糖代谢受损有关。

背景

全氟烷基物质和多氟烷基物质 (PFAS) 暴露在美国人群中普遍存在，并与不良健康结果相关，包括心脏代谢疾病、免疫失调和内分泌干扰。然而，PFAS 暴露对健康产生不良影响的代谢机制尚不清楚。

客观的

该项目的目的是调查 PFAS 暴露与年轻人心脏代谢风险增加相关的代谢途径改变之间的关系。

方法

2014 年至 2017 年间，南加州总共招募了 102 名年轻人，其中 82% 为超重或肥胖参与者。评估了心脏代谢结果，包括口服葡萄糖耐量试验 (OGTT) 测量、体脂和血脂状况。高分辨率代谢组学用于量化三种 PFAS 同系物的血浆暴露水平和非目标代谢组的强度分布。使用涉及脂肪酸和脂质代谢的 45 种靶向代谢物的空腹浓度来验证非靶向代谢组学结果。贝叶斯核机器回归 (BKMR) 用于检查 PFAS 暴露混合物与调整协变量的心脏代谢结果之间的关联。Mummichog通路富集分析用于探索 PFAS 相关的代谢通路。此外，还研究了 PFAS 暴露对代谢网络的影响，包括代谢组学特征和心脏代谢结果。

结果

较高的全氟辛酸 (PFOA) 暴露与 OGTT 期间较高的 30 分钟血糖水平和血糖曲线下面积 (AUC) 相关 (p < 0.001)。PFAS 暴露还与脂质途径的改变有关，这有助于连接 PFOA 和 OGTT 后较高的血糖水平的代谢网络。靶向代谢组学分析表明，较高的 PFOA 暴露与较高的甘油水平相关 (p = 0.006)，而甘油水平本身又与较高的 30 分钟血糖相关 (p = 0.006)。

结论

脂肪分解和脂肪酸氧化的增加可能有助于建立将年轻人中 PFAS 暴露与葡萄糖代谢受损联系起来的生物机制。这项研究的结果值得未来更大样本量的实验研究和流行病学研究进行复制。