Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
Environ Int. 2023 Oct;180:108198. doi: 10.1016/j.envint.2023.108198. Epub 2023 Sep 9.
Exposures to perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), environmentally persistent chemicals detectable in the blood of most Americans, have been associated with several health outcomes. To offer insight into their possible biologic effects, we evaluated the metabolomic correlates of circulating PFOS and PFOA among 3,647 participants in eight nested case-control serum metabolomic profiling studies from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.
Metabolomic profiling was conducted by Metabolon Inc., using ultra high-performance liquid chromatography/tandem accurate mass spectrometry. We conducted study-specific multivariable linear regression analyses estimating the associations of metabolite levels with levels of PFOS or PFOA. For metabolites measured in at least 3 of 8 nested case-control studies, random effects meta-analysis was used to summarize study-specific results (1,038 metabolites in PFOS analyses and 1,100 in PFOA analyses).
The meta-analysis identified 51 and 38 metabolites associated with PFOS and PFOA, respectively, at a Bonferroni-corrected significance level (4.8x10 and 4.6x10, respectively). For both PFOS and PFOA, the most common types of associated metabolites were lipids (sphingolipids, fatty acid metabolites) and xenobiotics (xanthine metabolites, chemicals). Positive associations were commonly observed with lipid metabolites sphingomyelin (d18:1/18:0) (P = 2.0x10 and 2.0x10, respectively), 3-carboxy-4-methyl-5-pentyl-2-furanpropionate (P = 2.7x10, 1.1x10), and lignoceroylcarnitine (C24) (P = 2.6x10, 6.2x10). The strongest positive associations were observed for chemicals 3,5-dichloro-2,6-dihydroxybenzoic acid (P = 3.0x10 and 6.8x10, respectively) and 3-bromo-5-chloro-2,6-dihydroxybenzoic acid (P = 1.6x10, 2.3x10). Other metabolites positively associated with PFOS included D-glucose (carbohydrate), carotene diol (vitamin A metabolism), and L-alpha-aminobutyric acid (glutathione metabolism), while uric acid (purine metabolite) was positively associated with PFOA. PFOS associations were consistent even after adjusting for PFOA as a covariate, while PFOA associations were greatly attenuated with PFOS adjustment.
In this large metabolomic study, we observed robust positive associations with PFOS for several molecules. Further investigation of these metabolites may offer insight into PFOS-related biologic effects.
全氟辛烷磺酸（PFOS）和全氟辛酸（PFOA）是两种在大多数美国人血液中都能检测到的持久性环境污染物，它们与多种健康结果有关。为了深入了解它们可能产生的生物学效应，我们评估了 8 项嵌套病例对照血清代谢组学研究中 3647 名参与者循环 PFOS 和 PFOA 的代谢组学相关性，这些研究来自前列腺癌、肺癌、结直肠癌和卵巢癌筛查试验。
代谢组学分析由 Metabolon Inc. 采用超高效液相色谱/串联精确质量质谱法进行。我们进行了特定于研究的多变量线性回归分析，估计了代谢物水平与 PFOS 或 PFOA 水平之间的关联。对于至少在 8 项嵌套病例对照研究中的 3 项研究中测量的代谢物，使用随机效应荟萃分析来总结特定于研究的结果（PFOS 分析中测量了 1038 种代谢物，PFOA 分析中测量了 1100 种代谢物）。
荟萃分析在经 Bonferroni 校正的显著水平（分别为 4.8x10 和 4.6x10）下，分别确定了 51 种和 38 种与 PFOS 和 PFOA 相关的代谢物。对于 PFOS 和 PFOA，最常见的相关代谢物类型是脂质（鞘脂、脂肪酸代谢物）和外源性物质（黄嘌呤代谢物、化学物质）。脂质代谢物鞘磷脂（d18:1/18:0）（P=2.0x10 和 2.0x10，分别）、3-羧基-4-甲基-5-戊基-2-呋喃丙酸（P=2.7x10、1.1x10）和木质酰肉碱（C24）（P=2.6x10、6.2x10）与 PFOS 呈正相关。与 PFOA 呈最强正相关的是 3,5-二氯-2,6-二羟基苯甲酸（P=3.0x10 和 6.8x10，分别）和 3-溴-5-氯-2,6-二羟基苯甲酸（P=1.6x10、2.3x10）。与 PFOS 呈正相关的其他代谢物包括 D-葡萄糖（碳水化合物）、胡萝卜二醇（维生素 A 代谢）和 L-α-氨基丁酸（谷胱甘肽代谢），而尿酸（嘌呤代谢物）与 PFOA 呈正相关。即使在调整了 PFOA 作为协变量后，PFOS 的相关性仍然很一致，而在调整了 PFOS 后，PFOA 的相关性大大减弱。
在这项大型代谢组学研究中，我们观察到 PFOS 与几种分子之间存在明显的正相关。对这些代谢物的进一步研究可能会深入了解 PFOS 相关的生物学效应。
