Associations of perfluoroalkyl substances (PFAS) with lipid and lipoprotein profiles

Abstract

Background Perfluoroalkyl substances (PFAS) are man-made chemicals with unique properties that are widely distributed in humans and the environment. Recent studies suggest that PFAS are involved in cholesterol metabolism, however, the mechanisms underlying the associations are poorly understood. Objective We aimed to evaluate associations of plasma PFAS with detailed lipid and lipoprotein subfractions in an adult population of men and women. Methods We measured concentrations of cholesterol and triglycerides in lipoprotein subfractions, apolipoprotein subclasses, as well as fatty acid and different phospholipid measures, using serum proton nuclear magnetic resonance (1H-NMR), and four plasma PFAS using liquid chromatography-mass spectrometry (UHPLC-MS/MS). Measurements were available for 493 participants (all aged 50 years, 50% female). Multivariable linear regression was used to estimate the association of four PFAS with 43 different 1H-NMR measures, with adjustment for body mass index (BMI), smoking, education, and physical activity. Results We found that perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDA), but not perfluorohexanesulfonate (PFHxS), concentrations were consistently positively associated with concentrations of cholesterol in lipoprotein subfractions, apolipoproteins, as well as composite fatty acid- and phospholipid profiles. The most consistent associations were found for the relationship of PFAS with total cholesterol in intermediate-density lipoprotein (IDL), across all low-density lipoprotein (LDL) subfractions and small high-density lipoprotein (HDL). Moreover, we found weak to null evidence for an association of any of the measured 13 triglyceride lipoprotein subfractions with PFAS. Conclusions Our results suggest that plasma PFAS concentrations are associated with cholesterol in small HDL, IDL and all LDL subfractions, as well as apolipoproteins and composite fatty acid and phospholipid profiles but to a lesser extent with triglycerides in lipoproteins. Our findings draw attention to the need for more detailed measurements of lipids across various lipoprotein subfractions and subclasses in assessing the role of PFAS in lipid metabolism. Impact By performing an in-depth characterization of circulating cholesterol and triglycerides in lipoprotein subfractions, apolipoprotein, fatty acid, and phospholipid concentrations, this study has expanded upon the limited literature available on the associations of plasma PFAS concentrations beyond clinical routine laboratory testing for lipids.

Mixture Effects of Per- and Polyfluoroalkyl Substances on Embryonic and Larval Sheepshead Minnows (Cyprinodon variegatus)

“…In rat hepatoma cells, PFOS was found to upregulate apoa4 roughly two-fold higher than PFOA when exposed at 100 µM but downregulated apoa4 at 10 µM while PFOA upregulated, and both compounds downregulated apoa4 at 1 and 0.1 µM [ 69 ]. While PFAS have been shown to affect lipid homeostasis and bioenergetics in several species [ 70 , 71 , 72 ], it is unknown how changes in apolipoprotein concentrations can influence PFAS toxicity, although some groups suggest that they may act as a transporter of PFAS throughout the body [ 73 ], and their concentrations are often positively correlated to PFOS and PFOA concentrations in humans [ 74 ]. It should also be noted that while apoa4 was used as a molecular biomarker to confirm pparα activation, the inverse trend was observed where PFOS did not upregulate pparα while upregulating apoa4 , while PFOA upregulated pparα but not apoa4 ( Figure 2 ).…”

All-cause, cardiovascular disease and cancer mortality in the population of a large Italian area contaminated by perfluoroalkyl and polyfluoroalkyl substances (1980–2018)

“…PFAS concentrations are primarily associated with blood lipids and apolipoproteins in subspecies of intermediate-, low-, and high-density lipoprotein containing apoC-III, which cause an elevated cardiovascular risk [ 73 ]. In more detail, the serum levels of PFOS, PFOA and PFDeA, but not PFHxS, are positively associated with the levels of cholesterol in lipoprotein subfractions, apolipoproteins, and composite fatty acid and phospholipid profiles [ 74 ]. The most consistent associations were found for the relationship of PFAS with total cholesterol in intermediate-density lipoprotein, across all low-density lipoprotein subfractions and small high-density lipoprotein.…”

Per‐ and polyfluoroalkyl substances and cardiometabolic diseases: A review

“…The limited evidence shows associations of PFAS with higher apoB and apoC-III (both associated with an increased risk of CVD and dyslipidemia) and also with apoA1 (associated with improved cardiometabolic health). 15,18,19…”

“…Much less investigated are associations with apolipoproteins, although this could provide more detailed mechanistic information. The limited evidence shows associations of PFAS with higher apoB and apoC‐III (both associated with an increased risk of CVD and dyslipidemia) and also with apoA1 (associated with improved cardiometabolic health) 15,18,19 …”