Abstract
Recent epidemiological studies suggest that human exposure to perfluoroalkyl substances (PFASs) may be associated with type 2 diabetes and other metabolic phenotypes. To gain further insights regarding PFASs exposure in humans, we here aimed to characterize the associations between different PFASs and the metabolome. In this cross-sectional study, we investigated 965 individuals from Sweden (all aged 70 years, 50% women) sampled in 2001–2004. PFASs were analyzed in plasma using isotope-dilution ultra-pressure liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). Non-target metabolomics profiling was performed in plasma using UPLC coupled to time-of-flight mass spectrometry (UPLC-QTOFMS) operated in positive electrospray mode. Multivariate linear regression analysis was used to investigate associations between circulating levels of PFASs and metabolites. In total, 15 metabolites, predominantly from lipid pathways, were associated with levels of PFASs following adjustment for sex, smoking, exercise habits, education, energy, and alcohol intake, after correction for multiple testing. Perfluorononanoic acid (PFNA) and perfluoroundecanoic acid (PFUnDA) were strongly associated with multiple glycerophosphocholines and fatty acids including docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA). We also found that the different PFASs evaluated were associated with distinctive metabolic profiles, suggesting potentially different biochemical pathways in humans.
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References
Wang Z, DeWitt JC, Higgins CP, Cousins IT. A never-ending story of per- and polyfluoroalkyl substances (PFASs)? Environ Sci Technol. 2017;51:2508–18.
OECD. Environment Directorate, risk reduction approaches for PFASs - a cross-country analysis. OECD environment, health and safety publications, Series on Risk Managment No 29. 2015;29:13–18.
Eriksen KT, Raaschou-Nielsen O, McLaughlin JK, Lipworth L, Tjønneland A, Overvad K, et al. Association between plasma PFOA and PFOS levels and total cholesterol in a middle-aged Danish population. PLoS One. 2013;8:e56969.
Skuladottir M, Ramel A, Rytter D, Haug LS, Sabaredzovic A, Bech BH, et al. Examining confounding by diet in the association between perfluoroalkyl acids and serum cholesterol in pregnancy. Environ Res. 2015;143:33–8. Part A
Qin X-D, Qian Z, Vaughn MG, Huang J, Ward P, Zeng X-W, et al. Positive associations of serum perfluoroalkyl substances with uric acid and hyperuricemia in children from Taiwan. Environ Pollut. 2016;212:519–24.
Gleason JA, Post GB, Fagliano JA. Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the US population (NHANES), 2007–2010. Environ Res. 2015;136:8–14.
Lind L, Zethelius B, Salihovic S, van Bavel B, Lind PM. Circulating levels of perfluoroalkyl substances and prevalent diabetes in the elderly. Diabetologia. 2014;57:473–9.
Fletcher T, Galloway TS, Melzer D, Holcroft P, Cipelli R, Pilling LC, et al. Associations between PFOA, PFOS and changes in the expression of genes involved in cholesterol metabolism in humans. Environ Int. 2013;57-58:2–10.
Starling AP, Engel SM, Whitworth KW, Richardson DB, Stuebe AM, Daniels JL, et al. Perfluoroalkyl substances and lipid concentrations in plasma during pregnancy among women in the Norwegian Mother and Child Cohort Study. Environ Int. 2014;62:104–12.
Zeng X-W, Qian Z, Emo B, Vaughn M, Bao J, Qin X-D, et al. Association of polyfluoroalkyl chemical exposure with serum lipids in children. Sci Total Environ. 2015;512–513:364–70.
Geiger SD, Xiao J, Ducatman A, Frisbee S, Innes K, Shankar A. The association between PFOA, PFOS and serum lipid levels in adolescents. Chemosphere. 2014;98:78–83.
Johnson CH, Ivanisevic J, Siuzdak G. Metabolomics: beyond biomarkers and towards mechanisms. Nat Rev Mol Cell Biol. 2016;17:451–9.
Huang SSY, Benskin JP, Veldhoen N, Chandramouli B, Butler H, Helbing CC, et al. A multi-omic approach to elucidate low-dose effects of xenobiotics in zebrafish (Danio rerio) larvae. Aquat Toxicol. 2017;182:102–12.
Mattsson A, Kärrman A, Pinto R, Brunström B. Metabolic profiling of chicken embryos exposed to perfluorooctanoic acid (PFOA) and agonists to peroxisome proliferator-activated receptors. PLoS One. 2015;10:e0143780.
Peng S, Yan L, Zhang J, Wang Z, Tian M, Shen H. An integrated metabonomics and transcriptomics approach to understanding metabolic pathway disturbance induced by perfluorooctanoic acid. J Pharm Biomed Anal. 2013;86:56–64.
Kariuki M, Nagato E, Lankadurai B, Simpson A, Simpson M. Analysis of sub-lethal toxicity of perfluorooctane sulfonate (PFOS) to Daphnia magna using 1H nuclear magnetic resonance-based metabolomics. Metabolites. 2017;7:15.
Lind L, Fors N, Hall J, Marttala K, Stenborg A. A comparison of three different methods to evaluate endothelium-dependent vasodilation in the elderly the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Arterioscler Thromb Vasc Biol. 2005;25:2368–75.
Salihovic S, Kärrman A, Lindström G, Lind PM, Lind L, van Bavel B. A rapid method for the determination of perfluoroalkyl substances including structural isomers of perfluorooctane sulfonic acid in human serum using 96-well plates and column-switching ultra-high performance liquid chromatography tandem mass spectrometry. J Chromatogr A. 2013;1305:164–70.
Broeckling CD, Heuberger AL, Prince JA, Ingelsson E, Prenni JE. Assigning precursor–product ion relationships in indiscriminant MS/MS data from non-targeted metabolite profiling studies. Metabolomics. 2013;9:33–43.
Ganna A, Fall T, Salihovic S, Lee W, Broeckling C, Kumar J, et al. Large-scale non-targeted metabolomic profiling in three human population-based studies. Metabolomics. 2015;12:1–13.
Sumner LW, Amberg A, Barrett D, Beale MH, Beger R, Daykin CA, et al. Proposed minimum reporting standards for chemical analysis Chemical Analysis Working Group (CAWG) Metabolomics Standards Initiative (MSI). Metabolomics. 2007;3:211–21.
Xia J, Wishart DS Using MetaboAnalyst 3.0 for comprehensive metabolomics data analysis. Curr Protoc Bioinformatics. 2016;55:14–10.
Kato K, Wong L-Y, Jia LT, Kuklenyik Z, Calafat AM. Trends in exposure to polyfluoroalkyl chemicals in the US population: 1999-2008. Environ Sci Technol. 2011;45:8037–45.
Nøst TH, Vestergren R, Berg V, Nieboer E, Odland JØ, Sandanger TM. Repeated measurements of per- and polyfluoroalkyl substances (PFASs) from 1979 to 2007 in males from Northern Norway: assessing time trends, compound correlations and relations to age/birth cohort. Environ Int. 2014;67:43–53.
Salihovic S, Kärrman A, Lind L, Lind PM, Lindström G, van Bavel B. Perfluoroalkyl substances (PFAS) including structural PFOS isomers in plasma from elderly men and women from Sweden: results from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). Environ Int. 2015;82:21–7.
Minatoya M, Itoh S, Miyashita C, Araki A, Sasaki S, Miura R, et al. Association of prenatal exposure to perfluoroalkyl substances with cord blood adipokines and birth size: The Hokkaido Study on environment and children’s health. Environ Res. 2017;156:175–82.
Halldorsson TI, Rytter D, Haug LS, Bech BH, Danielsen I, Becher G, et al. Prenatal exposure to perfluorooctanoate and risk of overweight at 20 years of age: a prospective cohort study. Environ Health Perspect. 2012;120:668.
Liu G, Dhana K, Furtado JD, Rood J, Zong G, Liang L, et al. Perfluoroalkyl substances and changes in body weight and resting metabolic rate in response to weight-loss diets: a prospective study. PLoS Med. 2018;15:e1002502.
Yu N, Wei S, Li M, Yang J, Li K, Jin L, et al. Effects of perfluorooctanoic acid on metabolic profiles in brain and liver of mouse revealed by a high-throughput targeted metabolomics approach. Sci Rep. 2016;6:23963.
Kuwabara M, Niwa K, Hisatome I, Nakagawa T, Roncal-Jimenez CA, Andres-Hernando A, et al. Asymptomatic hyperuricemia without comorbidities predicts cardiometabolic diseases: five-year Japanese Cohort Study. Hypertension. (Dallas, Tex: 1979). 2017;69:1036–44.
Steenland K, Tinker S, Shankar A, Ducatman A. Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric acid among adults with elevated community exposure to PFOA. Environ Health Perspect. 2010;118:229–33.
Costa G, Sartori S, Consonni D. Thirty years of medical surveillance in perfluooctanoic acid production workers. J Occup Environ Med. 2009;51:364–72.
Sakr CJ, Leonard RC, Kreckmann KH, Slade MD, Cullen MR. Longitudinal study of serum lipids and liver enzymes in workers with occupational exposure to ammonium perfluorooctanoate. J Occup Environ Med. 2007;49:872–9.
Guruge KS, Yeung LW, Yamanaka N, Miyazaki S, Lam PK, Giesy JP, et al. Gene expression profiles in rat liver treated with perfluorooctanoic acid (PFOA). Toxicol Sci. 2006;89:93–107.
Wang J, Yan S, Zhang W, Zhang H, Dai J. Integrated proteomic and miRNA transcriptional analysis reveals the hepatotoxicity mechanism of PFNA exposure in mice. J Proteome Res. 2015;14:330–41.
Wan HT, Zhao YG, Wei X, Hui KY, Giesy JP, Wong CKC. PFOS-induced hepatic steatosis, the mechanistic actions on β-oxidation and lipid transport. Biochim Et Biophys Acta (BBA) - General Subj. 2012;1820:1092–101.
Chinetti G, Fruchart J-C, Staels B. Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm Res. 2000;49:497–505.
Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414:799–806.
Nowak C, Salihovic S, Ganna A, Brandmaier S, Tukiainen T, Broeckling CD, et al. Effect of insulin resistance on monounsaturated fatty acid levels: a multi-cohort non-targeted metabolomics and Mendelian Randomization Study. PLoS Genet. 2016;12:e1006379.
Zhang Y, Beesoon S, Zhu L, Martin JW. Biomonitoring of perfluoroalkyl acids in human urine and estimates of biological half-life. Environ Sci Technol. 2013;47:10619–27.
Pawlosky RJ, Hibbeln JR, Lin Y, Goodson S, Riggs P, Sebring N, et al. Effects of beef- and fish-based diets on the kinetics of n−3 fatty acid metabolism in human subjects. Am J Clin Nutr. 2003;77:565–72.
Schmitz G, Ruebsaamen K. Metabolism and atherogenic disease association of lysophosphatidylcholine. Atherosclerosis. 2010;208:10–8.
Matsumoto T, Kobayashi T, Kamata K. Role of lysophosphatidylcholine (LPC) in atherosclerosis. Curr Med Chem. 2007;14:3209–20.
Meikle PJ, Summers SA. Sphingolipids and phospholipids in insulin resistance and related metabolic disorders. Nat Rev Endocrinol. 2017;13:79–91.
Orešič M, Hyötyläinen T, Kotronen A, Gopalacharyulu P, Nygren H, Arola J, et al. Prediction of non-alcoholic fatty-liver disease and liver fat content by serum molecular lipids. Diabetologia. 2013;56:2266–74.
Pietiläinen KH, Sysi-Aho M, Rissanen A, Seppanen-Laakso T, Yki-Jarvinen H, Kaprio J, et al. Acquired obesity is associated with changes in the serum lipidomic profile independent of genetic effects--a monozygotic twin study. PLoS One. 2007;2:e218.
Li Y, Wang DD, Chiuve SE, Manson JE, Willett WC, Hu FB, et al. Dietary phosphatidylcholine intake and type 2 diabetes in men and women. Diabetes Care. 2015;38:e13–e4.
Suvitaival T, Bondia-Pons I, Yetukuri L, Pöhö P, Nolan JJ, Hyötyläinen T, et al. Lipidome as a predictive tool in progression to type 2 diabetes in Finnish men. Metabolism. 2018;78(Supplement C):1–12.
Drogan D, Dunn WB, Lin W, Buijsse B, Schulze MB, Langenberg C, et al. Untargeted metabolic profiling identifies altered serum metabolites of type 2 diabetes mellitus in a prospective, nested case control study. Clin Chem. 2015;61:487–97.
Barber MN, Risis S, Yang C, Meikle PJ, Staples M, Febbraio MA, et al. Plasma lysophosphatidylcholine levels are reduced in obesity and type 2 diabetes. PLoS One. 2012;7:e41456.
Wallace M, Morris C, O’Grada CM, Ryan M, Dillon ET, Coleman E, et al. Relationship between the lipidome, inflammatory markers and insulin resistance. Mol Biosyst. 2014;10:1586–95.
Alshehry ZH, Mundra PA, Barlow CK, Mellett NA, Wong G, McConville MJ, et al. Plasma lipidomic profiles improve upon traditional risk factors for the prediction of cardiovascular events in type 2 diabetes. Circulation. 2016;134:1637–50.
Acknowledgements
This study received funding from the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS) under grant numbers 2015-756 and 2013-478. Tove Fall has personal grants from the Göran Gustafsson Foundation and the Swedish Research Council (2015–03477). We greatly acknowledge the contribution of Bert van Bavel (Norwegian Institute for Water Research, Oslo, Norway) with regard to the analytical methodology for PFASs. We greatly acknowledge Erik Lampa (Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden) for statistical assistance.
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Salihovic, S., Fall, T., Ganna, A. et al. Identification of metabolic profiles associated with human exposure to perfluoroalkyl substances. J Expo Sci Environ Epidemiol 29, 196–205 (2019). https://doi.org/10.1038/s41370-018-0060-y
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DOI: https://doi.org/10.1038/s41370-018-0060-y
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