Diabetogenic effects of per- and polyfluoroalkyl substances (PFAS) have been suggested. However, evidence based on prospective cohort studies is limited. We examined the association between serum PFAS concentrations and incident diabetes in the Study of Women’s Health Across the Nation Multi-Pollutant Study (SWAN-MPS).
We included 1237 diabetes-free women aged 45–56 years at baseline (1999–2000) who were followed up to 2017. At each follow-up visit, women with incident diabetes were identified by the presence of one or more of the following conditions: (1) use of a glucose-lowering medication at any visit; (2) fasting glucose ≥7 mmol/l on two consecutive visits while not on steroids; and (3) any two visits with self-reported diabetes and at least one visit with fasting blood glucose ≥7 mmol/l. Serum concentrations of 11 PFAS were quantified by online solid-phase extraction–HPLC–isotope dilution–tandem MS. Seven PFAS with high detection rates (>96%) (n-perfluorooctanoic acid [n-PFOA], perfluorononanoic acid [PFNA], perfluorohexane sulfonic acid [PFHxS], n-perfluorooctane sulfonic acid [n-PFOS], sum of perfluoromethylheptane sulfonic acid isomers [Sm-PFOS], 2-[N-methyl-perfluorooctane sulfonamido] acetic acid [MeFOSAA] and 2-[N-ethyl-perfluorooctane sulfonamido] acetic acid) were included in data analysis. Cox proportional hazards models were used to compute HRs and 95% CIs. Quantile-based g-computation was used to evaluate the joint effects of PFAS mixtures.
After adjustment for race/ethnicity, site, education, smoking status, alcohol consumption, total energy intake, physical activity, menopausal status and BMI, the HR (95% CI) comparing the lowest with the highest tertile was 1.67 (1.21, 2.31) for n-PFOA (ptrend = 0.001), 1.58 (1.13, 2.21) for PFHxS (ptrend = 0.003), 1.36 (0.97, 1.90) for Sm-PFOS (ptrend = 0.05), 1.85 (1.28, 2.67) for MeFOSAA (ptrend = 0.0004) and 1.64 (1.17, 2.31) for the sum of four common PFAS (n-PFOA, PFNA, PFHxS and total PFOS) (ptrend = 0.002). Exposure to seven PFAS as mixtures was associated with an HR of 2.62 (95% CI 1.12, 6.20), comparing the top with the bottom tertiles for all seven PFAS.
This study suggests that PFAS may increase diabetes risk in midlife women. Reduced exposure to these ‘forever and everywhere chemicals’ may be an important preventative approach to lowering population-wide diabetes risk.
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Centers for Disease Control and Prevention
2-(N-ethyl-perfluorooctane sulfonamido) acetic acid
Inverse probability weighting
Limit of detection
2-(N-methyl-perfluorooctane sulfonamido) acetic acid
Nurses’ Health Study-II
Per- and polyfluoroalkyl substances
Perfluorohexane sulfonic acid
Perfluorooctane sulfonic acid
Peroxisome proliferator-activated receptor
Sum of branched PFOA isomers
Sum of perfluoromethylheptane sulfonic acid isomers
Study of Women’s Health Across the Nation
Agency for Toxic Substances and Disease Registry (ATSDR) (2021) Toxicological profile for Perfluoroalkyls. U.S. Department of Health and Human Services, Public Health Service. Agency for Toxic Substances and Disease Registry, Atlanta, GA
Interstate Technology and Regulatory Council (ITRC) (2020) History and Use of Per-and Polyfluoroalkyl Substances (PFAS), ITRC, Washington, DC
Andrews DQ, Naidenko OV (2020) Population-wide exposure to per- and Polyfluoroalkyl substances from drinking water in the United States. Environ Sci Technol Lett 7(12):931–936. https://doi.org/10.1021/acs.estlett.0c00713
Centers for Disease Control and Prevention (CDC) (2019) Fourth Report on Human Exposure to Environmental Chemicals, Updated Tables. Centers for Disease Control and Prevention, National Center for Environmental Health. Atlanta, GA
Centers for Disease Control and Prevention (CDC) (2009) Fourth National Report on Human Exposure to Environmental Chemicals. Centers for Disease Control and Prevention, National Center for Environmental Health. Atlanta, GA
Qi W, Clark JM, Timme-Laragy AR, Park Y (2020) Per- and Polyfluoroalkyl substances and obesity, type 2 diabetes and non-alcoholic fatty liver disease: a review of epidemiologic findings. Toxicol Environ Chem 102(1–4):1–36. https://doi.org/10.1080/02772248.2020.1763997
Buck RC, Franklin J, Berger U et al (2011) Perfluoroalkyl and polyfluoroalkyl substances in the environment: terminology, classification, and origins. Integr Env Assess Manag 7(4):513–541. https://doi.org/10.1002/ieam.258
Grygiel-Górniak B (2014) Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications--a review. Nutr J 13:17. https://doi.org/10.1186/1475-2891-13-17
Jiang Q, Gao H, Zhang L (2015) Chapter 7. Metabolic effects PFAS. In: DeWitt JC (ed) Toxicological effects of Perfl uoroalkyl and Polyfluoroalkyl substances. Springer International Publishing, Switzerland
Watkins AM, Wood CR, Lin MT, Abbott BD (2015) The effects of perfluorinated chemicals on adipocyte differentiation in vitro. Mol Cell Endocrinol 400:90–101. https://doi.org/10.1016/j.mce.2014.10.020
Liu S, Yang R, Yin N, Wang Y-L, Faiola F (2019) Environmental and human relevant PFOS and PFOA doses alter human mesenchymal stem cell self-renewal, adipogenesis and osteogenesis. Ecotoxicol Environ Saf 169:564–572. https://doi.org/10.1016/j.ecoenv.2018.11.064
Lin CY, Chen PC, Lin YC, Lin LY (2009) Association among serum perfluoroalkyl chemicals, glucose homeostasis, and metabolic syndrome in adolescents and adults. Diabetes Care 32(4):702–707. https://doi.org/10.2337/dc08-1816
MacNeil J, Steenland NK, Shankar A, Ducatman A (2009) A cross-sectional analysis of type II diabetes in a community with exposure to perfluorooctanoic acid (PFOA). Environ Res 109(8):997–1003. https://doi.org/10.1016/j.envres.2009.08.002
Lind L, Zethelius B, Salihovic S, van Bavel B, Lind PM (2014) Circulating levels of perfluoroalkyl substances and prevalent diabetes in the elderly. Diabetologia 57(3):473–479. https://doi.org/10.1007/s00125-013-3126-3
Su T-C, Kuo C-C, Hwang J-J, Lien G-W, Chen M-F, Chen P-C (2016) Serum perfluorinated chemicals, glucose homeostasis and the risk of diabetes in working-aged Taiwanese adults. Environ Int 88:15–22. https://doi.org/10.1016/j.envint.2015.11.016
Zeeshan M, Zhang Y-T, Yu S et al (2021) Exposure to isomers of per- and polyfluoroalkyl substances increases the risk of diabetes and impairs glucose-homeostasis in Chinese adults: isomers of C8 health project. Chemosphere 278:130486. https://doi.org/10.1016/j.chemosphere.2021.130486
Duan Y, Sun H, Yao Y et al (2021) Serum concentrations of per−/polyfluoroalkyl substances and risk of type 2 diabetes: a case-control study. Sci Total Environ 787:147476. https://doi.org/10.1016/j.scitotenv.2021.147476
Han X, Meng L, Zhang G et al (2021) Exposure to novel and legacy per- and polyfluoroalkyl substances (PFASs) and associations with type 2 diabetes: a case-control study in East China. Environ Int 156:106637. https://doi.org/10.1016/j.envint.2021.106637
Dhingra R, Winquist A, Darrow LA, Klein M, Steenland K (2017) A study of reverse causation: examining the associations of Perfluorooctanoic acid serum levels with two outcomes. Env Heal Perspect 125(3):416–421. https://doi.org/10.1289/EHP273EHP273
Park SK, Ding N, Han D (2021) Perfluoroalkyl substances and cognitive function in older adults: should we consider non-monotonic dose-responses and chronic kidney disease? Environ Res 192:110346. https://doi.org/10.1016/j.envres.2020.110346
Sun Q, Zong G, Valvi D, Nielsen F, Coull B, Grandjean P (2018) Plasma concentrations of Perfluoroalkyl substances and risk of type 2 diabetes: a prospective investigation among U.S. women. Environ Health Perspect 126(3):037001. https://doi.org/10.1289/EHP2619
Cardenas A, Hivert M-F, Gold DR et al (2019) Associations of Perfluoroalkyl and Polyfluoroalkyl substances with incident diabetes and microvascular disease. Diabetes Care 42(9):1824–1832. https://doi.org/10.2337/dc18-2254
Donat-Vargas C, Bergdahl IA, Tornevi A et al (2019) Perfluoroalkyl substances and risk of type II diabetes: a prospective nested case-control study. Environ Int 123:390–398. https://doi.org/10.1016/j.envint.2018.12.026
Karnes C, Winquist A, Steenland K (2014) Incidence of type II diabetes in a cohort with substantial exposure to perfluorooctanoic acid. Environ Res 128:78–83. https://doi.org/10.1016/j.envres.2013.11.003
Park SK, Zhao Z, Mukherjee B (2017) Construction of environmental risk score beyond standard linear models using machine learning methods: application to metal mixtures, oxidative stress and cardiovascular disease in NHANES. Environ Heal A Glob Access Sci Source 16(1):102. https://doi.org/10.1186/s12940-017-0310-9
Braun JM, Gennings C, Hauser R, Webster TF (2016) What can epidemiological studies tell us about the impact of chemical mixtures on human health? Env Heal Perspect 124(1):A6–A9. https://doi.org/10.1289/ehp.1510569
Sowers MR, Crawford SL, Sternfeld B et al (2000) SWAN: a multicenter, multiethnic, community-based cohort study of women and the menopausal transition. In: Lobo RA, Kelsey J, Marcus R (eds) Menopause: biology and pathology. Academic Press, San Diego, CA, pp 175–188
Kato K, Basden BJ, Needham LL, Calafat AM (2011) Improved selectivity for the analysis of maternal serum and cord serum for polyfluoroalkyl chemicals. J Chromatogr A 1218(15):2133–2137. https://doi.org/10.1016/j.chroma.2010.10.051S0021-9673(10)01427-5
Park SK, Peng Q, Ding N, Mukherjee B, Harlow SD (2019) Determinants of per- and polyfluoroalkyl substances (PFAS) in midlife women: evidence of racial/ethnic and geographic differences in PFAS exposure. Environ Res 175:186–199. https://doi.org/10.1016/j.envres.2019.05.028
Ding N, Harlow SD, Batterman S, Mukherjee B, Park SK (2020) Longitudinal trends in perfluoroalkyl and polyfluoroalkyl substances among multiethnic midlife women from 1999 to 2011: the study of Women’s health across the nation. Environ Int 135:105381. https://doi.org/10.1016/j.envint.2019.105381
EFSA (European Food Safety Authority) (2020) Outcome of a public consultation on the draft risk assessment of perfluoroalkyl substances in food. EFSA Support Publ 2020EN-1931. https://doi.org/10.2903/SP.EFSA.2020.EN-1931
Ding N, Karvonen-Gutierrez CA, Herman WH, Calafat AM, Mukherjee B, Park SK (2021) Perfluoroalkyl and polyfluoroalkyl substances and body size and composition trajectories in midlife women: the study of women’s health across the nation 1999-2018. Int J Obes 45(9):1937–1948. https://doi.org/10.1038/s41366-021-00848-9
Ding N, Harlow SD, Randolph JF et al (2020) Associations of Perfluoroalkyl substances with incident natural menopause: the study of Women’s health across the nation. J Clin Endocrinol Metab 105(9):e3169–e3182. https://doi.org/10.1210/clinem/dgaa303
Zheng Y, Ley SH, Hu FB (2018) Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 14(2):88–98. https://doi.org/10.1038/nrendo.2017.151
Keil AP, Buckley JP, O’Brien KM, Ferguson KK, Zhao S, White AJ (2020) A quantile-based g-computation approach to addressing the effects of exposure mixtures. Environ Health Perspect 128(4):47004. https://doi.org/10.1289/EHP5838
Abdullah A, Peeters A, de Courten M, Stoelwinder J (2010) The magnitude of association between overweight and obesity and the risk of diabetes: a meta-analysis of prospective cohort studies. Diabetes Res Clin Pract 89(3):309–319. https://doi.org/10.1016/J.DIABRES.2010.04.012
Pan A, Wang Y, Talaei M, Hu FB, Wu T (2015) Relation of active, passive, and quitting smoking with incident diabetes: a meta-analysis and systematic review. Lancet Diabetes Endocrinol 3(12):958. https://doi.org/10.1016/S2213-8587(15)00316-2
Schlezinger JJ, Puckett H, Oliver J, Nielsen G, Heiger-Bernays W, Webster TF (2020) Perfluorooctanoic acid activates multiple nuclear receptor pathways and skews expression of genes regulating cholesterol homeostasis in liver of humanized PPARα mice fed an American diet. Toxicol Appl Pharmacol 405:115204. https://doi.org/10.1016/j.taap.2020.115204
Fragki S, Dirven H, Fletcher T et al (2021) Systemic PFOS and PFOA exposure and disturbed lipid homeostasis in humans: what do we know and what not? Crit Rev Toxicol 51(2):141–164. https://doi.org/10.1080/10408444.2021.1888073
Moreau A, Vilarem MJ, Maurel P, Pascussi JM (2008) Xenoreceptors CAR and PXR activation and consequences on lipid metabolism, glucose homeostasis, and inflammatory response. Mol Pharm 5(1):35–41. https://doi.org/10.1021/mp700103m
Qiu T, Chen M, Sun X et al (2016) Perfluorooctane sulfonate-induced insulin resistance is mediated by protein kinase B pathway. Biochem Biophys Res Commun 477(4):781–785. https://doi.org/10.1016/j.bbrc.2016.06.135
Salter DM, Wei W, Nahar PP, Marques E, Slitt AL (2021) Perfluorooctanesulfonic acid (PFOS) thwarts the beneficial effects of calorie restriction and metformin. Toxicol Sci 182(1):82–95. https://doi.org/10.1093/toxsci/kfab043
Li Y, Barregard L, Xu Y et al (2020) Associations between perfluoroalkyl substances and serum lipids in a Swedish adult population with contaminated drinking water. Environ Health 19(1):33. https://doi.org/10.1186/s12940-020-00588-9
Ahmad TR, Haeusler RA (2019) Bile acids in glucose metabolism and insulin signalling — mechanisms and research needs. Nat Rev Endocrinol 15(12):701–712. https://doi.org/10.1038/s41574-019-0266-7
Centers for Disease Control and Prevention (CDC) (2020) National Diabetes Statistics Report, 2020. Centers for Disease Control and Prevention, National Center for Environmental Health. Atlanta, GA
Kato K, Wong LY, Jia LT, Kuklenyik Z, Calafat AM (2011) Trends in exposure to polyfluoroalkyl chemicals in the U.S. population: 1999-2008. Env Sci Technol 45(19):8037–8045. https://doi.org/10.1021/es1043613
Whitehead HD, Venier M, Wu Y et al (2021) Fluorinated compounds in north American cosmetics. Environ Sci Technol Lett 8(7):538–544. https://doi.org/10.1021/acs.estlett.1c00240
Hu XC, Andrews DQ, Lindstrom AB et al (2016) Detection of poly- and Perfluoroalkyl substances (PFASs) in U.S. drinking water linked to industrial sites, military fire training areas, and wastewater treatment plants. Env Sci Technol Lett 3(10):344–350. https://doi.org/10.1021/acs.estlett.6b00260
Cousins IT, DeWitt JC, Glüge J et al (2020) The high persistence of PFAS is sufficient for their management as a chemical class. Environ Sci Process Impacts 22(12):2307–2312. https://doi.org/10.1039/d0em00355g
Agency for Toxic Substances and Disease Registry (ATSDR) (2019) PFAS: An overview of the science and guidance for clinicians on per- and polyfluoroalkyl substances (PFAS). U.S. Department of Health and Human Services, Public Health Service. Agency for Toxic Substances and Disease Registry. Atlanta, GA
We thank all the women who participated in SWAN. We also thank the late Xiaoyun Ye at CDC for her support in PFAS assessment. We thank the study staff and principal investigators at each of the following sites.
Clinical centres: University of Michigan, Ann Arbor, MI (C. Karvonen-Gutierrez, S. Harlow, M. Sowers); Massachusetts General Hospital, Boston, MA (J. Finkelstein, R. Neer); Rush University, Rush University Medical Center, Chicago, IL (H. Kravitz, L. Powell); University of California, Davis/Kaiser (E. Gold); University of California, Los Angeles (G. Greendale); Albert Einstein College of Medicine, Bronx, NY (C. Derby, R. Wildman, N. Santoro); University of Medicine and Dentistry, New Jersey Medical School, Newark, NJ (G. Weiss); and the University of Pittsburgh, Pittsburgh, PA (K. Matthews).
National Institutes of Health (NIH) Program Office: National Institute on Aging, Bethesda, MD (C. Dutta, W. Rossi, S. Sherman, M. Ory); National Institute of Nursing Research, Bethesda, MD (Program Officers).
Central Laboratory: Central Ligand Assay Satellite Services, University of Michigan, Ann Arbor, MI (D. McConnell).
CDC Laboratory: Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA.
SWAN Repository: University of Michigan, Ann Arbor, MI (S. Harlow, D. McConnell, M. Sowers).
Coordinating Center: University of Pittsburgh, Pittsburgh, PA (M. Mori Brooks, K. Sutton-Tyrrell); New England Research Institutes, Watertown, MA (S. McKinlay).
Steering Committee: S. Johnson, C. Gallagher.
SWAN provides access to public-use datasets that include data from SWAN screening, the baseline visit and follow-up visits (https://agingresearchbiobank.nia.nih.gov/). To preserve participant confidentiality, some, but not all, of the data used for this manuscript are contained in the public-use datasets. A link to the public-use datasets is also located on the SWAN website: http://www.swanstudy.org/swan-research/data-access/. Investigators who require assistance accessing the public use dataset may contact the SWAN Coordinating Center at the following e-mail address: firstname.lastname@example.org.
SWAN has grant support from the NIH, US Department of Health and Human Services (DHHS), through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR) and the NIH Office of Research on Women’s Health (ORWH) (grants U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495 and U19AG063720). The study was also supported by the SWAN Repository (U01AG017719). This publication was supported in part by the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH, through UCSF-CTSI grant no. UL1 RR024131. This study was also supported by grants from the National Institute of Environmental Health Sciences (NIEHS) R01-ES026578, R01-ES026964 and P30-ES017885, and by the CDC/National Institute for Occupational Safety and Health (NIOSH) grant T42-OH008455. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIA, NINR, ORWH or the NIH. The findings and conclusions of this report are those of the authors and do not necessarily represent the official position of the CDC. Use of trade names is for identification only and does not imply endorsement by the CDC, the Public Health Service or the DHHS.
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The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.
SKP was involved in the design of the analysis plan and wrote the manuscript. XW and ND conducted data analyses and critically revised the manuscript. CAKG, WHH, BM, AMC and SDH were involved in the design of the analysis plan, contributed to interpretation of the data, and critically revised the manuscript. All authors read and approved the final version of the paper. SKP is the guarantor of this work and had full access to all the data in the study and takes responsibility for the contents of the manuscript.
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Park, S.K., Wang, X., Ding, N. et al. Per- and polyfluoroalkyl substances and incident diabetes in midlife women: the Study of Women’s Health Across the Nation (SWAN). Diabetologia 65, 1157–1168 (2022). https://doi.org/10.1007/s00125-022-05695-5
- Midlife women
- Per- and polyfluoroalkyl substances
- Prospective cohort