Abstract
Sex hormones influence excretion of the biopersistent per-and polyfluoroalkyl substances (PFAS) in rodents, but such influences in human studies are less clear. Data from National Health and Nutrition Examination Survey (NHANES) for 2003–2018 for US females aged ≥ 20 years who reported having hysterectomy (HYST, N=1064) and who reported being in natural menopause (MENOP, N=1505) were analyzed for associations of ever use of birth control pills, past pregnancies, live births, and other factors with serum concentrations of six per- and polyfluoroalkyl substances (PFAS). For both HYST and MENOP, PFAS concentrations computed as adjusted geometric means (AGM) were higher among those who took female replacement hormone therapy (HRT) compared to nonusers in multivariable adjusted models, for example PFOS in HRT takers (10.70 ng/mL; 95% C.I. 9.46–12.11) vs. 8.70 ng/mL (95% C.I. 8.07–9.37) in nonusers (p<0.01), and PFOA in HRT users was 2.85 ng/mL (95% C.I. 2.53–3.21) vs. 2.44 ng/mL (95% C.I. 2.32–2.36) in nonusers (p=0.01), with similar findings across race/ethnicity stratifications. HYST participants with retained ovaries sometimes had higher serum PFAS than those without ovaries in post-HYST participants not taking HRT, but results had overlap** confidence intervals in all cases and were inconsistent. PFASs were inversely associated with obesity and directly associated with higher SES as reflected in poverty income ratio (PIR) in most cases, yet HRT results for the entire population are robust to adjustments for obesity and PIR. The results suggest the hypothesis that exogenous hormone use, and specifically estrogen hormones, are associated with higher serum PFAS in postmenopausal women. We discuss potential explanations for the findings, including data from other populations that estrogens may delay the onset of kidney disease, a finding which might paradoxically increase serum PFAS among the HRT population to explain some or all of our findings in a menopausal population.
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Data availability
All data used for analysis for this study are in public domain and available free of cost at www.cdc.gov/nchs/nhanes/index.htm.
References
Agarwal M, Selvan V, Freedman BI, Liu Y, Wagenknecht LE (2005) The relationship between albuminuria and hormone therapy in postmenopausal women. Am J Kidney Dis 45(6):1019–1025. https://doi.org/10.1053/j.ajkd.2005.02.025
Barrett ES, Chen C, Thurston SW, Haug LS, Sabaredzovic A, Fjeldheim FN, Frydenberg H, Lipson SF, Ellison PT, Thune I (2015) Perfluoroalkyl substances and ovarian hormone concentrations in naturally cycling women. Fertil Steril 103(5):1261–70.e3. https://doi.org/10.1016/j.fertnstert.2015.02.001
Bea JW, Zhao Q, Cauley JA, LaCroix AZ, Bassford T, Lewis CE, Jackson RD, Tylavsky FA, Chen Z (2011) Effect of hormone therapy on lean body mass, falls, and fractures: 6-year results from the Women’s Health Initiative hormone trials. Menopause 18(1):44–52. https://doi.org/10.1097/gme.0b013e3181e3aab1
Bianchi S, Bigazzi R, Campese VM (1999) Microalbuminuria in essential hypertension: significance, pathophysiology, and therapeutic implications. Am J Kidney Dis 34(6):973–995. https://doi.org/10.1016/S0272-6386(99)70002-8
Chang SC, Noker PE, Gorman GS, Gibson SJ, Hart JA, Ehresman DJ et al (2012) Comparative pharmacokinetics of perfluorooctanesulfonate (PFOS) in rats, mice, and monkeys. Reprod Toxicol 33(4):428–440
Charles D, Berg V, Nøst TH, Huber S, Sandanger TM, Rylander C (2020) Pre- and post-diagnostic blood profiles of perfluoroalkyl acids in type 2 diabetes mellitus cases and controls. Environ Int 145:106095. https://doi.org/10.1016/j.envint.2020.106095
Ding N, Harlow SD, Randolph JF, Calafat AM, Mukherjee B, Batterman S, Gold EB, Park SK (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
Ding N, Harlow SD, Randolph JF, Mukherjee B, Batterman S, Gold EB, Park SK (2022) Perfluoroalkyl substances and incident natural menopause in midlife women: the mediating role of sex hormones. Am J Epidemiol 191(7):1212–1223. https://doi.org/10.1093/aje/kwac052
Dzierlenga AL, Robinson VG, Waidyanatha S, DeVito MJ, Eifrid MA, Gibbs ST et al (2020) Toxicokinetics of perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) in male and female Hsd:Sprague dawley SD rats following intravenous or gavage administration. Xenobiotica 50(6):722–732
Ericson I, Gómez M, Nadal M, van Bavel B, Lindström G, Domingo JL (2007) Perfluorinated chemicals in blood of residents in Catalonia (Spain) in relation to age and gender: a pilot study. Environ Int 33(5):616–623. https://doi.org/10.1016/j.envint.2007.01.003
Farahmand M, Ramezani Tehrani F, Khalili D, Cheraghi L, Azizi F (2021) Endogenous estrogen exposure and chronic kidney disease; a 15-year prospective cohort study. BMC Endocr Disord 21(1):155. https://doi.org/10.1186/s12902-021-00817-3
Forsthuber M, Kaiser AM, Granitzer S, Hassl I, Hengstschläger M, Stangl H, Gundacker C (2020) Albumin is the major carrier protein for PFOS, PFOA, PFHxS, PFNA and PFDA in human plasma. Environ Int 137:105324. https://doi.org/10.1016/j.envint.2019.105324
Han X, Nabb DL, Russell MH, Kennedy GL, Rickard RW (2012) Renal elimination of perfluorocarboxylates (PFCAs). Chem Res Toxicol 25(1):35–46. https://doi.org/10.1021/tx200363w
Hanratty R, Chonchol M, Havranek EP, Powers JD, Dickinson LM, Ho PM, Magid DJ, Steiner JF (2011) Relationship between blood pressure and incident chronic kidney disease in hypertensive patients. Clin J Am Soc Nephrol 6(11):2605–2611. https://doi.org/10.2215/CJN.02240311
Hamoda H, Panay N, Pedder H, Arya R, Savvas M (2020) The British Menopause Society & Women’s Health Concern 2020 recommendations on hormone replacement therapy in menopausal women. Post Reprod Health 26(4):181–209. https://doi.org/10.1177/2053369120957514
Harlow SD, Hood MM, Ding N, Mukherjee B, Calafat AM, Randolph JF, Gold EB, Park SK (2021) Per- and polyfluoroalkyl substances and hormone levels during the menopausal transition. J Clin Endocrinol Metab 106(11):e4427–e4437. https://doi.org/10.1210/clinem/dgab476
Ingelido AM, Marra V, Abballe A, Valentini S, Iacovella N, Barbieri P, Porpora MG, Domenico A, De Felip E (2010) Perfluorooctanesulfonate and perfluorooctanoic acid exposures of the Italian general population. Chemosphere 80(10):1125–1130. https://doi.org/10.1016/j.chemosphere.2010.06.025
Jain RB, Ducatman A (2019) Perfluoroalkyl acids serum concentrations and their relationship to biomarkers of renal failure: serum and urine albumin, creatinine, and albumin creatinine ratios across the spectrum of glomerular function among US adults. Environ Res 174:143–151
Jain RB, Ducatman A (2022) Serum concentrations of selected perfluoroalkyl substances for US females compared to males as they age. Sci Total Environ 842:156891. https://doi.org/10.1016/j.scitotenv.2022.156891
Kingsley SL, Eliot MN, Kelsey KT, Calafat AM, Ehrlich S, Lanphear BP et al (2018) Variability and predictors of serum perfluoroalkyl substance concentrations during pregnancy and early childhood. Environ Res 165:247–257
Kotsopoulos J, Shafrir AL, Rice M, Hankinson SE, Eliassen AH, Tworoger SS, Narod SA (2015) The relationship between bilateral oophorectomy and plasma hormone levels in postmenopausal women. Horm Cancer 6(1):54–63. https://doi.org/10.1007/s12672-014-0209-7
Kovesdy CP, Furth SL, Zoccali C, World Kidney Day Steering Committee (2017) Obesity and kidney disease: hidden consequences of the epidemic. Can J Kidney Health Dis 4:2054358117698669. https://doi.org/10.1177/2054358117698669
Kudo N, Katakura M, Sato Y, Kawashima Y (2002) Sex hormone-regulated renal transport of perfluorooctanoic acid. Chem Biol Interact 139(3):301–316. https://doi.org/10.1016/s0009-2797(02)00006-6
Li Y, Fletcher T, Mucs D, Scott K, Lindh CH, Tallving P, Jakobsson K (2018) Half-lives of PFOS, PFHxS and PFOA after end of exposure to contaminated drinking water. Occup Environ Med 75(1):46–51. https://doi.org/10.1136/oemed-2017-104651
Lin C, Nian M, **e M, Zeng L, Qiu W, Zhang J, Yang H (2023) Associations of per- and polyfluoroalkyl substances and alternatives with reproductive hormones in women of childbearing age. Int J Hyg Environ Health 250:114158. https://doi.org/10.1016/j.ijheh.2023.114158
Lind PM, Lind L, Salihovic S, Ahlström H, Michaelsson K, Kullberg J, Strand R (2022) Serum levels of perfluoroalkyl substances (PFAS) and body composition - a cross-sectional study in a middle-aged population. Environ Res 209:112677. https://doi.org/10.1016/j.envres.2022.112677
Liu J, Liu Z, Sun W, Luo L, An X, Yu D, Wang W (2023) Role of sex hormones in diabetic nephropathy. Front Endocrinol 14:1135530. https://doi.org/10.3389/fendo.2023.1135530
Ma HY, Chen S, Du Y (2021) Estrogen and estrogen receptors in kidney diseases. Ren Fail 43(1):619–642. https://doi.org/10.1080/0886022X.2021.1901739
Mancini FR, Rajaobelina K, Praud D, Dow C, Antignac JP, Kvaskoff M, Severi G, Bonnet F, Boutron-Ruault MC, Fagherazzi G (2018) Nonlinear associations between dietary exposures to perfluorooctanoic acid (PFOA) or perfluorooctane sulfonate (PFOS) and type 2 diabetes risk in women: findings from the E3N cohort study. Int J Hyg Environ Health 221(7):1054–1060. https://doi.org/10.1016/j.ijheh.2018.07.007
Midasch O, Schettgen T, Angerer J (2006) Pilot study on the perfluorooctanesulfonate and perfluorooctanoate exposure of the German general population. Int J Hyg Environ Health 209(6):489–496. https://doi.org/10.1016/j.ijheh.2006.06.002
Moon J (2021) Perfluoroalkyl substances (PFASs) exposure and kidney damage: causal interpretation using the US 2003-2018 National Health and Nutrition Examination Survey (NHANES) datasets. Environ Pollut 288:117707. https://doi.org/10.1016/j.envpol.2021.117707
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
Park SK, Wang X, Ding N, Karvonen-Gutierrez CA, Calafat AM, Herman WH, Mukherjee B, Harlow SD (2022) Per- and polyfluoroalkyl substances and incident diabetes in midlife women: the Study of Women’s Health Across the Nation (SWAN). Diabetologia 65(7):1157–1168. https://doi.org/10.1007/s00125-022-05695-5
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
Reijnierse EM, Trappenburg MC, Leter MJ, Sipilä S, Stenroth L, Narici MV, Hogrel JY, Butler-Browne G, McPhee JS, Pääsuke M, Gapeyeva H, Meskers CG, Maier AB (2015) Serum albumin and muscle measures in a cohort of healthy young and old participants. Age 37(5):88. https://doi.org/10.1007/s11357-015-9825-6
Rickard BP, Rizvi I, Fenton SE (2022) Per- and poly-fluoroalkyl substances (PFAS) and female reproductive outcomes: PFAS elimination, endocrine-mediated effects, and disease. Toxicology 465:153031
Rivera-Núñez Z, Kinkade CW, Khoury L, Brunner J, Murphy H, Wang C, Kannan K, Miller RK, O'Connor TG, Barrett ES (2023) Prenatal perfluoroalkyl substances exposure and maternal sex steroid hormones across pregnancy. Environ Res 220:115233. https://doi.org/10.1016/j.envres.2023.115233
Rosenstock JL, Pommier M, Stoffels G, Patel S, Michelis MF (2018) Prevalence of proteinuria and albuminuria in an obese population and associated risk factors. Front Med (Lausanne) 5:122. https://doi.org/10.3389/fmed.2018.00122
Santoro N (2016) Perimenopause: from research to practice. J Womens Health 25(4):332–339. https://doi.org/10.1089/jwh.2015.5556
Sipilä S (2003) Body composition and muscle performance during menopause and hormone replacement therapy. J Endocrinol Invest 26(9):893–901. https://doi.org/10.1007/BF03345241
Stanifer JW, Stapleton HM, Souma T, Wittmer A, Zhao X, Boulware LE (2018) Perfluorinated chemicals as emerging environmental threats to kidney health. Clin J Am Soc Nephrol 13(10):1479–1492. https://doi.org/10.2215/CJN.04670418
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
Villeneuve DL, Blackwell BR, Cavallin JE, Collins J, Hoang JX, Hofer RN, Houck KA, Jensen KM, Kahl MD, Kutsi RN, Opseth AS, Santana Rodriguez KJ, Schaupp C, Stacy EH, Ankley GT (2023) Verification of in vivo estrogenic activity for four per- and polyfluoroalkyl substances (PFAS) identified as estrogen receptor agonists via new approach methodologies. Environ Sci Technol 57(9):3794–3803. https://doi.org/10.1021/acs.est.2c09315
Wise LA, Wesselink AK, Schildroth S, Calafat AM, Bethea TN, Geller RJ et al (2022) Correlates of plasma concentrations of per- and poly-fluoroalkyl substances among reproductive-aged black women. Environ Res 203:111860
**a J, Wang L, Ma Z, Zhong L, Wang Y, Gao Y, He L, Su X (2017) Cigarette smoking and chronic kidney disease in the general population: a systematic review and meta-analysis of prospective cohort studies. Nephrol Dial Transplant 32(3):475–487. https://doi.org/10.1093/ndt/gfw452
Yacoub R, Habib H, Lahdo A, Al Ali R, Varjabedian L, Atalla G, Kassis Akl N, Aldakheel S, Alahdab S, Albitar S (2010) Association between smoking and chronic kidney disease: a case control study. BMC Public Health 10:731. https://doi.org/10.1186/1471-2458-10-731
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Ram B Jain: study design, statistical analysis, interpretation of results, writing, editing, and reviewing of draft and final manuscript. Alan Ducatman: study design, interpretation of results, writing, editing, and reviewing of draft and final manuscript.
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Ram B Jain declares that he had no financial and other conflicts that could have affected the conclusions arrived at in this communication. Alan Ducatman has received funding for health communications related to the enrollment and health communications of the C8 Health Project and he has provided paid scientific support to communities seeking similar class action support to institute medical monitoring following exposure to drinking water contaminants.
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Jain, R.B., Ducatman, A. Factors affecting serum PFAS concentrations among US females with surgically and naturally induced menopause: data from NHANES 2003–2018. Environ Sci Pollut Res 30, 84705–84724 (2023). https://doi.org/10.1007/s11356-023-28395-y
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DOI: https://doi.org/10.1007/s11356-023-28395-y