Background:
• Identifying factors that impair bone accrual during childhood is a critical step toward osteoporosis prevention.
• One potential risk factor not well characterized in childhood is the role of chemicals in the environment.
• Perfluoroalkyl substances (PFASs) are synthetic additives used to make clothing, furniture, and cookware stain repellant and are detectable in almost all US adults.
• PFASs act as PPAR-γ agonists,2 androgen receptor antagonists, and directly intercalate into bone, raising the possibility that they may lead to low bone accrual.
• While two population-based studies in adults have shown associations between PFASs and low areal bone mineral density (aBMD),5,6 the extent to which PFASs may affect aBMD in children is unknown

Cluett, Rachel

Coull, Brent

Fleisch, Abby F

Gold, Diane R

Gordon, Catherine M

Oken, Emily

Rifas-Shiman, Sheryl L

Rokoff, Lisa B

Rosen, Clifford J

Sagiv, Sharon K

Seshasayee, Shravanthi M

English

MaineHealth Knowledge Connection

MaineHealthMaineHealth Knowledge ConnectionMaine Medical Center All MaineHealth5-1-2019Per- and Polyfluoroalkyl Substances and BoneMineral Density in Mid-childhoodShravanthi M. SeshasayeeMaine Medical CenterRachel CluettLisa B. RokoffSheryl L. Rifas-ShimanDiane R. GoldSee next page for additional authorsFollow this and additional works at: https://knowledgeconnection.mainehealth.org/mmcPart of the Pediatrics CommonsThis Poster is brought to you for free and open access by the All MaineHealth at MaineHealth Knowledge Connection. It has been accepted forinclusion in Maine Medical Center by an authorized administrator of MaineHealth Knowledge Connection. For more information, please contactmckeld1@mmc.org.Recommended CitationSeshasayee, Shravanthi M.; Cluett, Rachel; Rokoff, Lisa B.; Rifas-Shiman, Sheryl L.; Gold, Diane R.; Coull, Brent; Gordon, CatherineM.; Rosen, Clifford J.; Oken, Emily; Sagiv, Sharon K.; and Fleisch, Abby F., "Per- and Polyfluoroalkyl Substances and Bone MineralDensity in Mid-childhood" (2019). Maine Medical Center. 698.https://knowledgeconnection.mainehealth.org/mmc/698AuthorsShravanthi M. Seshasayee, Rachel Cluett, Lisa B. Rokoff, Sheryl L. Rifas-Shiman, Diane R. Gold, Brent Coull,Catherine M. Gordon, Clifford J. Rosen, Emily Oken, Sharon K. Sagiv, and Abby F. FleischThis poster is available at MaineHealth Knowledge Connection: https://knowledgeconnection.mainehealth.org/mmc/698Background• Identifying factors that impair bone accrual during childhood is a critical step toward osteoporosis prevention. • One potential risk factor not well characterized in childhood is the role of chemicals in the environment.• Perfluoroalkyl substances (PFASs) are synthetic additives used to make clothing, furniture, and cookware stain repellant and are detectable in almost all US adults1.• PFASs act as PPAR-γ agonists,2 androgen receptor antagonists,3 and directly intercalate into bone,4 raising the possibility that they may lead to low bone accrual.• While two population-based studies in adults have shown associations between PFASs and low areal bone mineral density (aBMD),5,6 the extent to which PFASs may affect aBMD in children is unknown.ObjectiveThe authors have received support from the National Institutes of Health (NIEHS R01ES021447, NICHD R01HD034568, NIEHS K23ES024803, OD UG3OD023286, NIEHS R01ES030101)Per- and Polyfluoroalkyl Substances and Bone Mineral Density in Mid-childhood1Center for Outcomes Research and Evaluation, Maine Medical Center Research Institute, 2Department of Environmental Health, Harvard T. H. Chan School of Public Health, 3Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, 4Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 5Department of Biostatistics, Harvard T. H. Chan School of Public Health, 6Division of Adolescent/Young Adult Medicine, Boston Children’s Hospital, 7Center for Clinical & Translational Research, Maine Medical Center Research Institute, 8Center for Environmental Research and Children's Health (CERCH), School of Public Health, University of California - Berkeley, 9Pediatric Endocrinology and Diabetes, Maine Medical CenterThe authors have no financial relationships to disclose or conflicts of interest to resolve.Examine the associations of plasma PFAS concentrations with aBMD Z-score in mid-childhood (mean 7.9 years)Shravanthi M. Seshasayee, BDS MPH,1* Rachel Cluett, MPH,2 Lisa B. Rokoff, MS,3 Sheryl L. Rifas-Shiman, MPH,3Diane R. Gold, MD MPH,2, 4 Brent Coull, PhD,5 Catherine M. Gordon, MD, MS,6 Clifford J. Rosen, MD,7 Emily Oken, MD MPH,3 Sharon K. Sagiv, PhD MPH,8 Abby F. Fleisch, MD MPH1, 9ResultsExposure (PFASs):• Perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorodecanoate (PFDA), perfluorohexane sulfonate (PFHxS), 2-(N-methyl-perfluorooctane sulfonamido) acetate (MeFOSAA), perfluorononanoate (PFNA)• Measured in plasma by CDC staff using on-line solid-phase extraction with isotope dilution high performance liquid chromatography mass spectrometryOutcome (aBMD Z-score):• Total body (excluding the skull) aBMD measured via dual-energy X-ray absorptiometry (DXA)• Analyzed DXA data with pediatric software (Hologic, version 12.6) and used U.S. national reference data to derive age-, sex-, race-, and height-adjusted aBMD Z-scores.7Statistical analyses:• Used linear regression to examine associations of each PFAS with aBMD Z-score separately in single-PFAS models, and mutually adjusted with other PFASs in a multi-PFAS model• Examined association between the PFAS mixture and aBMD Z-score via weighted quantile sum (WQS) regression. WQS generates a composite mixture index for each participant, assigning each PFAS within the mixture a weight reflecting:  Strength of its association with aBMD Z-score Collinearity with other PFASs within mixture • Log2 transformed plasma PFAS concentrations for linear associations with outcome• Covariates in final models were maternal age, education, annual household income, census tract median household income, and child age, sex, race/ethnicity,  and dairy intake, physical activity, and year of blood draw• No evidence for effect modification by sex, so present results without an interaction termFigure 1. Single and multi-PFAS models showing adjusted associations of individual PFAS plasma concentrations with aBMD Z-scoreStrengths and LimitationsStrengths• Among the first studies to evaluate role of toxicants on bone health in childhood• PFAS concentrations typical for US population during peak production• Used WQS regression to assess exposure to PFAS mixtureLimitations• High SES cohort limits generalizability• Cross sectional analysis, so unable to assess mediation by BMI or pubertal status Conclusions ReferencesEach IQR increment in the WQS index was associated with a -0.16 lower aBMD Z-score (95% CI: -0.28, -0.04).• Higher exposure to PFASs was associated with lower aBMD Z-scores in children.• Lower exposures to environmental toxicants such as PFASs may improve childhood bone accrual and optimize lifelong skeletal health.AcknowledgementsWe thank the staff and participants of Project Viva for their support. We also thank CDC staff for conducting PFAS measurements.1. Calafat AM, Kuklenyik Z, Reidy JA, Caudill SP, Tully JS, Needham LL. 2007. Serum concentrations of 11 polyfluoroalkyl compounds in the U.S. Population: Data from the National Health and Nutrition Examination Survey (NHANES). Environ Sci Technol 41:2237-2242.2. Yamamoto J, Yamane T, Oishi Y, Kobayashi-Hattori K. 2015. Perfluorooctanoic acid binds to peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation in 3T3-l1 adipocytes. Biosci Biotechnol Biochem 79:636-639.3. Kjeldsen LS, Bonefeld-Jorgensen EC. 2013. Perfluorinated compounds affect the function of sex hormone receptors. Environ Sci Pollut Res Int 20:8031-8044.4. Koskela A, Koponen J, Lehenkari P, Viluksela M, Korkalainen M, Tuukkanen J. 2017. Perfluoroalkyl substances in human bone: Concentrations in bones and effects on bone cell differentiation. Sci Rep 7:6841.5. Khalil N, Chen A, Lee M, Czerwinski SA, Ebert JR, DeWitt JC, et al. 2016. Association of perfluoroalkyl substances, bone mineral density, and osteoporosis in the U.S. Population in NHANES 2009–2010. Environ Health Perspect 124:81-87.6. Lin LY, Wen LL, Su TC, Chen PC, Lin CY. 2014. Negative association between serum perfluorooctane sulfate concentration and bone mineral density in U.S. premenopausal women: NHANES, 2005-2008. J Clin Endocrinol Metab 99:2173-2180.7. Zemel BS, Kalkwarf HJ, Gilsanz V, Lappe JM, Oberfield S, Shepherd JA, et al. 2011. Revised reference curves for bone mineral content and areal bone mineral density according to age and sex for black and non-black children: Results of the bone mineral density in childhood study. J Clin Endocrinol Metab 96:3160-3169.MethodsQuartiles of PFOA a plasma concentrationOverall n=576Q1n=145Q2 Q3n=140Q4n=144n=147Mean ± SD or n (% )Maternal characteristicsMaternal age at enrollment (years)31.8 ± 5.7 29.8 ± 6.5 31.6 ± 5.9 32.7 ± 5.0 33.1 ± 4.5College graduate (%) 364 (64) 59 (41) 89 (61) 101 (73) 115 (80)Individual household income (%)< $40,000/year 85 (16) 39 (30) 20 (14) 15 (11) 11 (8)$40,001-$70,000/year 89 (16) 25 (19) 23 (17) 22 (16) 19 (13)> $70,000/year 369 (68) 65 (51) 96 (69) 98 (73) 110 (79)Census tract median householdincome ($10,000/year) 62.7 ± 23.7 53.5 ± 21.0 60.4 ± 23.2 64.7 ± 21.0 72.4 ± 25.5Child characteristicsAge (years) 7.9 ± 0.8 8.2 ± 1.0 8.0 ± 0.8 7.8 ± 0.7 7.7 ± 0.6Female (%) 280 (49) 73 (50) 73 (50 101 (45) 71 (49)Race/ethnicity (%)White 328 (57) 37 (26) 80 (54) 94 (68) 117 (81)Black 129 (23) 66 (46) 32 (22) 21 (15) 10 (7)Other 117 (20) 41 (28) 35 (24) 24 (17) 17 (12)Dairy intake (servings/wk) 2.2 ± 1.5 2.0 ± 1.5 2.2 ± 1.5 2.3 ± 1.6 2.4 ± 1.5Physical activity (hrs/wk) 1.9 ± 1.4 1.9 ± 1.5 1.7 ± 1.3 1.9 ± 1.2 1.9 ± 1.5aBMD Z-score -0.86 ± 0.77 -0.73 ± 0.73 -0.81 ± 0.84 -0.95 ± 0.73 -0.93 ± 0.78a PFOA quartile minimum and maximum values: <0.1 (LOD)-3.0 ng/mL for Q1, 3.1-4.4 ng/mL for Q2, 4.5-6.1 ng/mL for Q3, and 6.2-14.3 ng/mL for Q4Table 1. Participant characteristics overall and by PFOA plasma concentrationPlasma PFAS concentrations (ng/mL)PFOA PFOS PFDA PFHxS MeFOSAA PFNAMedian (IQR) 4.4 (3.2) 6.4 (5.6) 0.3 (0.3) 1.9 (2.3) 0.3 (0.5) 1.5 (1.2)5th percentile 1.9 2.1 < LOD a 0.6 < LOD a 0.795th percentile 9.8 18.7 0.7 14.7 1.9 5.1Detection frequency (%) 99.5 99.5 88.4 99.5 65.6 99.5Spearman correlation coefficientsPFOA 1.00PFOS 0.79 1.00PFDA 0.69 0.59 1.00PFHxS 0.60 0.67 0.34 1.00MeFOSAA 0.50 0.63 0.32 0.37 1.00PFNA 0.43 0.35 0.57 0.13 0.22 1.00a Limit of detection (LOD) was 0.1 ng/mL for all PFASs Table 2. Plasma PFAS concentration distributions and correlations Study population (Project Viva)Boston-area pregnant women enrolled 1999-2002 into the prospective Project Viva birth cohortEnrolled: 2,128 mother-infant pairsMid-childhood follow-up: 1,116 childrenaBMDmeasured: 576 childrenPlasma PFAS measured: 653 childrenFigure 2. Weights assigned to individual PFASs within the WQS composite indexPFOA PFOS PFDA PFHxS MeFOSAA PFNA0.40.30.20.10.0-0.1-0.2-0.3-0.437%29%23%8%3%0%PFDAMeFOSAAPFOAPFOSPFHxSPFNA

Per- and Polyfluoroalkyl Substances and Bone Mineral Density in Mid-childhood

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Per- and Polyfluoroalkyl Substances and Bone Mineral Density in Mid-childhood

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