Fetal exposure to phthalates and bisphenols might have long-lasting effects on growth and fat development. Not much is known about the effects on general and organ fat development in childhood. We assessed the associations of fetal exposure to phthalates and bisphenols with general and organ fat measures in school-aged children.
In a population-based, prospective cohort study among 1128 mother–child pairs, we measured maternal urinary phthalate metabolites and bisphenol concentrations in first, second, and third trimester. Offspring body mass index, fat mass index by dual-energy X-ray absorptiometry, and visceral and pericardial fat indices and liver fat fraction were measured by magnetic resonance imaging at 10 years.
After adjustment for confounders and correction for multiple testing, an interquartile range increase in first trimester phthalic acid concentrations remained associated with a 0.14 (95% confidence interval: 0.05, 0.22) standard deviation score increase in pericardial fat index. We also observed tendencies for associations of higher maternal low molecular weight phthalate urinary concentrations in second trimester with childhood pericardial fat index, but these were not significant after adjustment for multiple testing. High molecular weight phthalate, di-2-ethylhexyl phthalate, and di-n-octyl phthalate concentrations were not associated with childhood outcomes. Maternal urinary bisphenol concentrations were not associated with childhood adiposity.
Maternal first trimester phthalic acid concentrations are associated with increased childhood pericardial fat index at 10 years of age, whereas maternal bisphenol concentrations are not associated with childhood adiposity. We did not find significant sex-specific effects. These findings should be considered as hypothesis generating and need further replication and identification of underlying mechanisms.
This is a preview of subscription content, access via your institution
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Woodruff TJ, Zota AR, Schwartz JM. Environmental chemicals in pregnant women in the United States: NHANES 2003-2004. Environ Health Perspect. 2011;119:878–85.
Ye X, Pierik FH, Hauser R, Duty S, Angerer J, Park MM, et al. Urinary metabolite concentrations of organophosphorous pesticides, bisphenol A, and phthalates among pregnant women in Rotterdam, the Netherlands: the Generation R Study. Environ Res. 2008;108:260–7.
Schettler T. Human exposure to phthalates via consumer products. Int J Androl. 2006;29:134–9.
Vandenberg LN, Hauser R, Marcus M, Olea N, Welshons WV. Human exposure to bisphenol A (BPA). Reprod Toxicol. 2007;24:139–77.
Wang Y, Zhu H, Kannan K. A review of biomonitoring of phthalate exposures. Toxics. 2019;7:21.
Mose T, Knudsen LE, Hedegaard M, Mortensen GK. Transplacental transfer of monomethyl phthalate and mono(2-ethylhexyl) phthalate in a human placenta perfusion system. Int J Toxicol. 2007;26:221–9.
Schonfelder G, Wittfoht W, Hopp H, Talsness CE, Paul M, Chahoud I. Parent bisphenol A accumulation in the human maternal-fetal-placental unit. Environ Health Perspect. 2002;110:A703–7.
Nahar MS, Liao C, Kannan K, Harris C, Dolinoy DC. In utero bisphenol A concentration, metabolism, and global DNA methylation across matched placenta, kidney, and liver in the human fetus. Chemosphere. 2015;124:54–60.
Mattison DR, Karyakina N, Goodman M, LaKind JS. Pharmaco- and toxicokinetics of selected exogenous and endogenous estrogens: a review of the data and identification of knowledge gaps. Crit Rev Toxicol. 2014;44:696–724.
Taxvig C, Dreisig K, Boberg J, Nellemann C, Schelde AB, Pedersen D, et al. Differential effects of environmental chemicals and food contaminants on adipogenesis, biomarker release and PPARgamma activation. Mol Cell Endocrinol. 2012;361:106–15.
Meng Z, Wang D, Liu W, Li R, Yan S, Jia M, et al. Perinatal exposure to bisphenol S (BPS) promotes obesity development by interfering with lipid and glucose metabolism in male mouse offspring. Environ Res. 2019;173:189–98.
Desai M, Ferrini MG, Jellyman JK, Han G, Ross MG. In vivo and in vitro bisphenol A exposure effects on adiposity. J Dev Orig Health Dis. 2018;9:678–87.
Lee KI, Chiang CW, Lin HC, Zhao JF, Li CT, Shyue SK, et al. Maternal exposure to di-(2-ethylhexyl) phthalate exposure deregulates blood pressure, adiposity, cholesterol metabolism and social interaction in mouse offspring. Arch Toxicol. 2016;90:1211–24.
Harley KG, Berger K, Rauch S, Kogut K, Claus Henn B, Calafat AM, et al. Association of prenatal urinary phthalate metabolite concentrations and childhood BMI and obesity. Pediatr Res. 2017;82:405–15.
Hoepner LA, Whyatt RM, Widen EM, Hassoun A, Oberfield SE, Mueller NT, et al. Bisphenol A and adiposity in an inner-city birth cohort. Environ Health Perspect. 2016;124:1644–50.
Harley KG, Aguilar Schall R, Chevrier J, Tyler K, Aguirre H, Bradman A, et al. Prenatal and postnatal bisphenol A exposure and body mass index in childhood in the CHAMACOS cohort. Environ Health Perspect. 2013;121:514–20.
Maresca MM, Hoepner LA, Hassoun A, Oberfield SE, Mooney SJ, Calafat AM, et al. Prenatal exposure to phthalates and childhood body size in an urban cohort. Environ Health Perspect. 2016;124:514–20.
Buckley JP, Engel SM, Mendez MA, Richardson DB, Daniels JL, Calafat AM, et al. Prenatal phthalate exposures and childhood fat mass in a New York City cohort. Environ Health Perspect. 2016;124:507–13.
Shoaff J, Papandonatos GD, Calafat AM, Ye X, Chen A, Lanphear BP, et al. Early-life phthalate exposure and adiposity at 8 years of age. Environ Health Perspect. 2017;125:097008.
Vafeiadi M, Myridakis A, Roumeliotaki T, Margetaki K, Chalkiadaki G, Dermitzaki E, et al. Association of early life exposure to phthalates with obesity and cardiometabolic traits in childhood: sex specific associations. Front Public Health. 2018;6:327.
Yang TC, Peterson KE, Meeker JD, Sanchez BN, Zhang Z, Cantoral A, et al. Bisphenol A and phthalates in utero and in childhood: association with child BMI z-score and adiposity. Environ Res. 2017;156:326–33.
Buckley JP, Herring AH, Wolff MS, Calafat AM, Engel SM. Prenatal exposure to environmental phenols and childhood fat mass in the Mount Sinai Children’s Environmental Health Study. Environ Int. 2016;91:350–6.
Buckley JP, Engel SM, Braun JM, Whyatt RM, Daniels JL, Mendez MA, et al. Prenatal phthalate exposures and body mass index among 4- to 7-year-old children: a pooled analysis. Epidemiology. 2016;27:449–58.
Yang TC, Peterson KE, Meeker JD, Sanchez BN, Zhang Z, Cantoral A, et al. Exposure to bisphenol A and phthalates metabolites in the third trimester of pregnancy and BMI trajectories. Pediatr Obes. 2018;13:550–7.
Lim S, Meigs JB. Ectopic fat and cardiometabolic and vascular risk. Int J Cardiol. 2013;169:166–76.
Kooijman MN, Kruithof CJ, van Duijn CM, Duijts L, Franco OH, van IMH, et al. The Generation R Study: design and cohort update 2017. Eur J Epidemiol. 2016;31:1243–64.
Philips EM, Jaddoe VWV, Asimakopoulos AG, Kannan K, Steegers EAP, Santos S, et al. Bisphenol and phthalate concentrations and its determinants among pregnant women in a population-based cohort in the Netherlands, 2004-5. Environ Res. 2018;161:562–72.
Hornung RWRL. Estimation of average concentration in the presence of nondetectable values. Appl Occup Environ Hyg. 1990;5:46–51.
Fredriks AM, van Buuren S, Wit JM, Verloove-Vanhorick SP. Body index measurements in 1996-7 compared with 1980. Arch Dis Child. 2000;82:107–12.
Kaul S, Rothney MP, Peters DM, Wacker WK, Davis CE, Shapiro MD, et al. Dual-energy X-ray absorptiometry for quantification of visceral fat. Obesity. 2012;20:1313–8.
Santos S, Monnereau C, Felix JF, Duijts L, Gaillard R, Jaddoe VWV. Maternal body mass index, gestational weight gain, and childhood abdominal, pericardial, and liver fat assessed by magnetic resonance imaging. Int J Obes. 2019;43:581–93.
Hu HH, Nayak KS, Goran MI. Assessment of abdominal adipose tissue and organ fat content by magnetic resonance imaging. Obes Rev. 2011;12:e504–15.
VanItallie TB, Yang MU, Heymsfield SB, Funk RC, Boileau RA. Height-normalized indices of the body’s fat-free mass and fat mass: potentially useful indicators of nutritional status. Am J Clin Nutr. 1990;52:953–9.
Wells JC, Cole TJ. ALSPAC study steam. Adjustment of fat-free mass and fat mass for height in children aged 8 y. Int J Obes Relat Metab Disord. 2002;26:947–52.
Nguyen AN, de Barse LM, Tiemeier H, Jaddoe VWV, Franco OH, Jansen PW, et al. Maternal history of eating disorders: diet quality during pregnancy and infant feeding. Appetite. 2017;109:108–14.
Santos S, Zugna D, Pizzi C, Richiardi L. Sources of confounding in life course epidemiology. J Dev Orig Health Dis. 2019;10:299–305.
Lewin A, Arbuckle TE, Fisher M, Liang CL, Marro L, Davis K, et al. Univariate predictors of maternal concentrations of environmental chemicals: the MIREC study. Int J Hyg Environ Health. 2017;220:77–85.
Al-Saleh I, Coskun S, Al-Doush I, Al-Rajudi T, Abduljabbar M, Al-Rouqi R, et al. The extent and predictors of phthalate exposure among couples undergoing in vitro fertilization treatment. Environ Monit Assess. 2019;191:316.
Gules O, Yildiz M, Naseer Z, Tatar M. Effects of folic acid on testicular toxicity induced by bisphenol-A in male Wistar rats. Biotech Histochem. 2019;94:26–35.
Dolinoy DC, Huang D, Jirtle RL. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci USA. 2007;104:13056–61.
Pauwels S, Ghosh M, Duca RC, Bekaert B, Freson K, Huybrechts I, et al. Maternal intake of methyl-group donors affects DNA methylation of metabolic genes in infants. Clin Epigenetics. 2017;9:16.
Li MX, Yeung JM, Cherny SS, Sham PC. Evaluating the effective numbers of independent tests and significant p-value thresholds in commercial genotyping arrays and public imputation reference datasets. Hum Genet. 2012;131:747–56.
Fall CH. Evidence for the intra-uterine programming of adiposity in later life. Ann Hum Biol. 2011;38:410–28.
Liu J, Fox CS, Hickson D, Sarpong D, Ekunwe L, May WD, et al. Pericardial adipose tissue, atherosclerosis, and cardiovascular disease risk factors: the Jackson heart study. Diabetes Care. 2010;33:1635–9.
Shah RV, Anderson A, Ding J, Budoff M, Rider O, Petersen SE, et al. Pericardial, but not hepatic, fat by CT is associated with CV outcomes and structure: the multi-ethnic study of atherosclerosis. JACC Cardiovasc Imaging. 2017;10:1016–27.
Ay L, Hokken-Koelega AC, Mook-Kanamori DO, Hofman A, Moll HA, Mackenbach JP, et al. Tracking and determinants of subcutaneous fat mass in early childhood: the Generation R Study. Int J Obes. 2008;32:1050–9.
Freitas D, Beunen G, Maia J, Claessens A, Thomis M, Marques A, et al. Tracking of fatness during childhood, adolescence and young adulthood: a 7-year follow-up study in Madeira Island, Portugal. Ann Hum Biol. 2012;39:59–67.
Botton J, Philippat C, Calafat AM, Carles S, Charles MA, Slama R, et al. Phthalate pregnancy exposure and male offspring growth from the intra-uterine period to five years of age. Environ Res. 2016;151:601–9.
Agay-Shay K, Martinez D, Valvi D, Garcia-Esteban R, Basagana X, Robinson O, et al. Exposure to endocrine-disrupting chemicals during pregnancy and weight at 7 years of age: a multi-pollutant approach. Environ Health Perspect. 2015;123:1030–7.
Valvi D, Monfort N, Ventura R, Casas M, Casas L, Sunyer J, et al. Variability and predictors of urinary phthalate metabolites in Spanish pregnant women. Int J Hyg Environ Health. 2015;218:220–31.
Braun JM, Li N, Arbuckle TE, Dodds L, Massarelli I, Fraser WD, et al. Association between gestational urinary bisphenol a concentrations and adiposity in young children: the MIREC study. Environ Res. 2019;172:454–61.
Braun JM, Lanphear BP, Calafat AM, Deria S, Khoury J, Howe CJ, et al. Early-life bisphenol a exposure and child body mass index: a prospective cohort study. Environ Health Perspect. 2014;122:1239–45.
Vafeiadi M, Roumeliotaki T, Myridakis A, Chalkiadaki G, Fthenou E, Dermitzaki E, et al. Association of early life exposure to bisphenol A with obesity and cardiometabolic traits in childhood. Environ Res. 2016;146:379–87.
Yamaguchi Y, Cavallero S, Patterson M, Shen H, Xu J, Kumar SR, et al. Adipogenesis and epicardial adipose tissue: a novel fate of the epicardium induced by mesenchymal transformation and PPARgamma activation. Proc Natl Acad Sci USA. 2015;112:2070–5.
Wei J, Lin Y, Li Y, Ying C, Chen J, Song L, et al. Perinatal exposure to bisphenol A at reference dose predisposes offspring to metabolic syndrome in adult rats on a high-fat diet. Endocrinology. 2011;152:3049–61.
Nohr EA, Liew Z. How to investigate and adjust for selection bias in cohort studies. Acta Obstet Gynecol Scand. 2018;97:407–16.
Braun JM, Sathyanarayana S, Hauser R. Phthalate exposure and children’s health. Curr Opin Pediatr. 2013;25:247–54.
Hauser R, Meeker JD, Park S, Silva MJ, Calafat AM. Temporal variability of urinary phthalate metabolite levels in men of reproductive age. Environ Health Perspect. 2004;112:1734–40.
Braun JM, Smith KW, Williams PL, Calafat AM, Berry K, Ehrlich S, et al. Variability of urinary phthalate metabolite and bisphenol A concentrations before and during pregnancy. Environ Health Perspect. 2012;120:739–45.
Mahalingaiah S, Meeker JD, Pearson KR, Calafat AM, Ye X, Petrozza J, et al. Temporal variability and predictors of urinary bisphenol A concentrations in men and women. Environ Health Perspect. 2008;116:173–8.
Zhang Y, Meng X, Chen L, Li D, Zhao L, Zhao Y, et al. Age and sex-specific relationships between phthalate exposures and obesity in Chinese children at puberty. PLoS ONE. 2014;9:e104852.
Wang H, Zhou Y, Tang C, He Y, Wu J, Chen Y, et al. Urinary phthalate metabolites are associated with body mass index and waist circumference in Chinese school children. PLoS ONE. 2013;8:e56800.
Teitelbaum SL, Mervish N, Moshier EL, Vangeepuram N, Galvez MP, Calafat AM, et al. Associations between phthalate metabolite urinary concentrations and body size measures in New York City children. Environ Res. 2012;112:186–93.
Trasande L, Attina TM, Sathyanarayana S, Spanier AJ, Blustein J. Race/ethnicity-specific associations of urinary phthalates with childhood body mass in a nationally representative sample. Environ Health Perspect. 2013;121:501–6.
We gratefully acknowledge the contribution of the participating children, their mothers, general practitioners, hospitals, midwives, and pharmacies in Rotterdam.
The general design of the Generation R Study is made possible by financial support from the Erasmus MC, University Medical Center, Rotterdam, the Netherlands, the Organization for Health Research and Development (ZonMw) and the Ministry of Health, Welfare and Sport. This study was supported by grant RO1-ES022972 and RO1-ES029779 from the National Institutes of Health, USA. This work was supported by the European Union’s Horizon 2020 research and innovation program under grant agreement 874583 (ATHLETE Project). The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health. VWVJ received an additional grant from the European Research Council (ERC Consolidator Grant, ERC-2014-CoG-64916).
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Sol, C.M., Santos, S., Duijts, L. et al. Fetal exposure to phthalates and bisphenols and childhood general and organ fat. A population-based prospective cohort study. Int J Obes 44, 2225–2235 (2020). https://doi.org/10.1038/s41366-020-00672-7