Blog

Aug 27, 2023

Prenatal exposure to common plasticizers: a longitudinal study on phthalates, brain volumetric measures, and IQ in youth

Molecular Psychiatry (2023)Cite this article Metrics details Exposure to phthalates, used as plasticizers and solvents in consumer products, is ubiquitous. Despite growing concerns regarding their

Molecular Psychiatry (2023)Cite this article

Metrics details

Exposure to phthalates, used as plasticizers and solvents in consumer products, is ubiquitous. Despite growing concerns regarding their neurotoxicity, brain differences associated with gestational exposure to phthalates are understudied. We included 775 mother-child pairs from Generation R, a population-based pediatric neuroimaging study with prenatal recruitment, who had data on maternal gestational phthalate levels and T1-weighted magnetic resonance imaging in children at age 10 years. Maternal urinary concentrations of phthalate metabolites were measured at early, mid-, and late pregnancy. Child IQ was assessed at age 14 years. We investigated the extent to which prenatal exposure to phthalates is associated with brain volumetric measures and whether brain structural measures mediate the association of prenatal phthalate exposure with IQ. We found that higher maternal concentrations of monoethyl phthalate (mEP, averaged across pregnancy) were associated with smaller total gray matter volumes in offspring at age 10 years (β per log10 increase in creatinine adjusted mEP = −10.7, 95%CI: −18.12, −3.28). Total gray matter volumes partially mediated the association between higher maternal mEP and lower child IQ (β for mediated path =−0.31, 95%CI: −0.62, 0.01, p = 0.05, proportion mediated = 18%). An association of higher monoisobutyl phthalate (mIBP) and smaller cerebral white matter volumes was present only in girls, with cerebral white matter volumes mediating the association between higher maternal mIBP and lower IQ in girls. Our findings suggest the global impact of prenatal phthalate exposure on brain volumetric measures that extends into adolescence and underlies less optimal cognitive development.

This is a preview of subscription content, access via your institution

Subscribe to this journal

Receive 12 print issues and online access

$259.00 per year

only $21.58 per issue

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Analyses were performed in R Package version 3.4.1. Codes will be available upon request and communication with the corresponding author.

GBD. 2017 Child and Adolescent Health Collaborator. Diseases, Injuries, and Risk Factors in Child and Adolescent Health, 1990 to 2017: Findings From the Global Burden of Diseases, Injuries, and Risk Factors 2017 Study. JAMA Pediatr. 2019;173:e190337.

Article Google Scholar

White TJ, Shaw P, Viding E. The what, where, and when of childhood psychopathology: first steps towards identifying the etiological factors that shape brain development. J Am Acad Child Adolesc Psychiatry. 2017;56:S326.

Article Google Scholar

Bennett D, Bellinger DC, Birnbaum LS, Bradman A, Chen A, Cory-Slechta DA, et al. Project TENDR: targeting environmental neuro-developmental risks The TENDR consensus statement. Environ Health Perspect. 2016;124:A118–22.

Article PubMed PubMed Central Google Scholar

Annex XVII to REACH – Conditions of Restriction, Entry 51. https://echa.europa.eu/documents/10162/aaa92146-a005-1dc2-debe-93c80b57c5ee, Accessed Date December 29, 2022.

Assessing and Managing Chemicals under TSCA: Phthalates. June 2022, https://www.epa.gov/assessing-and-managing-chemicals-under-tsca/phthalates. Accessed Date December 29, 2022.

Wu H, Kupsco AJ, Deierlein AL, Just AC, Calafat AM, Oken E, et al. Trends and patterns of phthalates and phthalate alternatives exposure in pregnant women from Mexico City during 2007–2010. Environ Sci Technol. 2020;54:1740–9.

Article CAS PubMed PubMed Central Google Scholar

Gao H, Zhu BB, Tao XY, Zhu YD, Tao XG, Tao FB. Temporal variability of cumulative risk assessment on phthalates in Chinese pregnant women: repeated measurement analysis. Environ Sci Technol. 2018;52:6585–91.

Article CAS PubMed Google Scholar

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.

Article PubMed PubMed Central Google Scholar

Shu H, Jonsson BA, Gennings C, Svensson A, Nanberg E, Lindh CH, et al. Temporal trends of phthalate exposures during 2007-2010 in Swedish pregnant women. J Expo Sci Environ Epidemiol. 2018;28:437–47.

Article CAS PubMed Google Scholar

Gaylord A, Kannan K, Lakuleswaran M, Zhu H, Ghassabian A, Jacobson MH, et al. Variability and correlations of synthetic chemicals in urine from a New York City-based cohort of pregnant women. Environ Pollut. 2022;309:119774.

Article CAS PubMed Google Scholar

Trasande L, Shaffer RM, Sathyanarayana S. Food additives and child health. Pediatrics 2018;142:e20181408.

Article PubMed Google Scholar

Engel SM, Patisaul HB, Brody C, Hauser R, Zota AR, Bennet DH, et al. Neurotoxicity of ortho-phthalates: recommendations for critical policy reforms to protect brain development in children. Am J Public Health. 2021;111:687–95.

Article PubMed PubMed Central Google Scholar

Zhang Q, Chen XZ, Huang X, Wang M, Wu J. The association between prenatal exposure to phthalates and cognition and neurobehavior of children-evidence from birth cohorts. Neurotoxicology. 2019;73:199–212.

Article CAS PubMed Google Scholar

Radke EG, Braun JM, Nachman RM, Cooper GS. Phthalate exposure and neurodevelopment: A systematic review and meta-analysis of human epidemiological evidence. Environ Int. 2020;137:105408.

Article CAS PubMed PubMed Central Google Scholar

van den Dries MA, Guxens M, Spaan S, Ferguson KK, Philips E, Santos S, et al. Phthalate and bisphenol exposure during pregnancy and offpsring non-verbal IQ. Environ Health Perspect. 2020;128:77009.

Article PubMed Google Scholar

van den Dries MA, Ferguson KK, Keil AP, Pronk A, Spaan S, Ghassabian A, et al. Prenatal Exposure to Nonpersistent Chemical Mixtures and Offspring IQ and Emotional and Behavioral Problems. Environ Sci Technol. 2021;55:16502–14.

Article PubMed Google Scholar

Casas M, Valvi D, Ballesteros-Gomez A, Gascon M, Fernandez MF, Garcia-Esteban R, et al. Exposure to Bisphenol A and Phthalates during Pregnancy and Ultrasound Measures of Fetal Growth in the INMA-Sabadell Cohort. Environ Health Perspect. 2016;124:521–8.

Article CAS PubMed Google Scholar

Fu Y, Dong J, You M, Cong Z, Wei L, Fu H, et al. Maternal di-(2-ethylhexyl) phthalate exposure inhibits cerebellar granule precursor cell proliferation via down-regulating the Shh signaling pathway in male offspring. Chemosphere. 2019;215:313–22.

Article CAS PubMed Google Scholar

Kougias DG, Sellinger EP, Willing J, Juraska JM. Perinatal exposure to an environmentally relevant mixture of phthalates results in a lower number of neurons and synapses in the medial prefrontal cortex and decreased cognitive flexibility in adult male and female rats. J Neurosci. 2018;38:6864–72.

Article CAS PubMed PubMed Central Google Scholar

Komada M, Gendai Y, Kagawa N, Nagao T. Prenatal exposure to di(2-ethylhexyl) phthalate impairs development of the mouse neocortex. Toxicol Lett. 2016;259:69–79.

Article CAS PubMed Google Scholar

Casey BJ, Giedd JN, Thomas KM. Structural and functional brain development and its relation to cognitive development. Biol Psychol. 2000;54:241–57.

Article CAS PubMed Google Scholar

Andreasen NC, Flaum M, Swayze V, O’Leary DS, Alliger R, Cohen G, et al. Intelligence and brain structure in normal individuals. Am J Psychiatry. 1993;150:130.

Article CAS PubMed Google Scholar

Reiss AL, Abrams MT, Singer HS, Ross JL, Denckla MB. Brain development, gender and IQ in children: A volumetric imaging study. Brain. 1996;119:1763–74.

Article PubMed Google Scholar

Muetzel RL, Mous SE, van der Ende J, Blanken LM, van der Lugt A, Jaddoe VW, et al. White matter integrity and cognitive performance in school-age children: A population-based neuroimaging study. Neuroimage. 2015;119:119–28.

Article PubMed Google Scholar

Lenroot RK, Giedd JN. Brain development in children and adolescents: Insights from anatomical magnetic resonance imaging. Neurosci Biobehav Rev. 2006;30:718–29.

Article PubMed Google Scholar

Thomason ME, Hect JL, Rauh VA, Trentacosta C, Wheelock MD, Eggebrecht AT, et al. Prenatal lead exposure impacts cross-hemispheric and long-range connectivity in the human fetal brain. NeuroImage. 2019;191:186–92.

Article CAS PubMed Google Scholar

Rauh VA, Perera FP, Horton MK, Whyatt RM, Bansal R, Hao X, et al. Brain anomalies in children exposed prenatally to a common organophosphate pesticide. Proc Natl Acad Sci USA. 2012;109:7871–6.

Article CAS PubMed PubMed Central Google Scholar

Peterson BS, Rauh VA, Bansal R, Hao X, Toth Z, Nati G, et al. Effects of prenatal exposure to air pollutants (polycyclic aromatic hydrocarbons) on the development of brain white matter, cognition, and behavior in later childhood. JAMA Psychiatry. 2015;72:531–40.

Article PubMed PubMed Central Google Scholar

Guxens M, Lubczynska MJ, Muetzel RL, Dalmau-Bueno A, Jaddoe VWV, Hoek G, et al. Air Pollution Exposure During Fetal Life, Brain Morphology, and Cognitive Function in School-Age Children. Biol Psychiatry. 2018;84:295–303.

Article CAS PubMed Google Scholar

England-Mason G, Grohs MN, Reynolds JE, MacDonald A, Kinniburgh D, Liu J, et al. White matter microstructure mediates the association between prenatal exposure to phthalates and behavior problems in preschool children. Environ Res. 2020;182:109093.

Article CAS PubMed Google Scholar

White T, Muetzel RL, El Marroun H, Blanken LME, Jansen P, Bolhuis K, et al. Paediatric population neuroimaging and the Generation R Study: the second wave. Eur J Epidemiol. 2017;33:99–125.

Article PubMed PubMed Central Google Scholar

Kruithof CJ, Kooijman MN, van Duijn CM, Franco OH, de Jongste JC, Klaver CCW, et al. The Generation R Study: Biobank update 2015. Eur J Epidemiol. 2014;29:911–27.

Article CAS PubMed Google Scholar

Kooijman MN, Kruithof CJ, van Duijn CM, Duijts L, Franco OH, van IJzendoorn MH, et al. The Generation R Study: design and cohort update 2017. Eur J Epidemiol. 2016;31:1243–64.

Article PubMed Google Scholar

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.

Article CAS PubMed PubMed Central Google Scholar

Fischl B, van der Kouwe A, Destrieux C, Halgren E, Segonne F, Salat DH, et al. Automatically parcellating the human cerebral cortex. Cereb Cortex. 2004;14:11–22.

Article PubMed Google Scholar

Desikan RS, Ségonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D, et al. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. NeuroImage. 2006;31:968–80.

Article PubMed Google Scholar

White T, Jansen PR, Muetzel RL, Sudre G, El Marroun H, Tiemeier H, et al. Automated quality assessment of structural magnetic resonance images in children: Comparison with visual inspection and surface-based reconstruction. Hum Brain Mapp. 2018;39:1218–31.

Article PubMed Google Scholar

Muetzel RL, Mulder RH, Lamballais S, Cortes Hidalgo AP, Jansen P, Güroğlu B, et al. Frequent Bullying Involvement and Brain Morphology in Children. Front Psychiatry. 2019;10:696.

Article PubMed PubMed Central Google Scholar

Kaufman AS, Raiford SE, Coalson DL (2015): Intelligent Testing with the WISC-V. First Edition ed. Hoboken: John Wiley & Sons.

Blok E, Schuurmans IK, Tijburg AJ, Hillegers M, Koopman-Verhoeff ME, Muetzel RL et al. Cognitive performance in children and adolescents with psychopathology traits: A cross-sectional multicohort study in the general population. Dev Psychopathol. 2023;35:926–940.

Daniel MH, Wahlstrom D, Zhang O. Equivalence of Q-interactive™ and Paper Administrations of Cognitive Tasks: WISC®–V. Q-Interactive Technical Report 2014; 8.

Prieler J. Raven’s Advanced Progressive Matrices 24. Mödling, Austria: Schufried 2003.

Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the royal statistical society Series B 1995;57:289–300.

MacKinnon DP. Introduction to statistical mediation analysis. Routledge. 2008.

Steen J, Loeys T, Moerkerke B, Vansteelandt S. medflex: An R Package for Flexible Mediation Analysis using Natural Effect Models. J Stat Softw 2017;76:46.

Article Google Scholar

R core Team. A language and environment for statistical computing. Vienna, Austria. R Foundation for Statistical Computing. 2015.

van Buuren S, Groothuis-Oudshoorn C. MICE: Multivariate Imputation by Chained Equations in R. 2011.

Von Hippel PT. How to impute interactions, squares, and other transfored variables 2009; 39: 265-91.

Van Buuren S. Flexible Imputation of Missing Data Second edition. 2nd edn. Chapman & Hall/CRC Boca Raton, 2018.

Nieuwenhuijsen MJ Exposure assessment in environmental epidemiology. Oxford University Press, USA. 2015.

van Smeden M, Lash TL, Groenwold RHH. Reflection on modern methods: five myths about measurement error in epidemiological research. Int J Epidemiol. 2019;49:338–47.

Article PubMed Central Google Scholar

Yu Z, Han Y, Shen R, Huang K, Xu YY, Wang QN, et al. Gestational di-(2-ethylhexyl) phthalate exposure causes fetal intrauterine growth restriction through disturbing placental thyroid hormone receptor signaling. Toxicol Lett. 2018;294:1–10.

Article CAS PubMed Google Scholar

Li X, Jiang L, Cheng L, Chen H. Dibutyl phthalate-induced neurotoxicity in the brain of immature and mature rat offspring. Brain Dev. 2014;36:653–60.

Article PubMed Google Scholar

Lin LC, Wang SL, Chang YC, Huang PC, Cheng JT, Su PH, et al. Associations between maternal phthalate exposure and cord sex hormones in human infants. Chemosphere. 2011;83:1192–9.

Article CAS PubMed Google Scholar

Miranda A, Sousa N. Maternal hormonal milieu influence on fetal brain development. Brain Behav. 2018;8:e00920.

Article PubMed PubMed Central Google Scholar

Wai J, Lubinski D, Benbow CPJJoeP. Spatial ability for STEM domains: Aligning over 50 years of cumulative psychological knowledge solidifies its importance. J Educ Psychol 2009;101:817–835.

King MJ, Katz DP, Thompson LA, Macnamara BN. Genetic and environmental influences on spatial reasoning: A meta-analysis of twin studies. Intelligence. 2019;73:65–77.

Article Google Scholar

Xu H, Shao X, Zhang Z, Zou Y, Chen Y, Han S, et al. Effects of di-n-butyl phthalate and diethyl phthalate on acetylcholinesterase activity and neurotoxicity related gene expression in embryonic zebrafish. Bull Environ Contam Toxicol. 2013;91:635–9.

Article CAS PubMed Google Scholar

Poopal RK, Ramesh M, Maruthappan V, Babu, Rajendran R. Potential effects of low molecular weight phthalate esters (C(16)H(22)O(4) and C(12)H(14)O(4)) on the freshwater fish Cyprinus carpio. Toxicol Res. 2017;6:505–20.

Article CAS Google Scholar

Tran CM, Do TN, Kim K-T. Comparative analysis of neurotoxicity of six phthalates in zebrafish embryos. Toxics 2021;9:5.

Article CAS PubMed PubMed Central Google Scholar

Whyatt RM, Liu X, Rauh VA, Calafat AM, Just AC, Hoepner L, et al. Maternal prenatal urinary phthalate metabolite concentrations and child mental, psychomotor, and behavioral development at 3 years of age. Environ Health Perspect. 2012;120:290–5.

Article CAS PubMed Google Scholar

Doherty BT, Engel SM, Buckley JP, Silva MJ, Calafat AM, Wolff MS. Prenatal phthalate biomarker concentrations and performance on the Bayley Scales of Infant Development-II in a population of young urban children. Environ Res. 2017;152:51–8.

Article CAS PubMed Google Scholar

Download references

The Generation R Study is conducted by the Erasmus Medical Center in close collaborations with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, Rotterdam, the Rotterdam Homecare Foundation, Rotterdam and the Stichting Trombosedienst and Artsenlaboratorium Rijnmond (STAR-MDC), Rotterdam. We gratefully acknowledge the contribution of children and parents, 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 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 R01ES022972 and R01ES029779 from the National Institutes of Health (NIH) to LT. Neuroimaging and infrastructure was supported by the Netherlands Organization for Health Research and Development (ZonMw) TOP project number 9121102. The work of AG is supported by grant R01ES032826 from NIH. The work of MD is supported by grant 824989 from the Horizon2020 programme of the European Union. HT is supported by the ZonMW grant 016.VICI.170.200. MG is funded by a Miguel Servet fellowship (CPII18/00018) awarded by the Spanish Institute of Health Carlos III. We acknowledge support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. SME was supported by P30ES010126 and R01ES021777. VWVJ and MG received funding from the European Union’s Horizon 2020 research and innovation programme (Grant Agreement No. 733206 LifeCycle and Grant Agreement No. 874583 ATHLETE). The research was supported in part by the Intramural Research Program of the NIMH.

These authors contributed equally: Akhgar Ghassabian, Michiel van den Dries.

Department of Pediatrics, New York University School of Medicine, New York, NY, USA

Akhgar Ghassabian, Leonardo Trasande & Kurunthachalam Kannan

Department of Population Health, New York University School of Medicine, New York, NY, USA

Akhgar Ghassabian & Leonardo Trasande

Department of Child and Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands

Michiel van den Dries & Mònica Guxens

The Generation R Study Group, Erasmus University Medical Center, Rotterdam, the Netherlands

Michiel van den Dries, Vincent W. V. Jaddoe & Henning Tiemeier

ISGlobal, Barcelona, Spain

Michiel van den Dries & Mònica Guxens

Pompeu Fabra University, Barcelona, Spain

Michiel van den Dries & Mònica Guxens

Spanish Consortium for Research on Epidemiology and Public Health, Instituto de Salud Carlos III, 28029, Madrid, Spain

Michiel van den Dries & Mònica Guxens

New York University College of Global Public Health, New York City, NY, USA

Leonardo Trasande

New York University Wagner School of Public Service, New York City, NY, USA

Leonardo Trasande

Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands

Sander Lamballais

Department of Risk Analysis for Products in Development, TNO, Utrecht, the Netherlands

Suzanne Spaan & Anjoeka Pronk

Oncology Area, Center for Biomedical Research of La Rioja, Logroño, Spain

Maria-Pilar Martinez-Moral

Department of Pediatrics, Erasmus University Medical Center, Rotterdam, the Netherlands

Vincent W. V. Jaddoe

Department of Epidemiology, Gilling School of Global Public Health, University of North Carolina Chapel Hill, Chapel Hill, NC, USA

Stephanie M. Engel

Section on Social and Cognitive Developmental Neuroscience, National Institute of Mental Health Bethesda, Bethesda, MD, USA

Tonya White

Department of Social and Behavioral Sciences, Harvard TH Chan School of Public Health, Boston, MA, USA

Henning Tiemeier

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

AG conceptualized and designed the study, drafted the manuscript, interpreted the results, and reviewed and revised the manuscript; MvdD conceptualized and designed the study, carried out the analysis, and reviewed and revised the manuscript; M-PM-M and KK performed laboratory analysis of phthalates in urine. SLcarried out the analysis, and reviewed and revised the manuscript; SS, White, Pronk, Kannan, Jaddoe, Engel, and LT interpreted the results and reviewed and revised the manuscript; HT and MG conceptualized and designed the study, interpreted the results, and reviewed and revised the manuscript; all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. MG has full access to all the data in the study.

Correspondence to Henning Tiemeier.

The spouse of HT is an employee of Eastman Chemical, a company that manufactures substitutes for ortho-phthalate plasticizers. Other authors have no conflict of interest.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

Ghassabian, A., van den Dries, M., Trasande, L. et al. Prenatal exposure to common plasticizers: a longitudinal study on phthalates, brain volumetric measures, and IQ in youth. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02225-6

Download citation

Received: 19 January 2023

Revised: 01 August 2023

Accepted: 08 August 2023

Published: 29 August 2023

DOI: https://doi.org/10.1038/s41380-023-02225-6

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative