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

Abstract

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.

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Fig. 1: Associations between prenatal monoethyl phthalate (mEP) exposure (averaged across pregnancy) and child full scale IQ score at age 14 years, mediated by total gray matter volume at age 10 years.
Fig. 2: Associations between prenatal monoisobutyl phthalate (mIBP) exposure and child full scale IQ score at age 14, mediated by cerebral white matter volume at age 10 years.

Code availability

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

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Acknowledgements

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.

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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.

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Correspondence to Henning Tiemeier.

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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.

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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

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