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Background: Prenatal exposure to organophosphate (OP) pesticides has been associated with altered neuronal cell development and behavioral changes in animal offspring. However, the few studies investigating the association between prenatal OP pesticide exposure and neurodevelopmental outcomes such as Attention-Deficit Hyperactivity Disorder (ADHD) and autistic traits in children produced mixed findings. Objective: The objective of the present study was to examine whether maternal urinary concentrations of OP pesticide metabolites are associated with ADHD and autistic traits in children participating in the Generation R Study, a population-based birth cohort from Rotterdam, the Netherlands. Method: Maternal concentrations of 6 dialkylphosphates (DAPs) were measured using gas chromatography coupled with tandem mass spectrometry in urine samples collected at 25 weeks of gestation in 784 mother-child pairs. DAP metabolite concentrations were expressed as molar concentrations divided by creatinine levels and log10 transformed. ADHD traits were measured at ages 3, 6, and 10 years using the Child Behavior Checklist (CBCL) (n = 781) and autistic traits were measured at age 6 years using the Social Responsiveness Scale (SRS) (n = 622). First, regression models were fit for the averaged prenatal exposure across pregnancy. Second, we investigated associations for each collection phase separately, and applied a mutually adjusted model in which the effect of prenatal DAP concentrations from each time period on ADHD and autistic traits were jointly estimated. All associations were adjusted for relevant confounders. Results: Median DAP metabolite concentration was 309 nmol/g creatinine at 25 weeks of gestation. Overall, DAP metabolite concentrations were not associated with ADHD traits. For instance, a log10 increase in averaged total DAP concentrations across gestation was not associated with a lower ADHD score (-0.03 per SD 95 CI: -0.28 to 0.23). Similarly, no associations between maternal DAP concentrations and autistic traits were detected. Conclusions: In this study of maternal urinary DAP metabolite concentrations during pregnancy, we did not observe associations with ADHD and autistic traits in children. These are important null observations because of the relatively high background DAP concentrations across pregnancy, the relatively large sample size, and the 10-year follow-up of the offspring. Given the measurement error inherent in our OP pesticide exposure biomarkers, future studies using more urine samples are needed to accurately measure OP pesticide exposure over pregnancy in relation to ADHD and autistic traits. ; This research received financial support from the National Institutes of Health Grants K12 ES019852 and P30 ES001247, and from the intramural research program of the National Institute of Environmental Health Sciences, National Institutes of Health. Henning Tiemeier was supported by a grant of the Netherlands Organization for Scientific Research (NWO grant No. 024.001.003, Consortium on Individual Development, and NWO/ZonMW grant 016.VICI.170.200). Mònica Guxens is funded by a Miguel Servet fellowship (MS13/00054, CPII18/00018) awarded by the Spanish Institute of Health Carlos III. ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. Dr. Hanan El Marroun was supported by Stichting Volksbond Rotterdam, the Dutch Brain Foundation (De Hersenstichting, project number GH2016.2.01) and the European Union's Horizon 2020 research and innovation programme (grant agreement No. 733206 LifeCycle).

Background: Air pollution exposure during fetal life has been related to impaired child neurodevelopment, but it is unclear if brain structural alterations underlie this association. The authors assessed whether air pollution exposure during fetal life alters brain morphology and whether these alterations mediate the association between air pollution exposure during fetal life and cognitive function in school-age children. Methods: We used data from a population-based birth cohort set up in Rotterdam, The Netherlands (2002–2006). Residential levels of air pollution during the entire fetal period were calculated using land-use regression models. Structural neuroimaging and cognitive function were performed at 6 to 10 years of age (n = 783). Models were adjusted for several socioeconomic and lifestyle characteristics. Results: Mean fine particle levels were 20.2 μg/m3 (range, 16.8–28.1 μg/m3). Children exposed to higher particulate matter levels during fetal life had thinner cortex in several brain regions of both hemispheres (e.g., cerebral cortex of the precuneus region in the right hemisphere was 0.045 mm thinner (95% confidence interval, 0.028–0.062) for each 5-μg/m3 increase in fine particles). The reduced cerebral cortex in precuneus and rostral middle frontal regions partially mediated the association between exposure to fine particles and impaired inhibitory control. Air pollution exposure was not associated with global brain volumes. Conclusions: Exposure to fine particles during fetal life was related to child brain structural alterations of the cerebral cortex, and these alterations partially mediated the association between exposure to fine particles during fetal life and impaired child inhibitory control. Such cognitive impairment at early ages could have significant long-term consequences. ; This work was supported by European Community Seventh Framework Program Grant Nos. GA#211250 (to BB) and GA#243406 (BB; principal investigator, Ranjeet S. Sokhi) for air pollution exposure assessment; The Netherlands Organization for Health Research and Development (Geestkracht Program Grant No. 10.000.1003 (to HT) and Grant No. TOP 40-00812-98-11021 [to TW]); the Health Effects Institute, an organization jointly funded by the U.S. Environmental Protection Agency (Assistance Award Grant No. R-82811201), and certain motor vehicle and engine manufacturers (to MG); The Netherlands Organization for Health Research and Development Grant Nos. VIDI 016.136.361 (to VWVJ) and The Netherlands Organization for Scientific Research Grant No. 016.VICI.170.200 (to HT); European Research Council Grant No. ERC-2014-CoG-64916 (to VWVJ); European Union Horizon 2020 research and innovation program Grant Nos. 633595 (DynaHEALTH) (to HT) and 733206 (LifeCycle) (to VWVJ); a personal fellowship (EUR Fellow 2014) from the Erasmus University Rotterdam (to HEM); and Miguel Servet fellowship Grant Nos. MS13/00054 and CP13/00054 (to MG) awarded by the Spanish Institute of Health Carlos III (Ministry of Economy and Competitiveness).

Background: Air pollution has been related to brain structural alterations, but a relationship with white matter microstructure is unclear. Objectives: We assessed whether pregnancy and childhood exposures to air pollution are related to white matter microstructure in preadolescents. Methods: We used data of 2,954 children from the Generation R Study, a population-based birth cohort from Rotterdam, Netherlands (2002-2006). Concentrations of 17 air pollutants including nitrogen oxides (NOX), particulate matter (PM), and components of PM were estimated at participants' homes during pregnancy and childhood using land-use regression models. Diffusion tensor images were obtained at child's 9-12 years of age, and fractional anisotropy (FA) and mean diffusivity (MD) were computed. We performed linear regressions adjusting for socioeconomic and lifestyle characteristics. Single-pollutant analyses were followed by multipollutant analyses using the Deletion/Substitution/Addition (DSA) algorithm. Results: In the single-pollutant analyses, higher concentrations of several air pollutants during pregnancy or childhood were associated with significantly lower FA or higher MD (p<0.05). In multipollutant models of pregnancy exposures selected by DSA, higher concentration of fine particles was associated with significantly lower FA [−0.71 (95% CI: −1.26, −0.16) per 5μg/m3 fine particles] and higher concentration of elemental silicon with significantly higher MD [0.06 (95% CI: 0.01, 0.11) per 100ng/m3 silicon]. Multipollutant models of childhood exposures selected by DSA indicated significant associations of NOX with FA [−0.14 (95% CI: −0.23, −0.04) per 20-μg/m3 NOX increase], and of elemental zinc and the oxidative potential of PM with MD [0.03 (95% CI: 0.01, 0.04) per 10-ng/m3 zinc increase and 0.07 (95% CI: 0.00, 0.44) per 1-nmolDTT/min/m3 oxidative potential increase]. Mutually adjusted models of significant exposures during pregnancy and childhood indicated significant associations of silicon during pregnancy, and zinc during childhood, with MD. Discussion: Exposure in pregnancy and childhood to air pollutants from tailpipe and non-tailpipe emissions were associated with lower FA and higher MD in white matter of preadolescents. https://doi.org/10.1289/EHP4709. ; The general design of the Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam; the Erasmus University Rotterdam; Netherlands Organization for Health Research and Development (ZonMw); the Netherlands Organization for Scientific Research (NWO); and the Ministry of Health, Welfare and Sport. Air pollution exposure assessment was made possible by funding from the European Community's Seventh Framework Program (Grant Agreement no. 211250, Grant Agreement no. 243406). In addition, the study was made possible by financial support from the ZonMw (Geestkracht Program 10.000.1003 and TOP 40-00812-98-11021). Neuroimaging was supported by the ZonMw TOP project no. 91211021 to T.W., Sophia Foundation Project S18-20 to R.L.M., and super computing computations for imaging processing were supported by the NWO Physical Sciences Division (Exacte Wetenschappen) and SURFsara (Cartesius compute cluster, https://www.surf.nl). Research described in this article was also conducted under contract to the HEI, an organization jointly funded by the U.S. EPA (Assistance Award No. R-82811201) and certain motor vehicle and engine manufacturers. The contents of this article do not necessarily reflect the views of HEI, or its sponsors, nor do they necessarily reflect the views and policies of the U.S. EPA or motor vehicle and engine manufacturers. V.W.V.J. and H.T. received funding from the ZonMw (VIDI 016.136.361 and NWO-grant 016.VICI.170.200, respectively), the European Research Council (ERC-2014-CoG-64916), and the European Union's Horizon 2020 research and innovation program under grant agreement no. 633595 (DynaHEALTH) and no. 733206 (LifeCycle). H.E.M. was supported by Stichting Volksbond Rotterdam and the Dutch Brain Foundation (De Hersenstichting, project number GH2016.2.01), and by the 2019 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation. M.G. is funded by a Miguel Servet fellowship (MS13/00054, CP13/00054, CI18/00018) awarded by the Spanish Institute of Health Carlos III. W.D. is funded in part by the Research Council of Norway (RCN) (grant 249779) and through the RCN Centers of Excellence funding scheme (grant 262700).