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Prenatal exposure to organophosphate esters and behavioral development in young children in the Pregnancy, Infection, and Nutrition Study.

ABSTRACT: Organophosphate esters (OPEs) are commonly used as plasticizers and flame retardants in consumer products, and exposure is relatively ubiquitous in most populations studied. This may be of concern as some OPEs may be neurotoxic, endocrine-disrupting, and interfere with behavioral development; however, observational evidence is limited. We used data from the Pregnancy, Infection, and Nutrition Study, a prospective birth cohort study, to investigate associations between maternal OPE metabolite concentrations during pregnancy and behavioral development in offspring. Women provided a urine sample during pregnancy that was analyzed for concentrations of OPE metabolites, including diphenyl phosphate (DPHP), bis(1,3-dichloro-2-propyl phosphate) (BDCIPP), isopropyl-phenyl phenyl phosphate (ip-PPP), and 1-hydroxyl-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP). Offspring's behavioral development was assessed by the Behavioral Assessment System for Children (2nd Edition) (BASC-2) at approximately 36 months. Linear regression was used to estimate associations between tertiles in specific gravity-corrected OPE metabolite concentrations and children's scores on the BASC-2, adjusted for maternal age, maternal BMI, maternal race, maternal education, familial income, maternal depression, quality of the home environment, and sex. Higher BDCIPP concentrations were associated with higher scores on the Behavioral Symptoms Index (1st vs. 3rd tertile: ??=?3.03; 95% CI?=?0.40, 5.67) and Externalizing Problems (1st vs. 3rd tertile: ??=?2.49; 95% CI: -0.12, 5.10) composites. Among BASC-2 scales, BDCIPP was most strongly associated with Withdrawal, Attention Problems, Depression, Hyperactivity, and Aggression. DPHP concentrations were also associated with higher scores on the Externalizing Problems and Behavioral Symptoms Index composites, but not as strongly as BDCIPP. Conversely, higher concentrations of ip-PPP were associated with fewer adverse behavioral symptoms, including an inverse association with the Internalizing Problems composite (1st vs. 3rd tertile: ? = -3.74; 95% CI = -6.75, -0.74) and constituent scales. BCIPHIPP was not strongly associated with any measured behavioral outcomes. Our results suggest that greater maternal exposure to tris(1,3-dichloro-2-propyl phosphate) (TDCIPP, parent compound of BDCIPP) and, to a lesser degree, triphenyl phosphate (TPHP, parent compound of DPHP) during pregnancy is associated with adverse behavioral development in children. Our study contributes to the growing body of evidence pertaining to adverse developmental effects of prenatal OPE exposure and highlights the need for further research to characterize risks associated with this ubiquitous family of chemicals.

SUBMITTER: Doherty BT

PROVIDER: S-EPMC6635002 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Prenatal exposure to organophosphate esters and behavioral development in young children in the Pregnancy, Infection, and Nutrition Study.

Doherty Brett T BT Hoffman Kate K Keil Alexander P AP Engel Stephanie M SM Stapleton Heather M HM Goldman Barbara D BD Olshan Andrew F AF Daniels Julie L JL

Neurotoxicology 20190403

Organophosphate esters (OPEs) are commonly used as plasticizers and flame retardants in consumer products, and exposure is relatively ubiquitous in most populations studied. This may be of concern as some OPEs may be neurotoxic, endocrine-disrupting, and interfere with behavioral development; however, observational evidence is limited. We used data from the Pregnancy, Infection, and Nutrition Study, a prospective birth cohort study, to investigate associations between maternal OPE metabolite con ...[more]

PMID: 30951742

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Project description:Organophosphate esters (OPEs) are a class of chemicals commonly used as flame retardants and plasticizers. OPEs are applied to a wide variety of consumer products and have a propensity to leach from these products. Consequently, OPEs are ubiquitous contaminants in many human environments and human exposure is pervasive. Accumulating evidence suggests that OPEs are capable of interfering with childhood cognitive development through both neurologic- and endocrine-mediated mechanisms. However, observational evidence of cognitive effects is limited. We used data collected in the third phase of the Pregnancy, Infection, and Nutrition Study to investigate cognitive effects of prenatal exposure to OPEs. In a spot prenatal maternal urine sample, we measured the following OPE metabolites: diphenyl phosphate (DPHP), bis(1,3-dichloro-2-propyl phosphate) (BDCIPP), isopropyl-phenyl phenyl phosphate (ip-PPP), and 1-hydroxyl-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP). We assessed children's language and multi-faceted and overall cognitive development between two and three years of age using the MacArthur-Bates Communicative Development Inventories (MB-CDI) and the Mullen Scales of Early Learning (MSEL). We used linear regression to estimate the change in children's scores on these developmental assessments per interquartile range (IQR) increase in log-transformed, specific-gravity-corrected prenatal OPE metabolite concentrations, adjusted for maternal age, education, income, race/ethnicity, BMI, and child's sex. A total of 149 children had both OPE metabolite measurements and MB-CDI scores, and 227 children had both OPE metabolite measurements and MSEL scores. We observed that higher concentrations of ip-PPP (ng/ml) were associated with lower scores on the MSEL Cognitive Composite Score (β = -2.61; 95% CI: -5.69, 0.46), and separately on two of the four MSEL Scales that comprise the Cognitive Composite, specifically the Fine Motor Scale (β = -3.08; 95% CI: -5.26, -0.91) and the Expressive Language Scale (β = -1.21; 95% CI: -2.91, 0.49). We similarly observed that prenatal ip-PPP concentrations were inversely associated with age-standardized scores on the MB-CDI Vocabulary assessment (β = -1.19; 95% CI: -2.53, 0.16). Other OPE metabolites were not strongly associated with performance on either assessment. Our results suggest that isopropylated triarylphosphate isomers, the presumed parent compounds of ip-PPP, may adversely impact cognitive development, including fine motor skills and early language abilities. Our study contributes to the growing body of observational evidence that suggests prenatal exposure to OPEs may adversely affect cognitive development.

Project description:BackgroundOrganophosphate esters (OPEs) are a class of flame retardants in common use. OPEs can easily leach from materials, resulting in human exposure. Increasing concentrations have been reported in human populations over the past decade. Recent studies have linked prenatal OPE exposure to hyperactivity and attention problems in children. Such behaviors are often found among children with attention-deficit hyperactivity disorder (ADHD), however, no study has investigated OPEs in relation to clinically assessed ADHD.ObjectiveTo evaluate prenatal exposure to OPEs as risk factors for clinically assessed ADHD using a case-cohort study nested within the Norwegian Mother, Father, and Child Cohort Study (MoBa).MethodsWe included in the case group 295 ADHD cases obtained via linkage with the Norwegian Patient Registry, and the sub-cohort group 555 children sampled at baseline, irrespective of their ADHD case status. Prenatal concentrations of OPE metabolites were measured in maternal urine collected at 17 weeks of gestation, and included diphenyl phosphate (DPHP), di-n-butyl phosphate (DNBP), bis(2-butoxyethyl) hydrogen phosphate (BBOEP), and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP). We estimated risk ratios and the corresponding 95% confidence intervals [95% CI] using logistic regression, adjusting for season of urine collection, child sex, birth year, and maternal depression, education, and sum of urinary di(2-ethylhexyl) phthalate metabolites (∑DEHP) concentration during pregnancy. To assess the overall impact of simultaneously decreasing exposure to all chemical constituents of an OPE-phthalate mixture, quantile based g-computation was implemented. The mixture constituents included OPE and phthalate metabolites commonly detected in our study. In all models, we considered effect measure modification by child sex and polymorphisms in genes encoding paraoxonase 1 (PON1) and cytochrome P450 (P450) enzymes. Mediation analysis was conducted using thyroid function biomarkers estimated from maternal blood collected at 17 weeks of gestation.ResultsDPHP was detected in nearly all samples (97.2%), with a higher geometric mean among the case group (0.70 µg/L) as compared to the sub-cohort (0.52 µg/L). DNBP was commonly detected as well (93.8%), while BBOEP (52.9%) and BDCIPP (22.9%) were detected less frequently. A higher risk of ADHD was observed in children with greater than median exposure to DPHP during pregnancy (risk ratio: 1.38 [95% CI: 0.96, 1.99]), which was slightly higher among girls (2.04 [1.03, 4.02]) and children of mothers with PON1 Q192R genotype QR (1.69 [0.89, 3.19]) or PON1 Q192R genotype RR (4.59 [1.38, 15.29]). The relationship between DPHP and ADHD (total risk ratio: 1.34 [0.90, 2.02]) was partially mediated through total triiodothyronine to total thyroxine ratio (natural direct effect: 1.29 [0.87, 1.94]; natural indirect effect: 1.04 [1.00, 1.10]; 12.48% mediated). We also observed an elevated risk of ADHD in relation to BDCIPP detection during pregnancy (1.50 [0.98, 2.28]). We did not observe notable differences in ADHD by DNBP (0.88 [0.62, 1.26]) or BBOEP (1.03 [0.73, 1.46]) during pregnancy. Simultaneously decreasing all constituents of common-detect OPE-phthalate mixture, specifically DPHP, DNBP, and 6 phthalate metabolites, by a quartile resulted in an ADHD risk ratio of 0.68 [0.64, 0.72].ConclusionPrenatal exposure to DPHP and BDCIPP may increase the risk of ADHD. For DPHP, we observed potential modification by child sex and maternal PON1 Q192R genotype and partial mediation through maternal thyroid hormone imbalance at 17 weeks gestation.

Dataset Information

Prenatal exposure to organophosphate esters and behavioral development in young children in the Pregnancy, Infection, and Nutrition Study.

Publications

Prenatal exposure to organophosphate esters and behavioral development in young children in the Pregnancy, Infection, and Nutrition Study.

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