Prenatal exposures to organophosphate ester metabolite mixtures and children's neurobehavioral outcomes in the MADRES pregnancy cohort

Abstract

Background: Evidence suggests organophosphate esters (OPEs) are neurotoxic; however, the epidemiological literature remains scarce. We investigated whether prenatal exposures to OPEs were associated with child neurobehavior in the MADRES cohort.

Methods: We measured nine OPE metabolites in 204 maternal urine samples (gestational age at collection: 31.4 ± 1.8 weeks). Neurobehavior problems were assessed among 36-month-old children using the Child Behavior Checklist's (CBCL) three composite scales [internalizing, externalizing, and total problems]. We examined associations between tertiles of prenatal OPE metabolites (> 50% detection) and detect/non-detect categories (< 50% detection) and CBCL composite scales using linear regression and generalized additive models. We also examined mixtures for widely detected OPEs (n = 5) using Bayesian kernel machine regression.

Results: Maternal participants with detectable versus non-detectable levels of bis(2-methylphenyl) phosphate (BMPP) had children with 42% (95% CI: 4%, 96%) higher externalizing, 45% (-2%, 114%) higher internalizing, and 35% (3%, 78%) higher total problems. Participants in the second versus first tertile of bis(butoxethyl) phosphate (BBOEP) had children with 43% (-1%, 109%) higher externalizing scores. Bis(1-chloro-2-propyl) phosphate (BCIPP) and child sex had a statistically significant interaction in internalizing (p = 0.02) and total problems (p = 0.03) models, with 120% (23%, 295%) and 57% (6%, 134%) higher scores in the third versus first BCIPP tertile among males. Among females, detectable vs non-detectable levels of prenatal BMPP were associated with 69% higher externalizing scores (5%, 170%) while the third versus first tertile of prenatal BBOEP was associated with 45% lower total problems (-68%, -6%). Although the metabolite mixture and each CBCL outcome had null associations, we observed marginal associations between di-n-butyl phosphate and di-isobutyl phosphate (DNBP + DIBP) and higher internalizing scores (0.15; 95% CrI: -0.02, 0.32), holding other metabolites at their median.

Conclusions: Our results generally suggest adverse and sex-specific effects of prenatal exposure to previously understudied OPEs on neurobehavioral outcomes in 36-month children, providing evidence of potential OPE neurotoxicity.

Keywords: Early childhood; Mixtures; Neurobehavior; OPE; OPFRs; Organophosphate esters.

Fig. 1

Consort diagram of included mother-infant dyads

Fig. 2

Spearman correlations of organophosphate ester metabolites (ng/mL) in third trimester maternal urine. Note: DPHP, Diphenyl phosphate; DNBP + DIBP, Sum of Di-n-butyl phosphate and Di-isobutyl phosphate; BDCIPP, Bis(1,3-dichloro-2-propyl) phosphate; BCEP, Bis(2-chloroethyl) phosphate; BBOEP, Bis(butoxethyl) phosphate; BCIPP, Bis(1-chloro-2-propyl) phosphate; BMPP, Bis(2-methylphenyl) phosphate; BEHP, Bis(2-ethylhexyl) phosphate; DPRP, Dipropyl phosphate

Fig. 3

Distributions of 36 month child behavior checklist (CBCL) composite raw scores (N = 204). Median (IQR) for internalizing, externalizing, and total problems scale, respectively: 6.0 (9.0), 8.0 (12.0), 24.0 (29.0)

Fig. 4

Associations between urinary prenatal OPE metabolite concentrations (ng/mL) and CBCL composite raw scores, using generalized additive models (N = 204). Note: All models adjusted for recruitment site, maternal age, race/ethnicity, household annual income, education, pre-pregnancy BMI, GA at sample collection, child adjusted age at CBCL administration, season, infant birth order, child sex. OPE, Organophosphate Ester; CBCL, Child Behavior Checklist; DPHP, Diphenyl phosphate; DNBP + DIBP, Sum of Di-n-butyl phosphate and Di-isobutyl phosphate; BDCIPP, Bis(1,3-dichloro-2-propyl) phosphate; BCEP, Bis(2-chloroethyl) phosphate; BBOEP, Bis(butoxethyl) phosphate. †Significant non-linearity

Fig. 5

Prenatal OPE urinary metabolite mixtures (ng/mL) and CBCL composite raw scores, using BKMR (N = 204). Figure 5 includes: 1) the estimated difference in CBCL composite score when setting all metabolites to the percentile specified on the x-axis compared with setting all metabolites to their median values (column 1), 2) the univariate relationship between each metabolite and CBCL outcome, while other metabolites are fixed at their medians, and a rug plot showing the distribution of the specified metabolite along the x-axis of each panel (column 2). All models were adjusted for recruitment site, maternal age, race/ethnicity, household annual income, education, pre-pregnancy BMI, GA at sample collection, child adjusted age at CBCL administration, season, infant birth order, child sex. OPE metabolites and CBCL raw scores were natural log-transformed, mean centered, and standard deviation scaled. Continuous covariates were mean-centered and standard deviation scaled. Note: BKMR, Bayesian Kernel Machine Regression; OPE, Organophosphate Ester; CBCL, Child Behavior Checklist; DPHP, Diphenyl phosphate; DNBP + DIBP, Sum of Di-n-butyl phosphate and Di-isobutyl phosphate; BDCIPP, Bis(1,3-dichloro-2-propyl) phosphate; BCEP, Bis(2-chloroethyl) phosphate; BBOEP, Bis(butoxethyl) phosphate

Fig. 6

Bivariate associations between prenatal OPE urinary metabolite mixtures (ng/mL) and CBCL composite raw scores, using BKMR (N = 204). Figure 6 shows the bivariate association between each OPE metabolite (labelled in the column) and CBCL composite score (Y axis), while setting a second metabolite (labelled in the row) to its 25^th, 50^th, and 75^th percentile and all other metabolites to their median. All models were adjusted for recruitment site, maternal age, race/ethnicity, household annual income, education, pre-pregnancy BMI, GA at sample collection, child adjusted age at CBCL administration, season, infant birth order, child sex. OPE metabolites and CBCL raw scores were natural log-transformed, mean centered, and standard deviation scaled. Continuous covariates were mean-centered and standard deviation scaled. Note: BKMR, Bayesian Kernel Machine Regression; OPE, Organophosphate Ester; CBCL, Child Behavior Checklist; DPHP, Diphenyl phosphate; DNBP + DIBP, Sum of Di-n-butyl phosphate and Di-isobutyl phosphate; BDCIPP, Bis(1,3-dichloro-2-propyl) phosphate; BCEP, Bis(2-chloroethyl) phosphate; BBOEP, Bis(butoxethyl) phosphate. Possible interactions were visually identified between the following metabolites for: internalizing scores (BDCIPP and BBOEP, DNBP + DIBP and BBOEP, DPHP and BBOEP, DNBP + DIBP and BCEP, DPHP and BCEP, BCEP and DNBP + DIBP, and DNBP + DIBP and BDCIPP), externalizing scores (BCEP and BBOEP, BDCIPP and BBOEP, DNBP + DIBP and BBOEP, and DPHP and BBOEP), and total problems scores (BCEP and BBOEP, BDCIPP and BBOEP, DNBP + DIBP and BBOEP, DPHP and BBOEP, DNBP + DIBP and BCEP, DPHP and BCEP, BCEP and DNBP + DIBP, BCEP and DPHP, and DNBP + DIBP and DPHP)