Prenatal exposures to organophosphate ester metabolite mixtures and children's neurobehavioral outcomes in the MADRES pregnancy cohort.
Ixel Hernandez-Castro, Sandrah P Eckel, Caitlin G Howe, Zhongzheng Niu, Kurunthachalam Kannan, Morgan Robinson, Helen B Foley, Tingyu Yang, Mario J Vigil, Xinci Chen, Brendan Grubbs, Deborah Lerner, Nathana Lurvey, Laila Al-Marayati, Rima Habre, Genevieve F Dunton, Shohreh F Farzan, Max T Aung, Carrie V Breton, Theresa M Bastain
Author Information
Ixel Hernandez-Castro: Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, 1845 N. Soto Street, Los Angeles, CA, USA.
Sandrah P Eckel: Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, 1845 N. Soto Street, Los Angeles, CA, USA.
Caitlin G Howe: Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Zhongzheng Niu: Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, 1845 N. Soto Street, Los Angeles, CA, USA.
Kurunthachalam Kannan: Wadsworth Center, New York State Department of Health, Albany, NY, USA.
Morgan Robinson: Wadsworth Center, New York State Department of Health, Albany, NY, USA.
Helen B Foley: Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, 1845 N. Soto Street, Los Angeles, CA, USA.
Tingyu Yang: Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, 1845 N. Soto Street, Los Angeles, CA, USA.
Mario J Vigil: Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, 1845 N. Soto Street, Los Angeles, CA, USA.
Xinci Chen: Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, 1845 N. Soto Street, Los Angeles, CA, USA.
Brendan Grubbs: Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Deborah Lerner: Eisner Health, Los Angeles, CA, USA.
Nathana Lurvey: Eisner Health, Los Angeles, CA, USA.
Laila Al-Marayati: Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Rima Habre: Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, 1845 N. Soto Street, Los Angeles, CA, USA.
Genevieve F Dunton: Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, 1845 N. Soto Street, Los Angeles, CA, USA.
Shohreh F Farzan: Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, 1845 N. Soto Street, Los Angeles, CA, USA.
Max T Aung: Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, 1845 N. Soto Street, Los Angeles, CA, USA.
Carrie V Breton: Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, 1845 N. Soto Street, Los Angeles, CA, USA.
Theresa M Bastain: Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, 1845 N. Soto Street, Los Angeles, CA, USA. bastain@usc.edu.
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.
