Association between prenatal organophosphate flame retardants (OPFRs) exposure and differential DNA methylation during infancy and their consequences for childhood neurobehavioral problems Restricted; Files Only

Abstract

Background: Organophosphate flame retardants (OPFRs), widely used in plastics and textiles, are increasingly detected in human samples. Given their structural similarity to organophosphate pesticides, concerns about their neurotoxicity have grown. Emerging human studies suggest prenatal OPFR exposure may be linked to neurobehavioral problems in offspring, though the biological mechanisms remain unclear. DNA methylation (DNAm) has been proposed as a potential mediator based on animal models, but human evidence is limited. Methods: We investigated associations between maternal OPFR exposure and childhood neurobehavioral outcomes in 705 mother-child pairs from the Drakenstein Child Health Study in South Africa. Maternal OPFR exposure was measured via urinary metabolites, bis(1,3-dichloro-2-propyl) phosphate (BDCPP) and diphenyl phosphate (DPHP), collected during the second trimester and at birth. Child DNAm was assessed from whole blood at age one using the Infinium MethylationEPIC v2.0 array (N=313). Child neurobehavioral problems were measured at 24, 42, and 60 months using the Child Behavior Checklist. Linear regression models adjusted for maternal age, BMI, ethnicity, and socioeconomic status assessed associations between OPFR exposure and internalizing/externalizing behavior. High-dimensional mediation analysis (HIMA1, HIMA2, HDMA, DACT, and MedFix) identified differentially methylated CpG sites mediating associations at 24 months. CpG sites significant in at least two methods were considered noteworthy mediators and validated using causal mediation analysis. Results: Higher prenatal BDCPP exposure was associated with increases in externalizing (1.26 points; 95% CI: 0.30, 2.21) and internalizing (1.14 points; 95% CI: 0.02, 2.25) behavior scores at 24 months. Similarly, DPHP exposure was associated with increased externalizing (1.19 points; 95% CI: 0.23, 2.16) and internalizing (1.00 points; 95% CI: -0.12, 2.13) scores. Associations at later ages were mostly null. We identified 26 and 21 CpG sites mediating the BDCPP-internalizing and BDCPP-externalizing associations, respectively. For DPHP, 19 and 18 CpG sites mediated internalizing and externalizing problems, respectively. Many of the identified CpG sites are related to genes that have been previously linked to schizophrenia and childhood emotional and behavioral difficulties, including cg01851990[ZDHHC18], cg21136443[COL6A3], cg21979351 [NUP93], and cg24097496 [UBXN11]. Conclusion: Prenatal exposure to OPFRs is positively associated with neurobehavioral problems in children at age two. DNAm in early life may mediate this relationship, offering insight into potential biological mechanisms linking prenatal OPFR exposure to childhood behaviors.

Table of Contents

Chapter 1: Association between maternal organophosphate flame retardants (OPFRs) exposure during pregnancy and internalizing and externalizing behavior at 2-5 years 1

Introduction 1

Methods 3

Results 6

Discussion 7

Figures and Tables 12

Chapter 2: Association between prenatal organophosphate flame retardants (OPFRs) exposure and differential DNA methylation during infancy and their consequences for childhood neurobehavioral problems at the age of two 17

Introduction 17

Methods 19

Results 26

Discussion 29

Figures and tables 33

References 40

Supplemental Materials 47

About this Master's Thesis

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School	Rollins School of Public Health
Department	Epidemiology
Subfield / Discipline	Epidemiology - MPH & MSPH
Degree	M.S.P.H.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Human Development Health Sciences, Obstetrics and Gynecology Health Sciences, Epidemiology
Keyword	childhood behaviors DNA methylation high-dimensional mediation analysis organophosphate flame retardants
Committee Chair / Thesis Advisor	Anke Hüls, Emory University

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