White matter microstructure mediates the association between prenatal exposure to phthalates and behavior problems in preschool children

Background: Previous research reports associations between prenatal exposure to phthalates and childhood behavior problems; however, the neural mechanisms that may underlie these associations are relatively unexplored. Objective: This study examined microstructural white matter as a possible mediator of the associations between prenatal phthalate exposure and behavior problems in preschool-aged children. Methods: Data are from a subsample of a prospective pregnancy cohort, the Alberta Pregnancy Outcomes and Nutrition (APrON) study (n = 76). Mother-child pairs were included if mothers provided a second trimester urine sample, if the child completed a successful magnetic resonance imaging (MRI) scan at age 3-5 years, and if the Child Behavior Checklist was completed within 6 months of the MRI scan. Molar sums of high (HMWP) and low molecular weight phthalates (LMWP) were calculated from levels in urine samples. Associations between prenatal phthalate concentrations, fractional anisotropy (FA) and mean diffusivity (MD) in 10 major white matter tracts, and preschool behavior problems were investigated. Results: Maternal prenatal phthalate concentrations were associated with MD of the right inferior fronto-occipital fasciculus (IFO), right pyramidal fibers, left and right uncinate fasciculus (UF), and FA of the left inferior longitudinal fasciculus (ILF). Mediation analyses showed that prenatal exposure to HMWP was indirectly associated with Internalizing (path ab = 0.09, CI.95 = 0.02, 0.20) and Externalizing Problems (path ab = 0.09, CI.95 = 0.01, 0.19) through MD of the right IFO, and to Internalizing Problems (path ab = 0.11, CI.95 = 0.01, 0.23) through MD of the right pyramidal fibers. Discussion: This study provides the first evidence of childhood neural correlates of prenatal phthalate exposure. Results suggest that prenatal phthalate exposure may be related to microstructural white matter in the IFO, pyramidal fibers, UF, and ILF. Further, MD of the right IFO and