Early Life Phthalate Exposures in Relation to Structural and Functional Brain Development

Abstract
In the first years of life, when the brain is rapidly developing, children are disproportionately exposed to
xenobiotics, including phthalates. However, the immaturity of the blood brain barrier cerebrovasculature and
xenobiotic metabolism and excretion pathways render the infant brain more vulnerable to toxic compounds.
Despite growing evidence of associations of prenatal phthalate exposures with diverse aspects of
neurobehavioral development, few studies have assessed the role of early life exposure to phthalates on
neurodevelopment. Furthermore, the findings on prenatal exposure have been paradoxical, suggesting that
phthalate exposure accelerates the maturity of functional networks in infancy but is maladaptive in later life. Our
objective is to examine the extent to which phthalate exposures change structural and functional brain
development at a critical window of vulnerability (from birth to age 5), and to reconcile the paradoxical findings
by tracking a variety of social, behavioral and developmental outcomes through longitudinal evaluation. We
propose to leverage the University of North Carolina Baby Connectome Project (BCP), the goal of which is to
map normative brain development in early life using serial structural (sMRI) and resting-state functional (rsfMRI)
magnetic resonance imaging paired with age-appropriate developmental assessments. In a pilot study, we found
that higher early life exposure to monobenzyl phthalate (MBzP) is associated with larger cortical gray matter
volumes in regions of the frontal cortex that direct language processing and executive function, as well as
dysregulated functional connectivity in the primary visual, default mode, and sensorimotor networks. While this
pilot established a strong scientific premise for further study, it had a limited sample size and only measured a
subset of relevant phthalates. To provide a comprehensive and unbiased understanding of the phthalate and
exposomic landscape in early life, we propose to extend our analysis to 19 phthalates and phthalate
replacements and to evaluate the unbiased, untargeted exposome. For a more in-depth developmental
perspective, we also propose to examine the longitudinal relationship between early life toxicant exposures and
sMRI, rsfMRIs and developmental inventories. We plan to increase enrollment by 50 children, resulting in a final
sample size of approximately 250 children contributing approximately 540 scans. Our group has pioneered the
quantitative characterization of spatiotemporal brain development in early infancy and includes a unique
assemblage of expertise in environmental epidemiology, infant brain imaging, early brain development,
toxicology, biostatistics, and child psychiatry that will ensure successful completion of this work. This study has
important public health significance because phthalate exposures are ubiquitous, largely unregulated in the US,
and more extensive and impactful to infants than to adults. Imaging biomarkers will provide crucial information
on the mechanism of phthalate neurotoxicity that will guide regulatory action to protect children from maladaptive
developmental outcomes.