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

生命早期接触邻苯二甲酸盐与大脑结构和功能发育的关系

• 批准号: 10316345
• 负责人: Stephanie Engel
• 金额: $ 66.09万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-13 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10316345
• 关键词: 5 year old; Address; Adult; Age; Area; Behavior; Behavioral; Biometry; Birth; Blood - brain barrier anatomy; Body Weight; Brain; Brain imaging; Cerebrovascular system; Chemicals; Child; Child Psychiatry; Childhood; Cognition; Cognitive; Development; Dibutyl Phthalate; Diethylhexyl Phthalate; Elderly; Enrollment; Ensure; Environmental Epidemiology; Equipment and supply inventories; Evaluation; Excretory function; Exhibits; Exposure to; Goals; Growth; Health; Hyperactivity; In Vitro; Infant; Infant Development; Language Development; Life; Magnetic Resonance Imaging; Maps; Mass Spectrum Analysis; Measures; Mediator of activation protein; Metabolism; Motor; North Carolina; Outcome; Pathway interactions; Pattern; Pilot Projects; Plasticizers; Play; Poison; Problem behavior; Public Health; Public Policy; Research; Resolution; Resources; Rest; Role; Sample Size; Sampling; Scanning; Structure; Surface; Toddler; Toxic Environmental Substances; Toxicant exposure; Toxicology; Universities; Urine; Visit; Visual; Work; Xenobiotic Metabolism; Xenobiotics; base; behavioral outcome; boys; brain overgrowth; brain volume; cognitive function; conduct problem; connectome; consumer product; early life exposure; emotional symptom; environmental chemical; executive function; externalizing behavior; frontal lobe; gray matter; high throughput screening; imaging biomarker; improved; infancy; language processing; neonatal period; neurobehavioral; neurodevelopment; neurotoxicity; phthalates; postnatal; prenatal; prenatal exposure; relating to nervous system; social; social cognition; spatiotemporal; toxicant; visual motor; welfare

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.

摘要