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: 10469465
• 负责人: Stephanie Engel
• 金额: $ 66.02万
• 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 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10469465
• 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.

抽象的 在生命的头几年，当大脑迅速发展时，儿童暴露于 异种生物，包括邻苯二甲酸酯。然而，血脑屏障脑堵塞的不成熟和 异种生物的代谢和排泄途径使婴儿大脑更容易受到有毒化合物的影响。 尽管有越来越多的证据表明邻苯二甲酸酯暴露与各种方面的相关性 神经行为的发展，很少有研究评估了早期生活暴露于邻苯二甲酸盐对 神经发育。此外，关于产前暴露的发现是自相矛盾的，表明 邻苯二甲酸酯暴露会加速婴儿期功能网络的成熟度，但在以后的生活中是不良适应性的。我们的 目的是检查邻苯二甲酸盐暴露改变结构和功能性大脑的程度 在脆弱性的关键窗口（从出生到5岁）的开发，并调和矛盾的发现 通过通过纵向评估跟踪各种社会，行为和发展成果。我们 提议利用北卡罗来纳大学婴儿连接计划（BCP）的目标，其目标是 使用串行结构（SMRI）和静止状态功能（RSFMRI），在早期生命中的规范性大脑发育（RSFMRI） 磁共振成像与适合年龄的发育评估配对。在一项试点研究中，我们发现 邻苯二甲酸单苯甲酸盐（MBZP）较高的早期寿命暴露与较大的皮质灰质有关 直接语言处理和执行功能的额叶皮层区域的卷，以及 主要视觉，默认模式和感觉运动网络中的功能连接失调。同时 飞行员为进一步研究建立了一个强大的科学前提，它的样本量有限，只测量了 相关邻苯二甲酸盐的子集。提供对邻苯二甲酸盐和公正的理解 早期的外博景观，我们建议将我们的分析扩展到19个邻苯二甲酸酯和邻苯二甲酸酯 替换并评估公正的，不靶向的展览组。更深入的发展 观点，我们还建议研究早期生活有毒物质的纵向关系和 SMRI，RSFMRIS和开发清单。我们计划增加50名儿童的入学人数，从而导致最终 大约250名儿童的样本大小约为540次扫描。我们的小组开创了 早期时期时空脑发育的定量表征，包括独特的 环境流行病学，婴儿脑成像，早期大脑发育的专业知识的组合， 毒理学，生物统计学和儿童精神病学将确保成功完成这项工作。这项研究有 重要的公共卫生意义，因为邻苯二甲酸盐的暴露无处不在，在美国很大程度上不受监管， 对婴儿比对成年人更广泛和影响力。成像生物标志物将提供关键信息 关于邻苯二甲酸酯神经毒性的机制，该机制将指导监管行动以保护儿童免受适应不良 发展结果。