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.

摘要 在生命的头几年，当大脑快速发育时，儿童不成比例地暴露在 外源生物，包括邻苯二甲酸盐。然而，血脑屏障脑血管的不成熟和 异种生物的代谢和排泄途径使婴儿的大脑更容易受到有毒化合物的影响。 尽管越来越多的证据表明，产前邻苯二甲酸盐暴露与糖尿病的各个方面有关 在神经行为发育方面，很少有研究评估早期接触邻苯二甲酸盐对 神经发育。此外，关于产前暴露的发现是自相矛盾的，表明 在婴儿期，邻苯二甲酸盐暴露会加速功能网络的成熟，但在以后的生活中会不适应。我们的 目的是研究邻苯二甲酸盐暴露在多大程度上改变大脑结构和功能。 在脆弱的关键窗口(从出生到5岁)发展，并调和矛盾的发现 通过纵向评估跟踪各种社会、行为和发展结果。我们 建议利用北卡罗来纳大学婴儿连接项目(BCP)，该项目的目标是 应用系列结构(SMRI)和静息状态功能(RsfMRI)绘制早期脑发育图 磁共振成像与适合年龄的发育评估相结合。在一项初步研究中，我们发现 早年接触邻苯二甲酸单苄酯(MBZP)越多，大脑皮质灰质越大 额叶皮质中指导语言处理和执行功能的区域以及 初级视觉、默认模式和感觉运动网络的功能连接失调。虽然这件事 Pilot为进一步研究建立了强有力的科学前提，它的样本量有限，只测量了 相关邻苯二甲酸酯的子集。以提供对邻苯二甲酸盐和 在早期生活中，我们建议将我们的分析扩展到19种邻苯二甲酸盐和邻苯二甲酸盐 并对无偏见、无针对性的曝光进行评估。以获得更深入的发展 展望未来，我们还建议研究早期生活中接触毒物和 SMRI、rsfMRI和发育量表。我们计划增加50个孩子的入学人数，结果是期末考试 样本大小约为250名儿童，提供了约540次扫描。我们的团队开创了 婴儿期早期时空脑发育的定量特征，包括一个独特的 汇集了环境流行病学、婴儿脑成像、早期脑发育、 毒理学、生物统计学和儿童精神病学，以确保这项工作的顺利完成。这项研究有 重要的公共卫生意义，因为邻苯二甲酸盐暴露在美国无处不在，基本上不受监管， 对婴儿的影响比对成年人更广泛和更有影响。成像生物标志物将提供关键信息 关于邻苯二甲酸盐神经毒性的机制将指导保护儿童免受适应不良的调节行动 发展成果。