From the womb to the classroom: Linking perinatal micronutrients and toxicants to neural and behavioral development in utero and in childhood

项目总结 母亲孕期接触毒物和营养状况有助于引起注意 缺陷多动障碍(ADHD)和严重的外化行为问题。一个普遍的观点是 毒物和胎儿微量营养素缺乏扰乱了胎儿的大脑发育，并伴随着长期的 对后代健康和发育的影响。然而，有证据表明，产前接触毒物和 缺乏微量营养素失衡对人类胎儿神经系统的影响，也缺乏证据表明微量营养素的变化 胎儿的大脑先于儿童时期与营养和毒物相关的发育问题。填补这些空白 鉴于世界各地产前毒物暴露的高流行率，以及有证据表明 妊娠期的事件会影响长期的健康和幸福。这项提议的中心目标是 检查人类神经网络在子宫内的发育，并将产前大脑发育的变异与 产前毒物和营养水平(在胎儿中测量)和儿童结局。这将以一种方式完成 它对化学混合物的影响和怀孕过程中的时变暴露都很敏感， 这两者都可能产生特定的神经发育后果。我们将配对胎儿的进展 静息状态功能连接(RSFC)MRI具有牙齿生物标记物分析的创新，以严格 产前化学/微量营养素暴露与人胎神经关系的研究 连接体发育，并将决定暴露组和子宫内连接体的发育如何与 儿童神经行为发育。底特律怀孕队列的数据收集开始得更多 比7年前，从胎儿大脑的RSFC MRI开始。随着时间的推移，孩子们一直被跟踪 在出生时、7个月、3岁和5岁时进行评估，并已开始自然脱落乳牙。这个 该项目的主要目标是(I)确定与产前有关的胎儿大脑连接体异常 毒物暴露和微量营养素失衡，并查明妊娠易损性的关键窗口； 评估产前暴露和胎儿神经连接作为执行功能的纵向预测指标， 5岁时的外在问题和就学准备情况；以及(Iii)隔离出生后的保护因素 促进产前微量营养素缺乏和中毒儿童恢复能力的环境 曝光。因此，我们将能够有意义地评估是否以及如何获得产前营养和 中毒事件会影响发育中的胎儿大脑的功能神经回路，从长远来看 这些联系的神经行为后果。这些工作将构成对我们的 了解产前微量营养素和毒物暴露的纵向影响 以及儿童神经行为障碍的起源。

PROJECT SUMMARY Maternal toxicant exposure and nutritional status during pregnancy contribute to the emergence of attention deficit hyperactivity disorder (ADHD) and serious externalizing behavioral problems. A prevailing belief is that toxicants and fetal micronutrient deficiencies disrupt fetal brain development, with subsequent long-term implications for offspring health and development. However, evidence that prenatal toxicant exposure and micronutrient imbalances influence fetal neural systems in humans is lacking, as is evidence that changes in the fetal brain precede nutrient- and toxicant-related developmental concerns of childhood. Filling these gaps in knowledge is critical, given the high prevalence of prenatal toxicant exposure worldwide and evidence that events during gestation influence long-range health and well-being. The central objective of this proposal is to examine development of human neural networks in utero, and to link variation in prenatal brain development to prenatal toxicant and nutrient levels (measured in the fetus) and to child outcomes. This will be done in a way that is sensitive both to chemical mixture effects and to time-variant exposure across the course of gestation, which are both likely to have specific neurodevelopmental consequences. We will pair advances in fetal resting-state functional connectivity (RSFC) MRI with innovations in tooth-biomarker assays to rigorously investigate associations between prenatal chemical/micronutrient exposures and human fetal neural connectome development, and will determine how exposome and connectome development in utero relate to child neurobehavioral development. Data collection in a Detroit-based pregnancy cohort was initiated more than 7 years ago, beginning with fetal brain RSFC MRI. Children have been followed over time, with assessments at birth, 7 months, age 3 and age 5, and have begun to naturally shed their deciduous teeth. The primary aims of this project are to (i) identify fetal brain connectome abnormalities associated with prenatal toxicant exposure and micronutrient imbalance, and identify key windows of gestational vulnerability; (ii) evaluate prenatal exposures and fetal neural connectivity as longitudinal predictors of executive function, externalizing problems and school readiness at age 5; and (iii) isolate protective factors in the postnatal environment that promote resilient outcomes in children with prenatal micronutrient deficiency and toxicant exposure. We will thus be able to meaningfully evaluate whether and how prenatal nutrient availability and toxic exposure events affect functional neurocircuitry of the developing fetal brain, and the longer-term neurobehavioral consequences of those associations. Such work would constitute a substantial advance in our understanding of both the longitudinal effects of micronutrient and toxicant exposures in the prenatal period and the origins of child neurobehavioral disorders.