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

项目摘要 孕妇在怀孕期间的毒物暴露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。一个普遍的看法是， 有毒物质和胎儿微量营养素缺乏会破坏胎儿大脑发育， 对后代健康和发育的影响。然而，有证据表明，产前接触有毒物质， 微量营养素不平衡影响人类胎儿神经系统的证据缺乏， 胎儿的大脑先于儿童时期与营养和有毒物质有关的发育问题。填补这些空白 鉴于全世界产前接触有毒物质的流行率很高，有证据表明， 怀孕期间发生的事件会影响长期的健康和福祉。这项建议的主要目的是 检查子宫内人类神经网络的发育，并将产前大脑发育的变化与 产前有毒物质和营养水平（在胎儿中测量）和儿童结局。这将以一种 对化学混合物的影响和整个妊娠过程中随时间变化的接触都很敏感， 两者都可能对神经发育产生特定的影响。我们将在胎儿中配对前进 静息态功能连接（RSFC）MRI与牙齿生物标志物测定的创新， 研究产前化学/微量营养素暴露与人类胎儿神经 连接体发育，并将决定子宫内的染色体组和连接体发育与 儿童神经行为发育在底特律的妊娠队列中开始收集数据， 7年前，从胎儿大脑RSFC MRI开始。孩子们被跟踪了一段时间， 在出生时，7个月，3岁和5岁的评估，并已开始自然脱落他们的乳牙。的 该项目的主要目的是（i）识别与产前检查相关的胎儿脑连接体异常， 毒物接触和微量营养素失衡，并确定妊娠脆弱性的关键窗口; ㈡ 评估产前暴露和胎儿神经连接作为执行功能的纵向预测因子， 外化问题和5岁时的入学准备;以及（iii）在产后隔离保护因素 促进产前微量营养素缺乏和有毒儿童恢复健康的环境 exposure.因此，我们将能够有意义地评估是否以及如何产前营养的可用性和 毒性暴露事件影响发育中的胎儿大脑的功能性神经回路， 神经行为的后果。这项工作将是我们在这方面取得的重大进展。 了解产前接触微量营养素和有毒物质的纵向影响 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.