Early life exposure to metal mixtures and neuroimaging of internalizing behaviors in childhood

项目摘要 儿童内化障碍，包括焦虑和抑郁，导致相当大的公共卫生负担。 我们对内化障碍的理解已经落后于我们对其他疾病的理解的进步。 儿科精神病理学内化行为背后的神经回路，包括前额叶 大脑皮层、外侧眶额皮层、前扣带皮层、杏仁核和海马在发育过程中发育较早。 发展过程。与相对稳定的成人神经网络不同，婴儿和儿童神经网络 网络是动态的，需要被视为脆弱的发展轨迹。即使是轻微 生命早期的环境破坏可以使人们偏离正常的轨道， 多年来临床表现明显。环境中的化学物质，如金属，可以发挥神经毒性作用，在这些过程中， 脆弱的关键窗口。神经影像学的进展（即，磁共振成像（MRI）使我们能够 非侵入性地测试环境暴露对儿童神经回路的影响。的 产前和幼儿期金属暴露对这些内在症状和潜在的影响 神经回路还没有被检查，即使早期接触金属已经被证明， 对由相同电路支持的认知域产生不利影响。在拟议的研究中，我们将利用 正在进行的前瞻性出生队列研究重点研究生命早期金属暴露之间的关联 和儿童认知。我们将引入新的后续措施，包括MRI和行为测试，以评估 对300名10 - 11岁接触过三氯甲烷的儿童进行了一次调查。使用创新的 牙齿生物标志物，重建整个妊娠期和早期金属暴露的综合措施 在儿童时期，我们关注3种神经活性金属，包括：铅（Pb），一种已知的有毒物质;锰（Mn）， 必需营养素，作为神经毒物的认识日益增加;和锌（Zn），作为必需营养素， 调节神经毒物的副作用使用数据驱动的统计模型， 牙齿数据的时间性，我们建议识别和定义易感性的关键发育窗口 单个金属和金属混合物。此外，探索性分析将检查 MRI结果和行为表型，以进一步了解金属神经毒性的机制。这 这项研究将情感神经科学和神经影像学领域与环境流行病学联系起来。几 环境健康研究将这三个领域纳入了一个大型队列，旨在测试风险 儿童神经发育的因素;因此，我们的研究将有助于塑造我们对长期的整体理解。 早期生命金属接触的影响，并为制定有效的公共卫生干预措施奠定基础， 可以改善儿童的情绪、行为和认知功能。

PROJECT SUMMARY Pediatric internalizing disorders, including anxiety and depression, lead to considerable public health burden. Our understanding of internalizing disorders has lagged behind advances in our understanding of other pediatric psychopathologies. The neural circuitry underlying internalizing behaviors, including the prefrontal cortex, lateral orbitofrontal cortex, anterior cingulate cortex, amygdala and hippocampus develop early during developmental processes. Unlike adult neural networks, which are relatively stable, infant and child neural networks are dynamic, and need to be considered as vulnerable developmental trajectories. Even minor environmental disruptions early in life can set in motion deviations from normative trajectories that are not clinically evident for years. Environmental chemicals, such as metals, can exert neurotoxic effects during these critical windows of vulnerability. Advances in neuroimaging (i.e., magnetic resonance imaging; MRI) allow us to non-invasively test the influence of the environmental exposures on the neural circuitry in children. The influence of prenatal and early childhood metal exposure on these internalizing symptoms and the underlying neural circuitry has not yet been examined, even though early exposures to metals has been shown to adversely affect cognitive domains supported by the same circuitry. In the proposed study, we will leverage an ongoing prospective birth cohort study focused on examining associations between early life metal exposure and child cognition. We will introduce new follow-up measures including MRI and behavioral testing to assess internalizing symptoms in a sample of 300 variably exposed children at age 10-11 years. Using an innovative tooth biomarker that reconstructs integrated measures of metal exposure throughout gestation and early childhood, we focus on 3 neuroactive metals including: lead (Pb), a known toxicant; manganese (Mn) an essential nutrient with growing recognition as a neurotoxicant; and zinc (Zn) an essential nutrient with potential to mediate adverse effects of neurotoxicants. Using data-driven statistical models designed to leverage the temporality of the tooth data, we propose to identify and define critical developmental windows of susceptibility to individual metals and to the metal mixture. In addition, exploratory analyses will examine the link between MRI findings and behavioral phenotypes to further understand the mechanisms of metal neurotoxicity. This study bridges the fields of affective neuroscience and neuroimaging with environmental epidemiology. Few environmental health studies have brought together these three fields within a large cohort designed to test risk factors of child neurodevelopment; thus our study will help shape our overall understanding of the long-term effects of early life metal exposure and set the stage for developing effective public health interventions that can improve emotional, behavioral and cognitive functioning in children.