PRENATAL AND POSTNATAL EXPOSURE TO ENVIRONMENTAL MIXTURES: NEURODEVELOPMENT AND DNA METHYLATION BIOMARKERS

项目摘要 出生前和出生后的儿童暴露于金属，必要的和非必要的，是普遍存在的，通过饮食和 环境来源。重金属，包括铅和甲基汞， 神经毒物，与认知能力低下和学习能力差有关。然而，我们对 许多其他常见的产前和产后金属暴露的神经毒性和联合影响仍然非常严重， 有限公司关于胎儿发育期间暴露于多种金属的综合影响， 或出生后在幼儿期接触，或其他环境混合物的影响，如营养素， 可能有共同的来源，对金属的神经发育的影响。为了弥补这一巨大差距， 我们的长期目标是量化无处不在的产前和产后环境对神经认知的影响， 混合物，并确定脐带血DNA甲基化生物标志物，可以重建产前环境 并预测儿童未来的神经认知发育。我们将测试关键指标的客观衡量标准， 产前母体营养素，如叶酸，维生素B12和必需金属，减弱或减轻 金属混合物的神经毒性。为了实现这一目标，我们将利用美国现有的资源。 出生前队列，万岁计划在这个队列中，我们测量了14种产前母体金属的浓度 在怀孕的前三个月和血液样本收集在幼儿（约3年）准备金属 检测以及准备使用全基因组脐带血DNA甲基化筛查。儿童被跟踪 前瞻性地对儿童早期（~3岁）和中期的神经发育进行详细测试 （7年）。我们假设产前、母亲妊娠早期和出生后儿童早期神经毒性金属 混合物与儿童早期和中期的神经发育不良有关（Aim 1）， 孕母血浆叶酸，维生素B12和血液中的必需金属浓度防止 产前金属混合物神经毒性（目的2）。我们还假设，DNA甲基化标记测量， 出生时的脐带血可以重建产前金属暴露（Aim 3.a）， 分数预测儿童早期和中期的未来神经认知发展（目标3.b）。通过测试纵向 在一个大的儿童队列中，详细的认知评估以及客观的生物标志物 金属和营养素，我们将克服目前面临的限制，现有的研究测试很少接触 同步我们将使用新的统计方法来模拟产前和产后的环境 混合物和机器学习算法来建立暴露和神经发育的表观遗传预测因子。 这项研究将提供一个全面的量化的认知负担的产前和产后 混合物，开发暴露和神经发育的生物标志物， 产前营养干预策略。

PROJECT SUMMARY Prenatal and postnatal childhood exposure to metals, essential and non-essential, is ubiquitous via dietary and environmental sources. Heavy metals, including lead and methylmercury, are well characterized as potent neurotoxicants, associated with lower cognition and poor learning abilities. Yet, our understanding of the neurotoxicity and joint impact of many other common prenatal and postnatal metal exposures remains extremely limited. Even less is known about the combined impact of exposure to multiple metals during fetal development or postnatal exposure during early childhood, or the influence of other environmental mixtures such as nutrients, which may have shared sources, on the neurodevelopmental effects of metals. To address this significant gap, our long-term goal is to quantify the neurocognitive impact of ubiquitous prenatal and postnatal environmental mixtures and identify cord blood DNA methylation biomarkers that can reconstruct prenatal environmental exposures and predict future neurocognitive development in children. We will test if objective measures of key prenatal maternal nutrients, such as folate, vitamin B12 and essential metals attenuate or mitigate the neurotoxicity of metal mixtures. To accomplish this goal, we will leverage resources from an established U.S. pre-birth cohort, Project Viva. In this cohort, we have measured concentrations for 14 prenatal maternal metals in the first trimester of pregnancy and blood samples collected in early-childhood (~3 years) ready for metal testing as well as ready to use genome-wide cord blood DNA methylation screens. Children have been followed prospectively and undergone detail testing for neurodevelopment in early (~3 years of age) and mid-childhood (~7 years). We hypothesize that prenatal maternal 1st trimester and postnatal early childhood neurotoxic metal mixtures are associated with poor neurodevelopment in early and mid-childhood (Aim 1), and that prenatal first trimester maternal plasma folate, vitamin B12 and blood concentration of essential metals protect against prenatal metal mixture neurotoxicity (Aim 2). We also hypothesize that DNA methylation marks measured in umbilical cord blood at birth can reconstruct prenatal exposure to metals (Aim 3.a) and that cord blood DNAm marks predict future neurocognitive development in early and mid-childhood (Aim 3.b). By testing longitudinal associations in a large cohort of children with detail cognitive assessments as well as objective biomarkers of metals and nutrients, we will overcome limitations currently faced by existing studies testing few exposures simultaneously. We will use novel statistical methodology to model prenatal and postnatal environmental mixtures and machine learning algorithms to build epigenetic predictors of exposure and neurodevelopment. This research will provide a comprehensive quantification of the cognitive burden of prenatal and postnatal mixtures, the development of biomarkers of exposure and neurodevelopment and the identification of potential prenatal nutritional intervention strategies.