Prenatal and Postnatal Exposure to Environmental Mixtures: Neurodevelopment and DNA Methylation Biomarkers

产前和产后接触环境混合物：神经发育和 DNA 甲基化生物标志物

• 批准号: 10186748
• 负责人: Andres Cardenas
• 金额: $ 42.54万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-08 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10186748
• 关键词: 3 year old; Address; Affect; Attenuated; Award; Biological Markers; Birth; Blood; Blood - brain barrier anatomy; Blood specimen; Chemicals; Child; Child Neurotoxicity; Childhood; Cognition; Consequentialism; DNA Methylation; Data; Data Science; Development; Dietary Intervention; Environment; Environmental Exposure; Environmental Health; Epigenetic Process; Expenditure; Exposure to; Fetal Development; First Pregnancy Trimester; Folic Acid; Future; Goals; Heavy Metals; Individual; Intervention; Joints; Lead; Learning Disabilities; Life; Measures; Mercury; Metal exposure; Metals; Methodology; Methylmercury Compounds; Modeling; Modification; Neurocognitive; Neurodevelopmental Disorder; Neurotoxins; Newborn Infant; Nutrient; Outcome; Performance; Placenta; Plasma; Policies; Population; Public Health; Research; Resources; Risk; Risk Factors; Source; Testing; Umbilical Cord Blood; Vitamin B 12; autism spectrum disorder; biomarker development; clinical application; cognitive ability; cognitive load; cognitive testing; cohort; cost; design; dietary; early childhood; exposed human population; genome-wide; in utero; innovation; learning ability; machine learning algorithm; machine learning method; methylation biomarker; neurocognitive test; neurodevelopment; neurodevelopmental effect; neurotoxic; neurotoxicity; novel; novel marker; offspring; postnatal; prenatal; prenatal environmental exposure; prenatal exposure; programs; prospective; routine screening; toxicant

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.

项目摘要 产前和产后儿童时期对金属的暴露（必不可少的和非必需的金属）无处不在，通过饮食和 环境来源。重金属，包括铅和甲基汞，被很好地描述为有效 神经毒性剂，与较低的认知和学习能力差有关。但是，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关节影响仍然极为 有限的。关于在胎儿发育过程中暴露于多种金属的综合影响的众所周知 或儿童早期的产后暴露，或其他环境混合物（例如营养素）的影响， 这可能具有共享的来源，这些来源是金属的神经发育效应。为了解决这一重大差距， 我们的长期目标是量化无处不在产前和产后环境的神经认知影响 混合物并识别脐带血DNA甲基化生物标志物，可以重建产前环境 暴露并预测儿童的未来神经认知发展。我们将测试关键的客观度量是否 产前孕产妇营养，例如叶酸，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，我们将利用已建立的美国的资源 viva Project viva前同类队列。在此队列中，我们测量了14个产前母体金属的浓度 在怀孕的头三个月和早期收集的血液样本（〜3年）准备金属准备金属 测试以及准备使用全基因组血液DNA甲基化筛选。孩子们遵循 前瞻性并经过了早期（〜3岁）和年龄段的神经发育的细节测试 （〜7年）。我们假设产前产妇的第一例和产后儿童时期神经毒性金属 混合物与早期和中期的神经发育不良有关（AIM 1），并且首先是产前 孕妇母体血浆叶酸，维生素B12和必需金属的血液浓度预防 产前金属混合物神经毒性（AIM 2）。我们还假设在 出生时脐带血可以重建产前暴露于金属（AIM 3.A）和脐带血dnam 标记预测了早期和中期的未来神经认知发展（AIM 3.B）。通过测试纵向 大量儿童的协会进行了详细认知评估以及客观的生物标志物 金属和营养素，我们将克服现有研究目前面临的局限性测试很少的暴露 同时地。我们将使用新颖的统计方法来建模产前和产后环境 混合物和机器学习算法以建立暴露和神经发育的表观遗传预测指标。 这项研究将对产前和产后的认知负担进行全面的量化 混合物，暴露和神经发育的生物标志物的发展以及潜力的识别 产前营养干预策略。