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: 10578793
• 负责人: Andres Cardenas
• 金额: $ 36.99万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578793
• 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; DNA Methylation; Data; Data Science; Dedications; 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; Predisposition; 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.

项目概要 产前和产后儿童期接触金属（无论是必需的还是非必需的）通过饮食和摄入是普遍存在的。 环境来源。重金属，包括铅和甲基汞，被充分表征为有效的 神经毒物，与认知能力较低和学习能力较差有关。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极其严重 有限的。关于胎儿发育过程中接触多种金属的综合影响知之甚少 或幼儿期产后接触，或其他环境混合物的影响，例如营养素、 关于金属对神经发育的影响，它们可能有共同的来源。为了解决这一重大差距， 我们的长期目标是量化普遍存在的产前和产后环境对神经认知的影响 混合物并鉴定脐带血 DNA 甲基化生物标志物，可重建产前环境 暴露并预测儿童未来的神经认知发展。我们将测试关键措施是否客观 产前母体营养素，如叶酸、维生素 B12 和必需金属，可减弱或减轻 金属混合物的神经毒性。为了实现这一目标，我们将利用成熟的美国的资源。 出生前队列，Project Viva。在该队列中，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幼儿期（约 3 岁）收集的血液样本准备用于金属 测试以及随时可用的全基因组脐带血 DNA 甲基化筛查。孩子被跟踪 前瞻性地对儿童早期（约 3 岁）和中期的神经发育进行详细测试 （~7 年）。我们假设产前孕早期和产后幼儿期神经毒性金属 混合物与儿童早期和中期的神经发育不良有关（目标 1），并且产前首先 孕期母体血浆叶酸、维生素 B12 和血液中必需金属浓度可预防 产前金属混合物神经毒性（目标 2）。我们还假设 DNA 甲基化标记在 出生时的脐带血可以重建产前金属暴露（目标 3.a），并且脐带血 DNAm 标记预测儿童早期和中期的未来神经认知发展（目标 3.b）。通过纵向测试 在一大群儿童中进行详细的认知评估以及客观的生物标志物的关联 金属和营养素，我们将克服现有研究测试少量暴露所面临的限制 同时地。我们将使用新颖的统计方法来模拟产前和产后环境 混合物和机器学习算法来构建暴露和神经发育的表观遗传预测因子。 这项研究将对产前和产后的认知负担进行全面量化 混合物、暴露和神经发育生物标志物的开发以及潜力的识别 产前营养干预策略。