Metal Exposure and Children?s Preschool Neurodevelopment

金属接触与儿童学前神经发育

• 批准号: 7350056
• 负责人: David C Bellinger
• 金额: $ 57.71万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7350056
• 关键词: Adverse effects; Age; Age-Years; Apolipoprotein E; Arsenic; Behavior; Biological Markers; Birth; Blood; Catechol O-Methyltransferase; Child; Cholesterol Homeostasis; Cohort Studies; Collection; Communities; Data; Data Analyses; Dose; Exposure to; Genetic Predisposition to Disease; Genetic Variation; Glutathione S-Transferase; Glycine Hydroxymethyltransferase; Goals; Hair; Heavy Metals; Individual; Intelligence; Intelligence Tests; Joints; Lead; Lead Poisoning; Manganese; Measures; Memory; Metabolism; Metal exposure; Metals; Methylation; Methylenetetrahydrofolate reductase (NADPH); Mining; Modeling; Monoamine Oxidase; Mothers; N-Methyl-D-Aspartate Receptors; Nail plate; Neuraxis; Neurodevelopmental Deficit; Norepinephrine Receptors; Oklahoma; Participant; Pathway interactions; Population; Pregnancy; Preschool Child; Prospective Studies; Purine-Nucleoside Phosphorylase; Research Infrastructure; Resources; Score; Selenium; Serotonin Receptor 5-HT1A; Site; Synaptic plasticity; Tars; Time; Toxic Environmental Substances; Transferrin; Variant; Work; base; cohort; dopamine D4 receptor; dopamine transporter; executive function; iron metabolism; lead exposure; metal metabolism; neurodevelopment; neurotoxicity; neurotransmitter metabolism; noradrenaline transporter; postnatal; prenatal; prenatal exposure; superfund site; visual motor

DESCRIPTION (provided by applicant): The developing central nervous system is particularly vulnerable to environmental toxicants such as heavy metals. While lead (Pb) poisoning has been extensively studied, the neurotoxicities and dose-effect relationships associated with other heavy metals, such as arsenic (As) and manganese (Mn), are poorly understood. Data are even more limited on the effects of joint exposures to these metals, even though this exposure scenario more accurately reflects the real world situation. In this project we will build upon an ongoing birth cohort study of 750 mothers and their children at a former hard rock mining community, the Tar Creek, OK, Superfund mega-site. To date, children have been followed to age 2 years, involving the collection of extensive Pb, Mn, and As biomarker data (blood, hair, nails), providing a record of lifetime (including prenatal) exposures to these metals. In the proposed project, assessments will be conducted when children are 5.5 years of age. At that time, Mn and Pb will be measured in blood; Mn, As, and selenium (Se) in hair; and As and Se in nails. The neurodevelopmental assessment will include tests of intelligence, memory, visual- motor/spatial abilities, executive functions, and behavior. Data analyses will model the associations between neurodevelopment and individual metals and between neurodevelopment and joint exposures to metals. Another goal is to determine if genetic susceptibility factors modify the associations between metal exposures and neurodevelopment, focusing on genetic variations in 4 pathways chosen to reflect metal metabolism or synaptic plasticity: iron metabolism (HFE, transferrin, DMT-1), cholesterol metabolism (apolipoprotein E), neurotransmitter metabolism (dopamine transporter, dopamine D4 receptor, norepinephrine transporter, monoamine oxidase, catechol O-methyltransferase, NMDA receptor, 5-HT1A receptor), and methylation metabolism (methylenetetrahydrofolate reductase, GST- M1, T1, P1, omega, purine nucleoside phosphorylase, cytosolic serine hydroxymethyltransferase). This prospective study will provide the most comprehensive data to date on the potential neurodevelopmental correlates of Mn and As exposures, and on the potential interactions among Pb, Mn, and As exposures. This prospective study of children from birth will provide the most comprehensive data available on the potential adverse effects on neurodevelopment of exposure to the heavy metals arsenic and manganese. The effects of exposures to combinations of metals, including lead, is also a major focus. This more closely mirrors "real world" exposures, which invariably involve a mixture of compounds rather than a single compound.

描述（由申请人提供）：发展中心神经系统尤其容易受到诸如重金属之类的环境有毒物质的影响。尽管已经对铅（PB）中毒进行了广泛的研究，但与其他重金属（例如砷（AS）和锰（MN））相关的神经毒性和剂量效应关系知之甚少。尽管这种暴露情况更准确地反映了现实世界的状况，但数据对这些金属的关节暴露的影响更加受到限制。在这个项目中，我们将基于一项正在进行的出生队列研究，对750位母亲及其子女的持续研究，在一个前硬岩矿业社区，Tar Creek，OK，Superfund Mega Site。迄今为止，儿童已经遵循到2岁，涉及广泛的PB，MN以及作为生物标志物数据（血液，头发，指甲）的收集，可为这些金属提供终生（包括产前）暴露的记录。在拟议的项目中，儿童年满5.5岁时将进行评估。当时，Mn和Pb将在血液中测量； Mn，AS和硒（SE）的头发；并在指甲中。神经发育评估将包括智力，记忆，视觉运动/空间能力，执行功能和行为的测试。数据分析将模拟神经发育与单个金属之间的关联，以及神经发育与金属关节暴露之间的关联。另一个目标是确定遗传敏感性因素是否修改了金属暴露与神经发育之间的关联，重点是4种途径的遗传变异，以反映金属代谢或突触可塑性：铁代谢（HFE，转移蛋白，DMT-1），胆固醇代谢（胆固醇代谢蛋白E）； dopamine D4 receptor, norepinephrine transporter, monoamine oxidase, catechol O-methyltransferase, NMDA receptor, 5-HT1A receptor), and methylation metabolism (methylenetetrahydrofolate reductase, GST- M1, T1, P1, omega, purine nucleoside phosphorylase, cytosolic serine羟甲基转移酶）。这项前瞻性研究将提供迄今为止最全面的数据，以了解MN和暴露的潜在神经发育相关性，以及PB，MN和AS暴露的潜在相互作用。这项对儿童出生的前瞻性研究将提供有关对重金属砷和锰暴露神经发育潜在不利影响的最全面数据。暴露于包括铅在内的金属组合的影响也是一个重点。这更紧密地反映了“现实世界”的暴露，它总是涉及各种化合物而不是一种化合物。