Metal Exposure and Children?s Preschool Neurodevelopment

描述(申请人提供)：发育中的中枢神经系统特别容易受到重金属等环境毒物的影响。虽然铅中毒已被广泛研究，但与砷(As)和锰(Mn)等其他重金属相关的神经毒性和剂量-效应关系却知之甚少。关于联合暴露于这些金属的影响的数据甚至更加有限，尽管这种暴露情景更准确地反映了现实世界的情况。在这个项目中，我们将建立在一项正在进行的出生队列研究的基础上，该研究对750名母亲和她们的孩子进行了研究，这些母亲和她们的孩子以前是一个硬岩采矿社区，俄克拉何马州焦油溪，超级基金巨型网站。到目前为止，对2岁的儿童进行了跟踪调查，收集了大量的铅、锰和生物标记物数据(血液、头发、指甲)，提供了一生(包括产前)接触这些金属的记录。在拟议的项目中，将在儿童年满5.5岁时进行评估。届时，将测定血液中的锰和铅，头发中的锰、砷和硒(Se)，以及指甲中的砷和硒。神经发育评估将包括智力、记忆力、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系，以及神经发育与联合接触金属之间的关系。另一个目标是确定遗传易感性因素是否改变了金属暴露和神经发育之间的关系，重点研究了被选择来反映金属代谢或突触可塑性的4条途径的遗传变异：铁代谢(HFE、转铁蛋白、DMT-1)、胆固醇代谢(载脂蛋白E)、神经递质代谢(多巴胺转运体、多巴胺D4受体、去甲肾上腺素转运体、单胺氧化酶、儿茶酚O-甲基转移酶、NMDA受体、5-HT1A受体)和甲基化代谢(亚甲基四氢叶酸还原酶、GST-M1、T1、P1、omega、嘌呤核苷磷酸化酶、胞浆丝氨酸羟甲基转移酶)。这项前瞻性研究将提供迄今为止关于锰和砷暴露的潜在神经发育相关性以及铅、锰和砷暴露之间的潜在相互作用的最全面的数据。这项从出生起对儿童进行的前瞻性研究将提供有关接触重金属砷和锰对神经发育的潜在不利影响的最全面的数据。暴露于包括铅在内的多种金属组合的影响也是一个主要关注点。这更贴切地反映了“真实世界”的暴露，它总是涉及化合物的混合物，而不是单一的化合物。

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.