Metal Exposure and Children?s Preschool Neurodevelopment

描述（由申请人提供）：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（Pb）中毒已被广泛研究，但与其他重金属（如砷（As）和锰（Mn））相关的神经毒性和剂量-效应关系却知之甚少。关于联合接触这些金属的影响的数据甚至更加有限，尽管这种接触情况更准确地反映了真实的世界局势。在这个项目中，我们将建立在一个正在进行的出生队列研究的750名母亲和他们的孩子在前硬岩采矿社区，焦油溪，OK，超级基金大型网站。到目前为止，儿童已被跟踪到2岁，涉及收集广泛的铅，锰和作为生物标志物数据（血液，头发，指甲），提供了一个记录的终身（包括产前）暴露于这些金属。在拟议的项目中，将在儿童年满5.5岁时进行评估。届时，将测量血液中的锰和铅;头发中的锰、砷和硒（Se）;指甲中的砷和硒。神经发育评估将包括智力、记忆、视觉运动/空间能力、执行功能和行为测试。数据分析将模拟神经发育和单个金属之间的关联，以及神经发育和金属联合暴露之间的关联。另一个目标是确定遗传易感性因素是否会改变金属暴露与神经发育之间的关联，重点是选择反映金属代谢或突触可塑性的4种途径的遗传变异：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（多巴胺转运蛋白、多巴胺D4受体、去甲肾上腺素转运蛋白、单胺氧化酶、儿茶酚O-甲基转移酶、NMDA受体、5-HT 1A受体）和甲基化代谢（亚甲基四氢叶酸还原酶、GST-M1、T1、P1、ω、嘌呤核苷磷酸化酶、胞质丝氨酸羟甲基转移酶）。这项前瞻性研究将提供迄今为止最全面的数据，锰和砷暴露的潜在神经发育相关性，铅，锰和砷暴露之间的潜在相互作用。这项对出生儿童的前瞻性研究将提供关于暴露于重金属砷和锰对神经发育的潜在不良影响的最全面的数据。接触包括铅在内的多种金属的影响也是一个主要重点。这更接近于反映“真实的世界”的曝光，这总是涉及混合的化合物，而不是一个单一的化合物。

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.