Metal Mixtures and Neurodevelopment

金属混合物和神经发育

• 批准号: 7650099
• 负责人: Robert O Wright
• 金额: $ 60.63万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-19 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7650099
• 关键词: 2 year old; Arsenic; Biological Markers; Birth; Child; Cities; Collaborations; Data; Development; Dose; Environment; Exposure to; Genes; Genetic Polymorphism; Genetic Variation; Glutathione S-Transferase; Haplotypes; Hemochromatosis; Individual Differences; Infant; Institutes; Joints; Lead; Lead Poisoning; Manganese; Measures; Metabolism; Metal exposure; Metals; Mexico; Mothers; Neuraxis; Neurotoxins; Outcome; Participant; Phenotype; Placenta; Play; Population; Predisposition; Pregnancy; Public Health; Receptor Gene; Research; Research Personnel; Role; TF gene; Target Populations; Testing; Toxic Environmental Substances; Transferrin; Transferrin Receptor; Variant; Work; blood lead; cohort; divalent metal; iron metabolism; metal transporting protein 1; neurodevelopment; neurotoxic; neurotoxicity; programs; sample collection; toxic metal

DESCRIPTION (provided by applicant): The developing central nervous system is particularly vulnerable to environmental toxicants. While lead poisoning has been extensively studied and public health measures to reduce exposure implemented, exposure is still high in some populations. Other toxic metals (arsenic and manganese for example) remain elevated in the environment, and the effects of arsenic and manganese on neurodevelopment remain poorly understood. Critical questions also remain regarding individual differences in susceptibility to metals (even lead) and whether combinations of neurotoxicants are synergistically toxic. Given this, the effect of joint exposure to combinations of metals is a critical public health issue, as this exposure scenario is more reflective of the real world situation. The role of iron metabolism genes, which may regulate the metabolism of multiple neurotoxic metals, may also play a key role in understanding the mechanisms by which metal mixtures produce neurotoxicity. In this project we will establish a new birth cohort in Mexico City to measure biomarkers of internal dose for manganese, arsenic and lead and analyze their interactions in predicting associations between metal exposure and neurodevelopment. Furthermore, we will study the modifying effects of iron metabolism gene variants (HFE, Transferrin, Transferrin Receptor, and Divalent Metal Transport Protein-1) on the neurotoxicity of these metals and their influence on placenta! transfer of metals. We will also explore the effect of variants in the GST-M1, T1 and P1 genes on Arsenic neurotoxicity. Our research team is particularly well situated to conduct this work as we have a long-standing collaboration with the National Institute of Public Health in Mexico, enabling us to quickly assemble highly skilled field teams for sample collection and phenotyping. Furthermore, our pilot data suggest that exposure to Mn, As and Pb are elevated in the target population, and that biomarkers of internal dose may be associated with poorer developmental outcomes.

描述（由申请人提供）：发展中心神经系统尤其容易受到环境有毒物质的影响。尽管已经对铅中毒进行了广泛的研究并采取了公共卫生措施以减少实施的暴露，但某些人群的暴露仍然很高。其他有毒金属（例如，砷和锰）在环境中仍然具有升高，并且砷和锰对神经发育的影响仍然很少了解。关于金属易感性（甚至铅）以及神经毒性的组合是否有毒性的个体差异，仍然存在关键问题。鉴于此，联合接触金属组合的影响是一个关键的公共卫生问题，因为这种暴露情况更反映了现实世界的状况。铁代谢基因的作用可能调节多种神经毒性金属的代谢，也可能在理解金属混合物产生神经毒性的机制中起关键作用。在这个项目中，我们将在墨西哥城建立一个新的出生队列，以测量锰，砷的内剂量生物标志物，并铅并分析其在预测金属暴露与神经发育之间关联时的相互作用。此外，我们将研究铁代谢基因变异（HFE，转铁蛋白，转铁蛋白受体和二价金属转运蛋白1）对这些金属神经毒性及其对胎盘的影响的修饰作用！金属的转移。我们还将探讨GST-M1，T1和P1基因对砷神经毒性的影响。我们的研究团队尤其良好，可以进行这项工作，因为我们与墨西哥的国家公共卫生研究所进行了长期合作，使我们能够迅速组装高技能的野外团队，以进行样本收集和表型。此外，我们的试点数据表明，目标人群中对MN的暴露率升高，并且内部剂量的生物标志物可能与较差的发育结果有关。