Heme Pathway Polymorphisms in Mercury Neurotoxicity in Adults and Children

这项拟议研究的目的是确定编码血红素生物合成途径酶、共比例卟啉原氧化酶(CPOX)的基因多态性、汞(Hg)的非典型致卟啉反应、汞暴露与汞介导的神经行为效应之间的关联。长期目标是通过确定可能改变汞毒性易感性的遗传因素，并通过确定已建立的汞暴露生物标记物识别易感个体的有效性，减少或预防低水平环境汞暴露可能导致的神经缺陷。 这项研究的具体目的是(1)确定环氧合酶基因多态与儿童对汞的非典型致卟啉反应之间的关联，(2)确定环氧合酶基因多态对儿童汞暴露与神经行为功能缺陷之间的关联的潜在影响，(3)确定环氧合酶基因多态对汞身体负担的潜在影响以及成人近期和长期汞暴露的措施，(4)比较野生型和多态环氧合酶基因产物的生化特性，以及(5)确定其他已知影响神经功能的候选基因(例如，BDNF、5-HTT、COMT、TOD2)关于汞和汞之间的联系 成人和儿童的暴露和神经行为表现。我们将使用成熟的基因分析技术，以及全面的、纵向的神经行为和神经测试结果，在长期、低水平汞暴露与居住在Superfund危险废物场地附近的人相当的成熟成人和儿童队列中实现这些目标。从这个项目中获得的知识将提高公众对低水平汞暴露对人类健康的影响、遗传因素对汞毒性的可能影响以及如何减少或预防汞暴露和毒性的了解。这些研究通过确定可用于评估暴露、潜在健康风险和改变的敏感性的生物标记物，直接满足超级基金计划的需求 对居住在被汞污染的危险废物场地附近的成人和儿童的汞毒性。

The objective of the proposed research is to define the association between an identified polymorphism in the gene encoding the heme biosynthetic pathway enzyme, coproporphyrinogen oxidase (CPOX), an atypical porphyrinogenic response to mercury (Hg), Hg exposure, and Hg-mediated neurobehavioral effects in adults and children. The long-term goal is to reduce or prevent neurological deficits potentially caused by low-level environmental Hg exposure by identifying genetic factors that may alter susceptibility to Hg toxicity and by defining the efficacy of an established biomarker of Hg exposure to identify suscepible individuals. The specific aims of the proposed research are to (1) define the association between the CPOX polymorphism and the atypical porphyrinogenic response to Hg in children, (2) define the potential effects of the CPOX polymorphism on the association between Hg exposure and neurobehavioral performance deficits in children, (3) define the potential effect of the CPOX polymorphism on Hg body burden and measures of recent and chronic Hg exposure in adults, (4) compare the the biochemical properties of the gene products of wildtype and polymorphic CPOX, and (5) define potential effects of additional candidate genes that are known to affect neurological function (e.g., BDNF, 5-HTT, COMT, TOD2) on the association between Hg exposure and neurobehavioral performance in adults and children. We will accomplish these objectives using established genetic analytical techniques, along with comprehensive, longitudinal neurobehavioral and neurological test results, in well-established cohorts of adults and children with prolonged, low-level Hg exposure comparable to that experienced by persons residing near Superfund hazardous waste sites. Knowledge gained from this project will improve public understanding about the effects of low-level Hg exposure on human health, the possible influence of genetic factors on Hg toxicity, and how Hg exposure and toxicity can be reduced or prevented. These studies directly address Superfund Program needs by identifying a biomarker that could be used assess exposure, potential health risks, and altered susceptibility to Hg toxicity in adults and children who reside near Hg-contaminated hazardous waste sites.