Heme Pathway Polymorphisms in Mercury Neurotoxicity in Adults and Children

成人和儿童汞神经毒性的血红素途径多态性

• 批准号: 7089369
• 负责人: JAMES S WOODS
• 金额: $ 52.27万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7089369
• 关键词: European; adolescence (12-20); biomarker; clinical research; developmental psychology; environmental exposure; environmental toxicology; genetic polymorphism; genetic susceptibility; human genetic material tag; human subject; hydrocarbon oxidoreductase; mercury poisoning; middle childhood (6-11); nervous system disorder epidemiology; neurogenesis; neuropsychological tests; neuropsychology; neurotoxicology; neurotoxins; porphyrin biosynthesis; toxin metabolism

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.

拟议的研究的目的是确定在编码血红素生物合成途径酶，粪卟啉原氧化酶（CPOX），一个非典型的卟啉反应（汞），汞暴露，汞介导的神经行为影响在成人和儿童的基因多态性之间的关联。长期目标是通过确定可能改变对汞毒性敏感性的遗传因素，并确定汞暴露的既定生物标志物对确定易感个体的效力，减少或预防低水平环境汞暴露可能造成的神经功能缺损。 本研究的具体目的是：（1）确定CPOX多态性与儿童对汞的非典型卟啉反应之间的关系，（2）确定CPOX多态性对儿童汞暴露与神经行为表现缺陷之间关系的潜在影响，（3）确定CPOX多态性对汞体内负荷的潜在影响，以及成年人近期和长期汞暴露的测量，（4）比较野生型和多态性CPOX的基因产物的生物化学性质，和（5）确定已知影响神经功能的其它候选基因的潜在作用（例如，BDNF、5-HTT、COMT、TOD 2）对汞与 暴露和成人和儿童的神经行为表现。我们将使用成熟的遗传分析技术，沿着全面的、纵向的神经行为和神经系统测试结果，在长期、低水平汞暴露的成年人和儿童的成熟队列中实现这些目标，这些暴露与居住在超级基金危险废物场地附近的人的经历相当。从该项目中获得的知识将使公众更好地了解低水平汞接触对人类健康的影响、遗传因素对汞毒性的可能影响，以及如何减少或预防汞接触和汞毒性。这些研究通过确定可用于评估暴露、潜在健康风险和易感性改变的生物标志物，直接满足了超级基金计划的需求 在汞污染的危险废物场地附近居住的成人和儿童中，汞毒性的影响。