Genetic Susceptibility to Mercury Toxicity in Children

描述(由申请人提供)：拟议研究的目的是确定已知与成人神经行为缺陷相关的特定基因多态对儿童汞合金充填物暴露于元素汞(Hg0)的神经毒性影响的潜在修饰效应。特别令人感兴趣的是编码血红素生物合成途径酶-共比例卟啉原氧化酶(CPOX4)的基因外显子4的单核苷酸多态(SNP)，它既增加了成年人对Hg0神经行为影响的敏感性，又非典型地改变了作为这种影响的潜在生物标志物的尿卟啉排泄。另一个令人感兴趣的是与神经递质运输和功能相关的基因(BDNF、5-HTTLPR、COMT、TDO2)的多态性，据报道，这些基因会导致与Hg0暴露影响相似的神经功能障碍。长期目标是通过识别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在易感儿童中的潜在疗效，来减少或预防汞暴露可能导致的神经缺陷。这些分析的具体目的是确定CPOX4基因多态性对汞暴露与儿童神经行为能力缺陷之间关系的潜在影响，并确定在患有CPOX4的成人受试者中观察到的对汞暴露的非典型产卟啉反应是否也可以作为儿童汞中毒易感性增加的生物标志物。另一个目的是确定其他已知影响成人神经功能的基因的多态对接触Hg0与儿童神经行为表现之间的关联的潜在影响。这些统计分析将利用已经收集的纵向数据，包括神经行为测试结果、尿汞水平、累积汞暴露指数和尿卟啉测量，这些数据每年从大约300名参加随机临床试验的8岁至18岁的儿童中获得，并随后对这些儿童进行感兴趣的多态基因分型。从这些分析中获得的知识可以确定从童年到青春期整个时期男孩和女孩对汞中毒的不同易感性的遗传因素。这项研究着眼于一个长期的公共卫生目标，旨在根据基因-环境相互作用对化学毒性的风险进行分层，这是一种对儿童特别重要的风险表征方法。此外，这些发现可以作为更全面的研究的基础，研究确定儿童对Hg0神经毒性的易感性所涉及的多种遗传变异和相关生化途径的相互作用。 与公共卫生相关：接触元素汞(HGO)对儿童，特别是那些可能特别容易受到发育中的中枢神经系统(CNS)损害以及伴随而来的认知、个性、运动功能和行为障碍的儿童，具有很高的毒性风险。这项拟议的研究利用纵向数据集来评估几种相对常见的基因多态的潜在影响，这些基因多态已知会改变成年人的神经行为功能，在从童年到青春期后期的一段时间内，儿童对HGO神经毒性的易感性。这项研究通过考虑与接触HGO和其他环境毒物相关的健康风险的遗传易感性的策略，解决了改善儿童健康风险评估的长期公共卫生目标。

DESCRIPTION (provided by applicant): The objective of the proposed research is to define the potentially modifying effects of specific genetic polymorphisms that are known to be associated with neurobehavioral deficits in adults, on the neurotoxic effects of elemental mercury (Hg0) exposure from dental amalgam fillings in children. Of particular interest is a single nucleotide polymorphism (SNP) in exon 4 of the gene encoding the heme biosynthetic pathway enzyme, coproporphyrinogen oxidase (CPOX4), which both increases sensitivity to the neurobehavioral effects of Hg0 in adults and atypically modifies urinary porphyrin excretion as a potential biomarker of this effect. Of additional interest are polymorphisms of genes associated with neurotransmitter transport and function (BDNF, 5- HTTLPR, COMT, TDO2) that are reported to confer neurological deficits similar to those affected by Hg0 exposure. The long-term goal is to reduce or prevent neurological deficits potentially caused by Hg0 exposure by identifying genetic factors that may alter susceptibility to Hg toxicity and by defining the potential efficacy of an established biomarker of Hg0 exposure in susceptible children. The specific aims of the proposed analyses are to define the potential effects of the CPOX4 polymorphism on the association between Hg0 exposure and neurobehavioral performance deficits in children, and to determine if an atypical porphyrinogenic response to Hg0 exposure that is observed in adult subjects with CPOX4 also serves as a biomarker of increased susceptibility to Hg toxicity in children. An additional aim is to define potential effects of polymorphisms in other genes that are known to affect neurologic function in adults on the association between Hg0 exposure and neurobehavioral performance in children. These statistical analyses will utilize already-collected longitudinal data that include neurobehavioral test results, urinary mercury levels, cumulative Hg0 exposure indices, and urinary porphyrin measurements obtained annually from approximately300 children who participated in a randomized clinical trial between ages 8 and 18, and who have subsequently been genotyped for the polymorphisms of interest. Knowledge gained from these analyses may define genetic factors that account for differential susceptibility in boys and girls to mercury toxicity throughout the period from childhood through adolescent development. This study addresses a long-term public health goal aimed at stratifying risk to chemical toxicity based on gene- environment interactions, an approach to risk characterization that is of particular importance for children. Additionally, these findings could serve as the basis for more comprehensive studies examining the interaction of multiple genetic variants and related biochemical pathways involved in defining susceptibility to Hg0 neurotoxicity in children. PUBLIC HEALTH RELEVANCE: Exposure to elemental mercury (Hgo) poses a high risk of toxicity to children, especially those who may be particularly vulnerable to impairment of the developing central nervous system (CNS) along with attendant cognitive, personality, motor function and behavioral disorders because of genetic predisposition. The proposed study utilizes a longitudinal dataset to evaluate potential effects of several relatively common genetic polymorphisms that are known to alter neurobehavioral functions in adults on susceptibility to the neurotoxicity of Hgo in children over a period of development from childhood through late adolescence. This study addresses the long-term public health goal of improving health risk assessment in children through strategies that consider genetic susceptibility to health risks associated with exposure to Hgo and other environmental toxicants.