Genetic Susceptibility to Mercury Toxicity in Children

儿童对汞中毒的遗传易感性

• 批准号: 8241024
• 负责人: Joan E. Russo
• 金额: $ 22.04万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-11 至 2013-09-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8241024
• 关键词: Accounting; Address; Adolescence; Adolescent Development; Adult; Affect; Age; Behavior Disorders; Biochemical Pathway; Bioinformatics; Biological; Biological Markers; Brain-Derived Neurotrophic Factor; Candidate Disease Gene; Chemicals; Child; Childhood; Clinical Trials; Cognitive; Collection; Consent; Data; Data Set; Dental Amalgam; Development; Environmental Exposure; Excretory function; Exons; Exposure to; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genotype; Goals; Health; Heme; Impairment; Knowledge; Measurement; Measures; Mercury; Motor; Nervous System Physiology; Neuraxis; Neurodevelopmental Disorder; Neurologic; Performance; Personality; Porphyrins; Predisposition; Program Research Project Grants; Public Health; Publications; Randomized; Randomized Clinical Trials; Reporting; Research; Risk; Risk Assessment; Sampling; Single Nucleotide Polymorphism; Superfund; Test Result; Toxic Environmental Substances; Toxic effect; Tryptophanase; Universities; Variant; Washington; Wood material; base; boys; cohort; coproporphyrinogen oxidase; enzyme pathway; gene environment interaction; genetic variant; girls; high risk; improved; indexing; interest; member; neurobehavioral; neurobehavioral test; neurotoxic; neurotoxicity; neurotransmitter transport; prevent; programs; prospective; public health relevance; response; urinary

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.

描述（由申请人提供）：拟议的研究的目的是定义特定遗传多态性的可能修饰作用，这些特定遗传多态性与成人的神经行为缺陷有关，对儿童牙科疗程汞接触的元素汞（HG0）暴露的神经毒性影响。特别感兴趣的是编码血红素生物合成途径酶的外显子4中的单个核苷酸多态性（SNP），cpox4）对HG0对这种效果的敏感性均增加了对HG0的神经性神经性效应的敏感性。与神经递质转运和功能相关的基因的多态性（BDNF，5- HTTLPR，COMT，TDO2）据报道赋予与受HG0暴露相似的神经功能缺陷相关的基因（BDNF，5- HTTLPR，COMT，TDO2）的多态性。长期目标是通过鉴定可能改变对HG毒性易感性的遗传因素，并确定易感儿童中HG0暴露的生物标志物的潜在疗效，从而减少或预防由HG0暴露引起的神经缺陷。所提出的分析的具体目的是定义CPOX4多态性对儿童HG0暴露与神经行为的性能缺陷之间的关联的潜在影响，并确定在CPOX4中对HG0受试者的非典型卟啉原性反应对HG0暴露的毒性是否与CPOX 4的毒性相关，这也是HIMES AS HIMECTIBINE HIM AS HIM ATS HIM AS HIMARKERIDICY hIMAKENIBINIAL，HIMARKESER hIMECTIDINE hIMAKENIBINIAL的HIMARKERIDICINE HAR的毒性。另一个目的是确定多态性在其他基因中的潜在影响，这些基因已知会影响成年人对儿童HG0暴露与神经行为性能之间关联的神经系统功能。这些统计分析将利用已经收集的纵向数据，其中包括神经行为测试结果，泌尿汞水平，累积HG0暴露指数以及每年从大约300名参与ages 8和18的随机临床试验的儿童中获得的每年获得的尿卟啉测量结果，并随后在基因组中获得了竞争的兴趣。从这些分析中获得的知识可以定义遗传因素，这些因素解释了从童年到青少年发育的整个时期，男孩和女孩对汞毒性的差异敏感性。这项研究解决了一个长期的公共卫生目标，旨在根据基因环境相互作用将化学毒性的风险分层，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研究的基础，研究了多种遗传变异和相关的生化途径的相互作用，这些途径涉及确定儿童HG0神经毒性的易感性。 公共卫生相关性：暴露于元素汞（HGO）对儿童的毒性高风险，尤其是那些可能特别容易受到发展中枢神经系统（CNS）损害的人，以及随之而来的认知，个性，运动功能和行为障碍，因为遗传倾向。拟议的研究利用纵向数据集来评估几种相对常见的遗传多态性的潜在影响，这些遗传多态性已知，这些遗传多态性会改变成年人对HGO对HGO神经毒性的易感性的神经行为功能，从童年到青春期晚期。这项研究解决了通过考虑遗传易感性与暴露于HGO和其他环境有毒物质相关的健康风险的策略来改善儿童健康风险评估的长期公共卫生目标。