Heme pathway polymorphisms in mercury induced porphyrinuria & toxicity

这项研究的目的是确定两种血红素生物合成途径酶--尿卟啉原脱羧酶(UROD)和共预防原氧化(CPOX)--一种对汞(HG)、汞暴露和低水平环境汞暴露期间汞毒性的非典型致卟啉反应(CPOX)--的遗传多态之间的关联，以确定在低水平环境汞暴露期间谁是汞中毒的高危人群。这项研究的具体目标是：(1)开发基于自动测序和寡核苷酸连接的分析方法，以识别和定义编码UROD和CPOX的基因的多态；(2)使用这些分析方法，在汞暴露人群中识别这些酶的遗传变异；(3)确定观察到的人类UROD和CPOX基因的多态与对汞的非典型致卟啉反应之间的关系；(4)确定UROD和CPOX多态的潜在影响修饰，作为汞诱导的肾脏变化的预测因子(生物标记物)以及UROD和CPOX多态的缺失和存在，作为汞引起的肾脏和神经行为功能改变的生物标志物。我们将使用新颖的基因分析技术以及经过验证的神经行为和临床测试程序来实现这些目标，在一个既定的、具有良好特征和高度积极性的人群中实现这些目标，这些人群的汞暴露水平与居住在Superfund危险废物场地附近的人相当。UROD和/或CPOX基因的特定多态与汞的非典型致卟啉反应之间的显著关系的发现，将是首次发现对汞的生物反应改变的遗传易感性，这可能反映在人体汞处置的改变和相关的健康风险上。由于对汞的非典型致卟啉反应可能作为汞毒性易感性的生物标志物，该项目直接针对超级基金立法的任务，开发先进的技术来检测、评估和评估与有害物质暴露相关的人类健康风险。

The objective of the proposed research is to define the association between genetic polymorphisms of two heme biosynthetic pathway enzymes, uroporphyrinogen decarboxylase (UROD) and co- coprophyrinogen oxidative (CPOX), an atypical porphyrinogenic response to mercury (hg), Hg exposure, and Hg toxicity during low-level environmental Hg exposure that could be used to identify persons who are at increased risk of Hg toxicity during low-level environmental Hg exposure. The specific aims of the proposed research are to (1) develop automated sequencing-based and oligonucleotide ligation assays to identify and define polymorphisms in genes that encode UROD and CPOX, (2) use these assays to identify genetic variants of these enzymes within a well- characterized population of Hg-exposed subjects, (3) define the relationship between observed polymorphisms in the human UROD and CPOX genes and the atypical porphyrinogenic response to Hg, (4) define the potential effect modification of UROD and CPOX polymorphisms, as predictors (biomarkers) of Hg-induced changes in kidney and absence and presence of UROD and CPOX polymorphisms, as predictors (biomarkers of Hg-induced changes in kidney and neurobehavioral functions. We will approach these objectives using novel and establish genetic analytical techniques, along with validated neurobehavioral and clinical testing procedures, in an established, well-characterized and highly motivated human population with low-level Hg exposure comparable to that experienced by persons residing near Superfund hazardous waste sites. The finding of a significant relationship between specific polymorphisms in the UROD and/or CPOX genes and the atypical porphyrinogenic response to Hg would represent the first such discovery of a genetic predisposition to an altered biological response to Hg that could be reflected in altered Hg disposition and associated health risks in human subjects. Inasmuch as the atypical porphyrinogenic response to Hg may serve as a biomarker of susceptibility to Hg toxicity, this project directly addresses the Superfund-legislated mandate to develop advanced techniques to detect, assess, and evaluate human health risks associated with hazardous substances exposures.