Heme pathway polymorphisms in mercury induced porphyrinuria & toxicity

本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-卟啉原氧化酶（CPOX）的遗传多态性之间的关系，这是一种对汞（hg）、汞暴露和低水平环境汞暴露期间汞毒性的非典型卟啉反应，可用于识别在低水平环境汞暴露期间汞毒性风险增加的人群。拟议研究的具体目标是：(1)开发基于自动测序和寡核苷酸连接的检测方法，以识别和定义编码UROD和CPOX的基因的多态性；(2)使用这些检测方法在具有良好特征的Hg暴露受试者群体中识别这些酶的遗传变异；(3)定义观察到的人类UROD和CPOX基因多态性与汞非典型卟啉反应之间的关系。(4)将UROD和CPOX多态性的潜在影响修饰定义为hg诱导的肾脏变化的预测因子（生物标志物），将UROD和CPOX多态性的缺失和存在定义为hg诱导的肾脏和神经行为功能变化的预测因子（生物标志物）。我们将使用新的和已建立的基因分析技术，以及经过验证的神经行为和临床测试程序，在已建立的，具有良好特征和高度积极性的低水平汞暴露人群中实现这些目标，这些人群与居住在超级基金危险废物场附近的人的经历相当。UROD和/或CPOX基因的特定多态性与对汞的非典型卟啉反应之间的重要关系的发现，将代表首次发现对汞的生物反应改变的遗传易感性，这可能反映在人类受试者的汞倾向改变和相关的健康风险中。由于对汞的非典型卟啉反应可作为对汞毒性易感性的生物标志物，本项目直接解决了超级基金的立法任务，即开发先进技术，以检测、评估和评估与危险物质接触有关的人类健康风险。

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.