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）和辅辅酶A原氧化酶（CPOX）的遗传多态性，对汞（Hg）的非典型卟啉反应，汞暴露，和汞毒性，可用于确定在低汞暴露环境中汞毒性风险增加的人群，水平的环境汞暴露。拟议研究的具体目的是（1）开发基于自动测序和寡核苷酸连接测定法，以鉴定和定义编码UROD和CPOX的基因中的多态性，（2）使用这些测定法鉴定这些酶在充分表征的汞暴露受试者群体中的遗传变体，（3）确定在人类UROD和CPOX基因中观察到的多态性与对汞的非典型卟啉反应之间的关系，（4）确定UROD和CPOX多态性的潜在效应修饰，作为汞诱导的肾脏变化的预测因子（生物标志物）以及UROD和CPOX多态性的存在和缺失，作为汞诱导的肾脏和神经行为功能变化的预测因子（生物标志物）。我们将采用新的和建立的遗传分析技术，沿着经验证的神经行为和临床测试程序，在一个建立的，特征良好的和高度积极的低水平汞暴露的人群中接近这些目标，与居住在超级基金危险废物场地附近的人的经历相当。UROD和/或CPOX基因中的特定多态性与汞的非典型卟啉反应之间存在显著关系，这一发现将代表首次发现对汞的生物反应改变的遗传易感性，这种遗传易感性可反映在人类受试者的汞处置改变和相关健康风险中。由于对汞的非典型卟啉反应可作为对汞毒性敏感性的生物标志物，本项目直接涉及超级基金立法的任务，即开发先进技术来检测、评估和评价与危险物质接触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.