PORPHYRIN PROFILES AS BIOMARKERS OF TRACE METAL EXPOSURE AND TOXICITY

拟议研究的目的是验证 作为汞(Hg)生物标志物的尿卟啉谱测量 汞暴露、汞诱发的神经行为效应与人体汞负荷 研究对象。我们的长期目标是提供一个敏感和准确的 汞暴露的生物标志物和可用于减少 低水平汞中毒的发生率和严重程度 暴露在环境中。 该项目的具体目标是：(1)描述人类个体 尿卟啉和点尿汞排泄率的变异性 样本，并确定现场尿样的程度 代表24小时的卟啉和汞排泄率，(2)确定 尿卟啉作为检测亚慢性和慢性前列腺癌的敏感性 慢性低水平汞暴露，(3)测定尿液敏感性 卟啉作为一种与低水平的神经影响相关的衡量标准 汞暴露，以及(4)确定尿卟啉的敏感性作为 汞身体负荷量的测量。这些目标将通过以下方式实现 评价尿液中的卟啉含量及其相关性 通过特定的汞暴露、神经行为功能和 受试者(牙医和牙科助理)汞累积剂量 特征良好、长期、低水平的汞暴露，可与 居住在超级基金危险废物场地附近的人经历过的。 其他特定目标，使用已建立的动物来实现 模型，是(5)将尿卟啉浓度定义为定量的 肾脏中活动性汞的测量和(6)定义化学物质 一种非典型卟啉的结构和生化病因学， 由汞暴露的动物和人类排泄出来的“前盆底比例卟啉”。 这些研究的预期结果是一个具有良好特征的生物标记物。 基于靶组织对汞的生物反应，这将 显著加强对低水平汞暴露和潜力的评估 对人体的毒性。这些研究还将进一步界定 支持这种特异性的生化机制 汞暴露所致的卟啉反应。

The objective of the proposed research is to validate the efficacy of urinary porphyrin profile measurements as a biomarker of mercury (Hg) exposure, Hg-induced neurobehavioral effects and Hg body burden in human subjects. The long-term goal is to provide a sensitive and accurate biomarker of Hg exposure and effects which can be used to reduce the incidence and severity of Hg toxicity in people with low-level environmental exposure. The specific aims of the project are to (1) describe individual human variability in urinary porphyrin and Hg excretion rates in spot urine samples, and determine the extent to which spot urine samples are representative of 24 hour porphyrin and Hg excretion rates, (2) determine the sensitivity of urinary porphyrins as a measure of sub-chronic and chronic low-level Hg exposure, (3) determine the sensitivity of urinary porphyrins as a measure of neurological effects associated with low-level Hg exposure, and (4) determine the sensitivity of urinary porphyrins as a measure of Hg body burden. These objectives will be accomplished by evaluating urinary porphyrin profiles with respect to their correlation with specific measures of Hg exposure, neurobehavioral function and cumulative Hg dose among subjects (dentists and dental assistants) with well-characterized, prolonged, low-level Hg exposure comparable to that experienced by persons residing near Superfund hazardous waste sites. Additional specific aims, to be accomplished using an established animal model, are to (5) define urinary porphyrin concentrations as a quantitative measure of mobilizable Hg in the kidney and (6) define the chemical structure and biochemical etiology of an atypical porphyrin, "precoproporphyrin", excreted by mercury-exposed animals and humans. The anticipated outcome of these studies is a well characterized biomarker based on a biological response to Hg in target tissues, which will significantly enhance the assessment of low-level Hg exposure and potential toxicity in human subjects. These studies will also further define the biochemical mechanisms which underlie the specificity of the porphyrinogenic response to Hg exposure.