IMMUNOTOXIC PROPERTIES OF MERCURIC COMPOUNDS

描述（改编自研究者摘要）：汞及其 同系物是以无机形式存在的剧毒物质， 汞（Hg++）、有机汞和汞蒸气（Hg 0）。来源 人类接触汞的途径包括海产品、种子、食品、水， 牙科汞合金在之前的研究中，主要研究者 表明低浓度的汞会杀死人体淋巴细胞 与细胞凋亡一致目标是那个 导致渗透性过渡态发展的细胞器 和氧化应激。在这些研究中要检验的假设是 接触汞可能会损害宿主的健康， 防御机制此外，线粒体功能紊乱 为汞化合物提供了一个主要的细胞毒性途径。在这 建议中，汞引起的 将进一步定义人的细胞凋亡。的免疫毒性作用 Hg 0将被表征以确定其是否通过以下途径杀死人类T细胞： 细胞凋亡是氧化应激的结果。研究分为 四个具体目标。首先是确定汞引起的 线粒体功能障碍是由于毒物的直接作用， 凋亡细胞Bcl-2蛋白家族成员的表达或功能 调节蛋白第二个具体目标是确定汞是否- 线粒体功能的依赖性变化促进胱天蛋白酶活性， 诱导T细胞凋亡。有人提出，半胱天冬酶的激活 级联反应是汞诱导的线粒体通透性的结果 过渡第三个具体目标是测量汞的影响 （a）氧化还原敏感性的表达和活性 转录因子NF-κ B和AP-1的表达，以及（B）新的转录因子NF-κ B和AP-1的表达。 与氧化应激相关的基因。第四个具体目标是 确定汞是否诱导T细胞凋亡，并了解细胞死亡是否是 与线粒体功能障碍有关建议暴露于Hg 0 导致快速的T细胞凋亡，这是由于 不带电的物种本应用程序的目标是更好地了解 导致汞毒性和健康的途径 与接触含汞化合物有关的影响。

DESCRIPTION (adapted from the Investigator's abstract): Mercury and its congeners are extremely toxic substances which exist as inorganic mercury (Hg++), organic mercury, and mercury vapor (Hg0). Sources of human exposure to mercury include seafood, seeds, foodstuffs, water, and dental amalgam. In previous studies, the Principal Investigator has shown that mercury, at low concentrations, kills human lymphoid cells in a manner consistent with apoptosis. The mitochondrion is the target organelle resulting in development of the permeability transition state and oxidative stress. The hypothesis to be tested in these studies is that exposure to mercury may cause health deficits by impairing host defense mechanisms. In addition, perturbed mitochondrial function provides a major cytotoxic pathway for mercurial compounds. In this proposal, the cascade of events responsible for mercury-induced apoptosis in humans will be further defined. The immunotoxic effects of Hg0 will be characterized to determine if it kills human T cells via apoptosis as a consequence of oxidative stress. The study is divided into four specific aims. The first is to determine if mercury-induced mitochondrial dysfunction is due to direct effects of the toxicant on the expression or function of Bcl-2 protein family members of apoptotic regulatory proteins. The second specific aim is to ascertain if mercury- dependent changes in mitochondrial function promote caspase activity and induce T cell apoptosis. It is proposed that activation of the caspase cascade is a result of mercury-induced mitochondrial permeability transition. The third specific aim is to measure the effect of mercury on (a) the expression and activity of the redox sensitivity transcription factors NF-kB and AP-1, and (b) the expression of novel genes associated with oxidative stress. The fourth specific aim is to determine if Hg0-induces T cell apoptosis and learn if cell death is linked to mitochondrial dysfunction. It is proposed that exposure to Hg0 leads to rapid T cell apoptosis due to physical characteristics of the uncharged species. The goal of this application is to better understand the pathways responsible for mercury toxicity, as well as health implications associated with exposure to mercury-containing compounds.