THE MOLECULAR BASIS FOR MERCURY TOXICITY

汞毒性的分子基础

• 批准号: 7370428
• 负责人: GRAHAM N GEORGE
• 金额: $ 0.41万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7370428
• 关键词: MOLECULAR; BASIS; MERCURY; TOXICITY

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The high toxicity of mercury compounds is well known, but the mechanisms of toxicity remain largely obscure. Human exposure to mercury comes from many sources, including predatory marine fish and from vaccines, where Thimerosal (ethylmercurithiosalicylate), a commonly-added fungicide and bactericide, has been implicated in autism and Asperger's syndrome. The nature and development of the toxic effects are critically dependent upon the chemical form of the mercury, but very little is known about the chemical fate of the metal after it has been ingested. One major reason for this is a lack of good in situ probes for mercury. X-ray absorption spectroscopy can provide information on the chemical environment of metals and metalloids in situ. We propose to apply Hg L-edge XAS to develop an understanding of the chemical toxicology of mercury in rats, as a model for human exposure. The ultimate goal of this work is to provide the chemical basis for effective chelation therapy treatment of mercury poisoning in humans. Current mercury chelation therapy drugs are not very effective. A striking illustration of their inadequacy is provided by the tragic case of a chemist at Dartmouth College, who was accidentally exposed to a small quantity of dimethylmercury and died ten months later despite intensive chelation therapy. The drugs currently used for mercury chelation therapy - dimercapto propanesulfonic acid, and dimercapto succinic acid - have their origins in antidotes for arsenic war agents such as Lewisite. While mercury is well known for its affinity for thiols, these viscinal dithiols are poorly suited as ligands for Hg due to their inability to coordinate the metal linearly. A knowledge of the chemical forms of mercury in tissues is an essential prerequisite for chelation therapy design, and we plan to use the information obtained from XAS, together with computational chemistry, to this end.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。汞化合物的高毒性是众所周知的，但是毒性的机制在很大程度上仍然是晦涩的。人类接触汞的暴露来自许多来源，包括掠食性海鱼和来自硫镁（乙酰硫硫代硫硫代硫此水杨酸酯）的疫苗，一种常见的杀菌剂和杀菌剂已与自闭症和阿斯伯格综合征有关。毒性作用的性质和发育至关重要地取决于汞的化学形式，但是对金属摄入后的化学命运知之甚少。造成这种情况的主要原因是缺乏对汞的原位探测。 X射线吸收光谱可以提供有关原位金属和金属素化学环境的信息。我们建议将Hg L边缘XAS应用于大鼠中汞的化学毒理学的理解，作为人类暴露的模型。这项工作的最终目标是为人类汞中毒有效的螯合治疗提供化学基础。当前的汞螯合药物不是很有效。达特茅斯学院（Dartmouth College）的一名化学家的悲惨案例为他们提供了惊人的例证，他意外暴露于少量二甲基汞，并在十个月后死亡，尽管进行了严格的螯合疗法。目前用于汞螯合疗法的药物 - Dimercapto丙二硫酸和Dimercapto琥珀酸 - 起源于砷战争剂（如Lewisite）的解毒剂。尽管汞以其对硫醇的亲和力而闻名，但由于无法线性地协调金属，因此这些粘性二硫醇作为HG的配体非常不适。对组织中汞的化学形式的了解是螯合治疗设计的重要先决条件，我们计划将从XAS获得的信息与计算化学一起获得。