THE MOLECULAR BASIS FOR MERCURY TOXICITY

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。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。汞化合物的高毒性是众所周知的，但毒性机制在很大程度上仍然不清楚。人类接触汞的来源有很多，包括食肉海洋鱼类和疫苗，其中噻汞（硫代水杨酸乙汞）是一种常见的杀菌剂和杀虫剂，与自闭症和自闭症综合征有关。毒性作用的性质和发展严重依赖于汞的化学形式，但人们对摄入后金属的化学命运知之甚少。其中一个主要原因是缺乏良好的汞原位探测器。X射线吸收光谱可以提供金属和准金属原位化学环境的信息。我们建议应用汞的L-边缘XAS开发的化学毒理学的汞在大鼠中的理解，作为一个模型，为人类暴露。这项工作的最终目标是提供有效的螯合疗法治疗汞中毒的人类的化学基础。目前的汞螯合治疗药物不是很有效。达特茅斯学院的一位化学家意外接触到少量的二甲基汞，尽管进行了密集的螯合治疗，但他在10个月后死亡，这一悲惨的案例生动地说明了他们的不足。目前用于汞螯合治疗的药物-二巯基丙磺酸和二巯基琥珀酸-起源于砷战剂的解毒剂，如路易氏剂。虽然汞对硫醇的亲和力是众所周知的，但这些粘性二硫醇由于不能线性配位金属而不适合作为汞的配体。汞在组织中的化学形式的知识是螯合疗法设计的一个必要前提，我们计划使用从XAS获得的信息，与计算化学，为此。

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.