THE MOLECULAR BASIS FOR MERCURY TOXICITY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 汞化合物的高毒性是众所周知的，但其毒性机制仍很不清楚。人类接触汞的来源很多，包括捕食性海鱼和疫苗，在疫苗中，一种常见的杀菌剂和杀菌剂硫柳汞(乙基汞)与自闭症和阿斯伯格综合症有关。毒性效应的性质和发展严重依赖于汞的化学形态，但人们对汞被摄入后的化学命运知之甚少。造成这种情况的一个主要原因是缺乏良好的原位汞探头。X射线吸收光谱可以提供有关金属和类金属的原位化学环境的信息。我们建议应用汞L EDGE XAS来发展对汞在大鼠体内的化学毒理学的理解，作为人类暴露的模型。这项工作的最终目的是为有效的螯合疗法治疗人体汞中毒提供化学基础。目前的汞螯合治疗药物效果不是很好。达特茅斯学院的一名化学家的悲剧证明了他们的不足，他意外地接触了少量的二甲基汞，尽管进行了密集的螯合治疗，但他在10个月后死亡。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-起源于路易斯特等砷战剂的解毒剂。虽然汞对硫醇的亲和力是众所周知的，但这些粘性二硫醇不太适合作为汞的配体，因为它们不能线性配位金属。对组织中汞的化学形态的了解是螯合治疗设计的基本前提，我们计划将从XAS获得的信息与计算化学一起用于这一目的。

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.