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 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中出现。列出的机构是中心的机构，不一定是研究者的机构。汞化合物的高毒性是众所周知的，但其毒性机制在很大程度上仍不清楚。人类接触汞的来源有很多，包括掠食性海鱼和疫苗，其中硫柳汞（乙基汞硫代水杨酸盐）是一种常见的杀真菌剂和杀菌剂，与自闭症和阿斯伯格综合症有关。毒性作用的性质和发展很大程度上取决于汞的化学形态，但人们对金属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汞原位探针。 X射线吸收光谱可以提供有关金属和准金属原位化学环境的信息。我们建议应用 Hg L-edge XAS 来了解大鼠体内汞的化学毒理学，作为人类暴露的模型。这项工作的最终目标是为有效的螯合疗法治疗人类汞中毒提供化学基础。目前的汞螯合治疗药物不是很有效。达特茅斯学院的一名化学家的悲惨案例提供了其不足之处的一个引人注目的例证，他意外接触了少量二甲基汞，尽管进行了强化螯合治疗，但十个月后还是死亡。目前用于汞螯合疗法的药物——二巯基丙磺酸和二巯基琥珀酸——起源于砷战剂（例如路易氏剂）的解毒剂。虽然汞因其对硫醇的亲和力而闻名，但这些内二硫醇由于无法线性配位金属，因此不太适合作为汞的配体。了解组织中汞的化学形式是螯合疗法设计的重要先决条件，为此我们计划使用从 XAS 获得的信息以及计算化学。