Probing the biochemistry of toxic metals in the bloodstream

人类活动，如化石燃料消耗和采矿活动排放的有毒金属数量与全球自然排放量相当或超过，预计它们将增加（例如，煤炭消费量将在未来25年内增加五分之一）。这将与进入人体血液的无机污染物的增加有关。尽管进行了大量的研究，但就我们对血液中有毒金属的生物化学的理解而言，存在相当大的知识差距。然而，迫切需要更好地了解这些过程，以确定可能将人类（包括儿童）接触有毒金属与疾病联系起来的生化机制，并制定从体内排出有毒金属的战略。然而，对血液中发生的生化事件的可视化提出了一个主要问题。盖勒博士的研究小组开发了一种方法，可以分析血浆中含有结合金属（如铁、铜或锌）的蛋白质，因此被称为血浆金属蛋白。由于这种方法可以同时检测到添加到血浆中的任何有毒金属，我们可以从根本上对有毒金属可能对必需金属代谢产生不利影响的生化过程有新的认识。此外，它还允许研究药物（所谓的螯合剂）的作用，这些药物可以给中毒的人服用，以增加体内有毒金属的动员。该方法将系统地应用于在金属蛋白水平上探测血浆中有毒金属的影响以及研究螯合剂的效果。新的含金属代谢物将使用先进的光谱技术进行结构表征（加拿大光源，萨斯卡通）。该方法有望为环境中丰富的有毒金属和类金属化合物的毒理学提供令人兴奋的新见解，并且是开发针对人类金属/类金属慢性毒性的补救措施的先决条件。因此，拟议的研究代表了在21世纪促进人类健康的一项倡议。

Human activities, such as fossil fuel consumption and mining activities emit quantities of toxic metals that rival or exceed natural global emissions and they are projected to increase (e.g. coal consumption will increase by 1/5th over the next 25 years). This will be associated with an increased influx of inorganic pollutants into the human bloodstream. Despite much research, there exist considerable knowledge gaps with regard to our understanding of the biochemistry of toxic metals in the bloodstream. A better understanding of these processes, however, is urgently needed to establish the biochemical mechanisms which may link the exposure of humans - including children - to toxic metals with diseases and to develop strategies to efflux toxic metals from the body. The visualization of biochemical events that occur in the bloodstream, however, poses a major problem. Dr. Gailer's group has developed a methodology which allows to analyze blood plasma for proteins which contain a bound metal (e.g. iron, copper or zinc) and are therefore referred to as plasma metalloproteins. Since this methodology can simultaneously detect any toxic metals that are added to plasma, we can gain fundamentally new insight into biochemical processes by which toxic metals may adversely effect the metabolism of essential metals. In addition, it allows to study the effect of drugs (so-called chelating agents) which can be administered to intoxicated humans to increase the mobilization of a toxic metal from the body. The developed methodology will be systematically applied to probe the effect of toxic metals in plasma at the metalloprotein level and to study the efficacy of chelating agents. Novel metal-containing metabolites will be structurally characterized using an advanced spectroscopic technique (Canadian Light Source, Saskatoon). This approach is expected to provide exciting new insights into the toxicology of environmentally abundant toxic metals and metalloid compounds and is the prerequisite for the development of remedies against the chronic toxicity of metal/metalloids in humans. The proposed research thus represents an initiative to advance human health in the 21st century.