Probing bioinorganic chemistry processes in the bloodstream

今天，人类活动向环境中排放的“有毒金属和类金属”(从现在起将缩写为“有毒金属”)的数量将与全球自然排放量相媲美或超过，而且预计还会增加。尽管过去已经采取了严格的措施，尽量减少人类接触有毒金属的机会，但土壤中仍有相当数量的有毒物质，因此继续进入食物链。因此，数以百万计的人--包括儿童--暴露在这些持久性污染物中，普通人群的血液浓度就证明了这一点。然而，对这些浓度的解释造成了一个重大问题，因为接触这些无机污染物与它们与特定人类疾病(如自闭症)的可能联系之间的功能性生化联系在很大程度上是未知的。在这种情况下，血流代表着一个关键的生物部位，在这里，毒理学上高度相关的基于生物无机化学的相互作用展开。虽然这些过程共同决定了靶器官(如肾脏)的损害，但人们对它们的了解还不够清楚。这种令人不快的情况必须归因于所涉及的有毒金属浓度较低，以及分析由红细胞和血浆组成的全血的普遍困难。我的研究计划将包括应用非常合适的先进研究工具来探索血液中与毒性相关的砷、镉、汞和/或铅物种的生物化学。由于将采用的分析方法允许直接分析生物体液(如血浆、红细胞胞浆)中的必需和有毒金属物种，拟议的方法注定将为后者的哺乳动物毒理学提供全新的见解。长期目标将集中在更好地了解血浆、红细胞胞浆、全血、靶器官和整个动物中持久性有毒金属的生物化学。特别是，我们将：a)探索有毒金属与血浆蛋白和血浆中人类血液代谢物的动态相互作用；b)确定红细胞胞浆中有毒金属的新靶蛋白；c)从结构上表征全血中形成的新型有毒金属代谢物；d)识别在血流中形成并转移到毒理靶器官的实际有毒金属物种或代谢物；e)观察有毒金属物种引起全动物(新西兰白兔)血浆金属蛋白质组的系统性扰动，该蛋白质是指含有铜、铁、锌、钴、锰和硒的所有结合蛋白。从这些研究中获得的新见解将有助于制定政策，更好地保护人类免受持久性有毒金属的长期暴露。

Human activities today emit quantities of 'toxic metals and metalloids' (this phrase will be shortened to 'toxic metals' from now on) into the environment that rival or exceed natural global emissions and they are projected to increase. Although stringent measures have been put into place in the past to minimize the exposure of human populations to toxic metals, considerable levels of these toxins persist in soils and thus continue to enter the food chain. Consequently, millions of people - including children - are exposed to these persistent pollutants as is evidenced by their blood concentrations in the general population. The interpretation of these concentrations, however, poses a major problem because the functional biochemical connections between the exposure to these inorganic pollutants and their possible link to specific human diseases (e.g. autism) are largely unknown. In this context, the bloodstream represents a critical biological site where toxicologically highly relevant bioinorganic chemistry-based interactions unfold. Although these processes collectively determine the damage of target organs (e.g. the kidneys), they are not well understood. This undesirable situation must be attributed to the low concentrations of the toxic metals involved and the general difficulty of analyzing whole blood, which is comprised of red blood cells and blood plasma. My research program will involve the application of highly appropriate advanced research tools to probe the biochemistry of toxicologically relevant arsenic, cadmium, mercury and/or lead species in the bloodstream. Since the analytical methodology that will be employed allows to directly analyze biological fluids (e.g. blood plasma, red blood cell cytosol) for essential and toxic metal species, the proposed approach is destined to provide fundamentally new insight into the mammalian toxicology of the latter. The long-term goals will focus on better understanding the biochemistry of persistent toxic metals in plasma, red blood cell cytosol, whole blood, target organs and whole animals. In particular, we will: a) probe dynamic interactions of toxic metals with plasma proteins and human blood metabolites in plasma b) identify novel target proteins of toxic metals in red blood cell cytosol c) structurally characterize novel toxic metal metabolites that are formed in whole blood d) identify the actual toxic metal species or metabolites that are formed in the bloodstream and translocated to toxicological target organs and e) observe toxic metal species-induced systemic perturbations of the plasma metalloproteome, defined as all proteins that contain bound copper, iron, zinc, cobalt, manganese and selenium, in whole animals (New Zealand white rabbits). The new insight that will be gained from these studies will contribute to develop policies that better protect humans from the chronic exposure to persistent toxic metals.