Probing bioinorganic chemistry processes in the bloodstream

当今的人类活动向环境排放大量“有毒金属和类金属”（从现在起，这个短语将简称为“有毒金属”），其排放量相当于或超过全球自然排放量，并且预计还会增加。虽然过去已采取严格措施，尽量减少人类接触有毒金属，但土壤中仍有大量的有毒物质，因此继续进入食物链。因此，数百万人-包括儿童-接触这些持久性污染物，其在一般人群中的血液浓度就是证明。然而，对这些浓度的解释提出了一个主要问题，因为暴露于这些无机污染物之间的功能性生物化学联系及其与特定人类疾病（如自闭症）的可能联系在很大程度上是未知的。在这种情况下，血流代表了一个关键的生物位点，在那里，毒理学上高度相关的生物无机化学相互作用展开。尽管这些过程共同决定了靶器官（例如肾脏）的损伤，但它们并不被很好地理解。这种不希望的情况必须归因于所涉及的有毒金属的低浓度和分析由红细胞和血浆组成的全血的一般困难。我的研究计划将涉及高度适当的先进研究工具的应用，以探测血液中毒理学相关的砷，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流体（例如血浆，红细胞胞质）的基本和有毒金属物种，所提出的方法注定要提供从根本上新的见解，后者的哺乳动物毒理学。长期目标将侧重于更好地了解血浆、红细胞胞浆、全血、目标器官和整个动物体内持久性有毒金属的生物化学。我们尤其会：a）探测血浆中有毒金属与血浆蛋白和人血液代谢物的动态相互作用，B）鉴定红细胞胞质溶胶中有毒金属的新靶蛋白，c）从结构上表征在全血中形成的新有毒金属代谢物，d）鉴定在血流中形成并易位至毒理学靶器官的实际有毒金属物质或代谢物，以及e）在整个动物（新西兰白色兔）中观察有毒金属物质诱导的血浆金属蛋白质组的全身性扰动，金属蛋白质组定义为含有结合铜、铁、锌、钴、锰和硒的所有蛋白质。 从这些研究中获得的新见解将有助于制定更好地保护人类免受持久性有毒金属长期暴露的政策。

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.