Probing bioinorganic chemistry processes in the bloodstream

今天，人类活动向环境排放了大量的“有毒金属和类金属”（从现在起，这个短语将被缩短为“有毒金属”），与全球自然排放量相当或超过，而且预计还会增加。尽管过去已经采取了严格的措施来尽量减少人类接触有毒金属，但这些毒素仍大量存在于土壤中，从而继续进入食物链。因此，包括儿童在内的数百万人都暴露在这些持久性污染物中，这一点可以从一般人群的血液浓度中得到证明。然而，对这些浓度的解释提出了一个重大问题，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生化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学位点，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得以展开。虽然这些过程共同决定了目标器官（如肾脏）的损害，但它们并没有得到很好的理解。这种不受欢迎的情况必须归因于所涉及的有毒金属浓度低，以及分析全血（由红细胞和血浆组成）的普遍困难。******我的研究计划将涉及应用高度适当的先进研究工具来探测血液中与毒理学相关的砷、镉、汞和/或铅的生物化学。由于将采用的分析方法允许直接分析生物液体（例如血浆、红细胞细胞质）中必需和有毒金属物种，因此拟议的方法注定要为后者的哺乳动物毒理学提供根本的新见解。长期目标将集中在更好地了解血浆、红细胞细胞质、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)探测血浆中有毒金属与血浆蛋白和人体血液代谢物的动态相互作用***b)鉴定红细胞胞浆中有毒金属的新型靶蛋白***c)结构表征全血中形成的新型有毒金属代谢物***d)鉴定在血液中形成并转运到毒理学目标器官的实际有毒金属物种或代谢物***e)观察有毒金属物种诱导的全身血浆金属蛋白组的扰动*，定义为所有含有结合铜、铁、锌、钴、锰和硒的蛋白质，在整个动物（新西兰白兔）中。******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长期接触持久性有毒金属的政策。

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.