Probing bioinorganic chemistry processes in the bloodstream

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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.