801840.fig.002
Figure 2: Conceptual depiction of the reductionist causal chain to construct an organism (black arrows) as well as the systems biology view of downward causation (blue arrows) adapted from [69]. There are two principle ways by which a toxic metal species that has entered the bloodstream may exert adverse health effects. Red arrows: a metal species interacts with an endogenous target ligand in the bloodstream (e.g., formation of compounds with As-Se and Hg-Se bonds [32, 82]; binding of cis-platin derived hydrolysis products with HSA block the Zn2+ binding site [83] or the displacement of Zn from the extracellular glycoprotein Cu, Zn superoxide dismutase [26]) which may affect cell signalling, gene expression, and/or the distribution of an essential ultratrace element to organs and therefore affect the whole organism [84]. Dashed red arrows: a metal species enters a specific cell type where it interacts with intracellular target ligands (e.g., binding of cis-platin derived hydrolysis products to DNA [55]) to induce apoptosis. Note that the red arrows pertain to all organs within an organism (systemic toxicity), whereas the dashed red arrows correspond to the target organ only (selective toxicity). In the context of developing more targeted metal-based anticancer drugs, it is therefore critical not only to increase their selective toxicity (i.e., their preferential delivery toward cancer cells), but also to minimize/avoid systemic toxicity caused by unintended interactions with endogenous ligands in the bloodstream [83].