Copper and iron transport across the placenta: Regulation and interactions

Iron and copper are both essential micronutrients and are required for a wide variety of enzymatic and other processes within the developing foetus. Transfer of both nutrients across the placenta is tightly regulated. In this review, we consider their mechanisms of transport, how the transfer is modulated in response to nutritional requirements and how the two metals interact. Iron uptake is via the transferrin receptor, followed by endocytosis, acidification of the vesicle, and release of the iron into the cytosol, and transfer across the basolateral membrane. Many of the genes involved have been identified, and, to varying extents, their mechanisms of regulation clarified, but there are still unanswered questions and conundrums. For example, although the ion channel DMT1 (now formally known as slc11a2) is essential for iron uptake in the gut, knockout mice, which have no slc11a2 protein, have apparently normal transfer across the placenta. There must, therefore, be an alternative mechanism, which remains unclear, although nonspecific calcium channels have been proposed as one possibility. For copper, uptake is a carrier-mediated process, and intracellular transfer is mediated by proteins known as chaperones. Efflux is through ATPases, but their localisation and how they are regulated is only now being elucidated. Regulation of copper proteins appears to be different from that of iron, with localisation of the protein, rather than changing levels, being responsible for altering rates of transfer. This may not be true for all the proteins and genes involved in the delivery of copper, and, again, there is much that remains to be clarified. Finally, we consider the interactions that occur between the two metals, reviewing the data that show how alterations in levels of one of the nutrients changes that of the other, and we examine the hypotheses explaining the interactions.