Copper and Iron Transport Across the Placenta: Regulation and Interactions

Abstract

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.

Maternofetal and neonatal copper requirements revealed by enterocyte-specific deletion of the Menkes disease protein

“…7B; ϩCu). These observations reveal a necessary role for Atp7a for intestinal copper acquisition during late stage pregnancy when maternal copper transfer across the placenta peaks in mammals (20). Consistent with this role was the finding that fetuses harvested from pregnant Atp7a int/int females just prior to parturition (E19) contained less than 20% of the copper content of the same-aged fetuses derived from wild-type females (Fig.…”

“…Moreover, the finding that late-term fetuses from affected mothers were severely copper deficient, despite a normal size and morphology, provided further evidence that late gestational development rather than embryogenesis was sensitive to the loss of Atp7a in the maternal enterocyte. Since the most active transfer of copper across the placenta to the fetus occurs during the last trimester of pregnancy in mammals (20,21), these observations suggest that maternal expression of Atp7a in the enterocyte is necessary to meet this demand, a conclusion that was also supported by the finding that copper supplementation of Atp7a int/int fe- males at day E17 of pregnancy could prevent sudden perinatal death of the offspring.…”

ZRT/IRT-like Protein 14 (ZIP14) Promotes the Cellular Assimilation of Iron from Transferrin

“…Of particular interest is the placenta, which has been shown to express ZIP14 (17). Placental iron transport involves endocytosis of TF from the maternal circulation and dissociation of iron from TF prior to export into the fetal circulation (43). The transport of iron out of the endosome in syncytiotrophoblast cells of the placenta was thought to be mediated by DMT1 (44), until the generation of DMT1 knockout mice demonstrated that it was not required (6).…”

Iron Homeostasis in Mother and Child during Placental Malaria Infection

“…13 In addition, animal studies revealed that hepcidin and iron levels in the fetal liver may also regulate maternal-fetal iron transport. [14][15][16] We aimed to study maternal and fetal hepcidin and other iron parameters to improve our understanding of human placental iron transport. Therefore, we retrospectively assessed plasma concentrations of these indices in primigravidae, as a function of placental P. falciparum infection and maternal anemia, and in corresponding cord-blood samples.…”