Hanif, R.; (2012) Molecular mechanism of regulation of iron transport across placenta. Doctoral thesis , UCL (University College London).

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Abstract

During the third trimester of pregnancy, iron transport from mother to the foetus against a concentration gradient determines the iron endowment in foetal and neonatal life. Hfe functions as an upstream regulator of liver hepcidin which has been demonstrated to be a negative regulator of intestinal absorption of dietary iron and macrophage efflux of recycled iron. Hepcidin has also been proposed to be a negative regulator of iron efflux from the placenta, however it is not known if hepcidin is of maternal or foetal origin during pregnancy. The exact mechanism and molecules involved in the regulation of iron transport across the placenta are not well understood. In this study the effects of Hfe and dietary iron levels on transfer of iron from mother to foetus was investigated in order to determine the importance of maternal and foetal Hfe status on iron transport. The effect of maternal hepcidin on placental iron transport in WT and Hfe KO dams was also studied. The molecular mechanism of iron transport across placenta was elucidated by using BeWo cells as a model for iron uptake, transport and efflux. This study has shown that the mechanism regulating iron metabolism during pregnancy is dependent on the iron status of the mother and its genotype. A clear link could be seen between the maternal iron status and foetal body iron stores. The lack of Hfe in both dams and pups increased iron absorption in the body and raised serum iron levels but the effect of Hfe was diet dependent. However, foetal genotype seems to affect liver iron accumulation and certain iron transporter gene expression only with low and normal iron diets. In this study BeWo cells were utilised to model the placental syncytiotrophoblasts. The insensitivity of iron transporter proteins in BeWo cells to hepcidin treatment might be due to the cell-specific response of hepcidin. TfR1, DMT1 and FPN1 were localised in these cells to understand the molecular mechanism of iron transport across placenta. Finally, the presence of ZIP14 and its response to hepcidin treatment in mice may indicate the presence of an alternative pathway of iron transport across placenta.

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