Fetal Growth Restriction (FGR) effects approximately 10% of pregnancies globally and is frequently attributed to placental insufficiency, compromising fetal growth. Iron plays diverse roles during gestation. Maternally, iron facilitates erythrocyte and plasma expansion, while in the placenta, iron is crucial for erythropoiesis, promoting mitochondrial heme synthesis and globin production, thus ensuring optimal fetal oxygenation. This study examines the role of placental iron transporters, mitochondrial heme synthesis pathways, globin chains, and proteins associated with erythropoiesis in FGR.
Placental tissue from healthy (n=19) and FGR (n=18) pregnancies, delivered between 37-40 weeks gestation was analysed. Placental gene and protein levels of iron transporters, mitochondrial heme synthesis enzymes and erythrocyte-associated proteins were investigated by RT-qPCR and liquid chromatography-mass spectrometry.
FGR placentae, had significantly higher mRNA expression of the iron transporter, TFRC (p=0.006) compared with controls. Conversely, placental levels of the iron exporter protein ferroportin were 1.56-fold lower in FGR placentae compared with controls, suggesting increased iron demands in FGR placentae. Mitochondrial heme synthesis enzymes, HMBS (1.15- fold), UROD (1.13-fold), CPOX (1.12-fold) and FECH (1.28-fold) were higher in FGR placentae. Globin chain levels were significantly lower in FGR placentae compared to controls, with lower HBA1 (1.15-fold), HBG1 (1.25-fold), HBG2 (1.07-fold), and HBB (1.5-fold). Furthermore, erythrocyte membrane proteins EPB41 (1.19-fold), EPB42 (1.48-fold), and SLC4A1 (1.41-fold) were lower in FGR placentae relative to controls. These decreases in globin chain and erythrocyte membrane proteins may impair fetal oxygen delivery, potentially contributing to hypoxia in FGR fetuses.
This study demonstrated that placentae from FGR pregnancies have dysregulated iron transport pathways. FGR placentae exhibited elevated levels of mitochondrial heme synthesis enzymes and compromised expression of globin chains and structural proteins crucial for erythrocyte membrane integrity, potentially exacerbating fetal hypoxia. This study stresses significant placental adaptations in associated iron pathways in FGR, offering novel insights into the molecular mechanisms underlying FGR.