Effect of Monoferric Transferrins on Fetal Iron Homeostasis and Erythropoiesis

Introduction: Marked changes in maternal iron metabolism and erythropoietic activity are required to meet fetal iron needs in pregnancy. Maternal iron deficiency, with or without anemia, is common despite prescribed iron supplementation. Dysregulated fetal iron accrual occurs in multiple conditions despite adequate maternal iron status and absence of anemia. These include maternal diabetes, placental insufficiency and fetal liver disease. Abnormal fetal iron status is associated with negative fetal outcomes. The processes regulating fetal/maternal iron transfer are incompletely understood. We hypothesize that signaling properties of transferrin regulate fetal-maternal iron homeostasis and fetal erythropoiesis.

Methods: We investigated the effect of lobe specificity of iron binding to the transferrin (Tf) N or C lobe on fetal iron homeostasis. We utilized female mice homozygous for either the wild-type TF allele, N-blocked TF allele (permitting iron binding only to the TF C-lobe), or C-blocked TF allele (permitting iron binding to only the TF N lobe). These were mated to mice which were either wild-type or heterozygous for the TF N-blocked or the C-blocked TF allele. At E17.5 pregnant dams were sacrificed. Placenta and fetuses were genotyped and analyzed for tissue iron concentration, expression of selected genes participating in iron homeostasis, and hematologic parameters.

Results: Litter sizes, distribution of genotypes, fetal weights and placental weights were similar in pregnancies of wild-type, N-blocked and C-blocked mice. Homozygous N-blocked fetuses (N/N) had lower hematocrits (27.5% +/-6.3) compared with homozygous C-blocked (C/C) fetuses (33.7+/-5.8%; p<0.05) and wild type (WT) fetuses (42.0% +/- 3.7, p<0.001). N/N fetuses had significantly higher liver iron concentrations (484.9+/-24.4 µg Fe/g dry wt) compared with C/C (322.1+/-40.1) and WT (345+/-41.0), p<0.002. N/N fetuses had significantly higher hepatic Bmp6 and Hamp1 mRNA expression compared with C/C and WT fetuses. Although no significant differences were detected in placental ferroportin protein across strains, N/N fetuses had higher placental ferroportin mRNA expression compared to C/C.

Conclusions: Whereas placental iron concentration is unaffected, iron distribution across fetal hepatic and erythroid compartments is strongly influenced by the transferrin lobe occupied by iron. Despite blunted iron utilization for hemoglobin production, N/N mice accrue iron--leading to fetal hepatic iron loading, and consequently increased liver Bmp6 and Hamp1 expression. Despite the higher liver Hamp1 expression in N/N fetuses, placental ferroportin protein is similar to that observed in placentas from C/C fetuses. We speculate that any inhibitory effect of hepcidin on ferroportin protein might be offset by a hypoxia mediated upregulation of ferroportin gene expression in the setting of fetal anemia.