Placental transferrin receptor in diabetic pregnancies with increased fetal iron demand

Abstract

Augmented fetal hemoglobin synthesis during diabetic pregnancy increases fetal iron demand. To study the effect of increased fetal iron demand on placental transferrin receptor (TR), we utilized a monoclonal antibody to localize placental TR immunoreactivity and 125I-labeled transferrin to study TR binding characteristics in 10 placentas from poorly controlled diabetic mothers with increased fetal iron demand and 10 placentas from nondiabetic mothers. The infants born to the diabetics had higher cord serum C-peptide, erythropoietin, and hemoglobin concentrations, indicating fetal hyperinsulinemia and hypoxia, with augmented erythropoiesis and iron demand. TR immunoreactivity was localized to the syncytiotrophoblast in both groups, was greater in the diabetic group, and was inversely correlated with fetal storage iron (r = -0.75; P < 0.001). Scatchard analysis of 125I transferrin binding data confirmed greater receptor number (Bmax 17.9 +/- 2.2 vs. 12.6 +/- 1.3 pM/mg protein, P = 0.05), but reduced binding affinity [dissociation constant (Kd) 7.6 +/- 0.9 vs. 5.4 +/- 0.4 nM/l, P = 0.03] in the diabetic group. The TR staining intensity, Bmax, and Kd were each correlated with cord C-peptide, suggesting either a primary or secondary role for fetal hyperinsulinemia in TR expression. This study provides in vivo evidence that fetal factors, such as iron demand or hyperinsulinemia, influence regulation of placental TR in humans. The increase in placental syncytiotrophoblastic TR expression associated with reduced cord serum ferritin concentration suggests that the fetus utilizes both increased placental iron transport and mobilization of fetal iron stores to support augmented fetal erythropoiesis.

Effects of chronic hypoxia in vivo on the expression of human placental glucose transporters

“…In this report, EPO-R, a recognized marker of hypoxia, increased in the high altitude syncytial membranes, as predicted from cellular studies. However, both nutrient transporters (TfR and GLUT1), in contrast to what is observed in vitro [7,9,10,12] showed decreased protein expression. The reduction in basal membrane GLUT1 is especially noteworthy, as the basal membrane is the rate-limiting step in transplacental glucose transfer [18].…”

“…The increase in EPO-R in response to chronic hypoxia suggests this protein could be a useful marker of placental hypoxia in studies of pregnancy complications. In contrast, the nutrient transporters, TfR and GLUT1, are decreased in the MVM and BM, respectively, despite the fact that they are increased by hypoxia in vitro [7,9,10,12]. The results support that reduction in fetal growth at high altitude is not necessarily a direct effect of reduced PO 2 (e.g.…”

“…In view of the lack of appropriate markers for placental hypoxia, we sought also to identify discrete markers of hypoxia that could be used, regardless of altitude, to determine whether the placenta had been subjected to long-term, chronic hypoxia. Two markers, the erythropoietin receptor (EPO-R) and the transferrin receptor (TfR) were chosen for investigation because previous studies in placenta or trophoblast [9,10] as well as other cell [11][12][13], and tissue [14] models show that they are upregulated by hypoxia.…”

Elevated zinc protoporphyrin/heme ratios in umbilical cord blood after diabetic pregnancy

“…11,12,25 In diabetes, specific defects in placental function are unable to compensate for increased iron needs accompanying fetal overgrowth and increased erythrocyte mass. 26 Although we found no relationship between cord ZnPP/H and hemoglobin concentration, postnatal polycythemia is influenced by mode of delivery, delay in cord clamping and postnatal fluid shifts, 27,28 such that hemoglobin from cord blood may not adequately estimate red cell mass or polycythemia. Another possibility is that hemoglobin concentration does not measure total hemoglobin produced.…”

Novel Red Cell Indices Indicating Reduced Availability of Iron are Associated With High Erythropoietin Concentration and Low pH Level in the Venous Cord Blood of Newborns

“…Furthermore, low ferritin levels have been shown to be present in newborns whose mothers have diabetes mellitus or GDM (33,(37)(38)(39), and this has been found to be related to chronic intrauterine hypoxia (40). Even though we did not have pregnant women with DM in our study, we did have a few women with GDM.…”