Placental Iron Uptake Research Articles

Effects of maternal iron status on placental and fetal iron homeostasis.

Iron deficiency is common worldwide and is associated with adverse pregnancy outcomes. The increasing prevalence of indiscriminate iron supplementation during pregnancy also raises concerns about the potential adverse effects of iron excess. We examined how maternal iron status affects the delivery of iron to the placenta and fetus. Using mouse models, we documented maternal homeostatic mechanisms that protect the placenta and fetus from maternal iron excess. We determined that under physiological conditions or in iron deficiency, fetal and placental hepcidin did not regulate fetal iron endowment. With maternal iron deficiency, critical transporters mediating placental iron uptake (transferrin receptor 1 [TFR1]) and export (ferroportin [FPN]) were strongly regulated. In mice, not only was TFR1 increased, but FPN was surprisingly decreased to preserve placental iron in the face of fetal iron deficiency. In human placentas from pregnancies with mild iron deficiency, TFR1 was increased, but there was no change in FPN. However, induction of more severe iron deficiency in human trophoblast in vitro resulted in the regulation of both TFR1 and FPN, similar to what was observed in the mouse model. This placental adaptation that prioritizes placental iron is mediated by iron regulatory protein 1 (IRP1) and is important for the maintenance of mitochondrial respiration, thus ultimately protecting the fetus from the potentially dire consequences of generalized placental dysfunction.

MRNA Levels of Placental Iron and Zinc Transporter Genes Are Upregulated in Gambian Women with Low Iron and Zinc Status

Background: The role of the placenta in regulating micronutrient transport in response to maternal status is poorly understood.Objective: We investigated the effect of prenatal nutritional supplementation on the regulation of placental iron and zinc transport.Methods: In a randomized trial in rural Gambia [ENID (Early Nutrition and Immune Development)], pregnant women were allocated to 1 of 4 nutritional intervention arms: 1) iron and folic acid (FeFol) tablets (FeFol group); 2) multiple micronutrient (MMN) tablets (MMN group); 3) protein energy (PE) as a lipid-based nutrient supplement (LNS; PE group); and 4) PE and MMN (PE+MMN group) as LNS. All arms included iron (60 mg/d) and folic acid (400 μg/d). The MMN and PE+MMN arms included 30 mg supplemental Zn/d. In a subgroup of ∼300 mother-infant pairs, we measured maternal iron status, mRNA levels of genes encoding for placental iron and zinc transport proteins, and cord blood iron levels.Results: Maternal plasma iron concentration in late pregnancy was 45% and 78% lower in the PE and PE+MMN groups compared to the FeFol and MMN groups, respectively (P < 0.001). The mRNA levels of the placental iron uptake protein transferrin receptor 1 were 30–49% higher in the PE and PE+MMN arms than in the FeFol arm (P < 0.031), and also higher in the PE+MMN arm (29%; P = 0.042) than in the MMN arm. Ferritin in infant cord blood was 18–22% lower in the LNS groups (P < 0.024). Zinc supplementation in the MMN arm was associated with higher maternal plasma zinc concentrations (10% increase; P < 0.001) than in other intervention arms. mRNA levels for intracellular zinc-uptake proteins, in this case zrt, irt-like protein (ZIP) 4 and ZIP8, were 96–205% lower in the PE+MMN arm than in the intervention arms without added zinc (P < 0.025). Furthermore, mRNA expression of ZIP1 was 85% lower in the PE+MMN group than in the PE group (P = 0.003).Conclusion: In conditions of low maternal iron and in the absence of supplemental zinc, the placenta upregulates the gene expression of iron and zinc uptake proteins, presumably in order to meet fetal demands in the face of low maternal supply. The ENID trial was registered at www.controlled-trials.com as ISRCTN49285450.

Deficiency of the placenta- and yolk sac-specific tristetraprolin family member ZFP36L3 identifies likely mRNA targets and an unexpected link to placental iron metabolism.

The ZFP36L3 protein is a rodent-specific, placenta- and yolk sac-specific member of the tristetraprolin (TTP) family of CCCH tandem zinc finger proteins. These proteins bind to AU-rich elements in target mRNAs, and promote their deadenylation and decay. We addressed the hypotheses that the absence of ZFP36L3 would result in the accumulation of target transcripts in placenta and/or yolk sac, and that some of these would be important for female reproductive physiology and overall fecundity. Mice deficient in ZFP36L3 exhibited decreased neonatal survival rates, but no apparent morphological changes in the placenta or surviving offspring. We found Zfp36l3 to be paternally imprinted, with profound parent-of-origin effects on gene expression. The protein was highly expressed in the syncytiotrophoblast cells of the labyrinth layer of the placenta, and the epithelial cells of the yolk sac. RNA-Seq of placental mRNA from Zfp36l3 knockout (KO) mice revealed many significantly upregulated transcripts, whereas there were few changes in KO yolk sacs. Many of the upregulated placental transcripts exhibited decreased decay rates in differentiated trophoblast stem cells derived from KO blastocysts. Several dozen transcripts were deemed high probability targets of ZFP36L3; these include proteins known to be involved in trophoblast and placenta physiology. Type 1 transferrin receptor mRNA was unexpectedly decreased in KO placentas, despite an increase in its stability in KO stem cells. This receptor is crucial for placental iron uptake, and its decrease was accompanied by decreased iron stores in the KO fetus, suggesting that this intrauterine deficiency might have deleterious consequences in later life.

Iron transport across cell membranes: molecular understanding of duodenal and placental iron uptake.

Iron is an essential element playing a vital role in many cellular processes. This requirement is complicated by the fact that environmental iron is invariably present as insoluble Fe(3+) leading to poor bioavailability and toxicity, since even low concentrations of iron catalyse the production of damaging reactive oxygen species. As a result organisms have evolved efficient uptake and transport systems to extract iron from their environment as well as ferritins that store iron in a non-toxic form. In higher organisms, the first membrane barrier encountered is the apical surface of the duodenal enterocyte, a specialized absorptive cell of the intestinal epithelium that undertakes vectorial transport of iron. Iron is initially solubilized by reduction and Fe(2+) is transported across the cell membrane by a carrier-mediated transport process. This is followed by intracellular transfer of iron to the basolateral enterocyte membrane with subsequent transfer and release of iron to transferrin in the portal blood. A second site of iron transport is at the placento-fetal barrier where similar principles operate. In this review we describe recently identified transmembrane transporters and associated accessory proteins responsible for iron transport at these two sites.

Iron transport across cell membranes: molecular understanding of duodenal and placental iron uptake

Iron is an essential element playing a vital role in many cellular processes. This requirement is complicated by the fact that environmental iron is invariably present as insoluble Fe 3+ leading to poor bioavailability and toxicity, since even low concentrations of iron catalyse the production of damaging reactive oxygen species. As a result organisms have evolved efficient uptake and transport systems to extract iron from their environment as well as ferritins that store iron in a non-toxic form. In higher organisms, the first membrane barrier encountered is the apical surface of the duodenal enterocyte, a specialized absorptive cell of the intestinal epithelium that undertakes vectorial transport of iron. Iron is initially solubilized by reduction and Fe 2+ is transported across the cell membrane by a carrier-mediated transport process. This is followed by intracellular transfer of iron to the basolateral enterocyte membrane with subsequent transfer and release of iron to transferrin in the portal blood. A second site of iron transport is at the placento–fetal barrier where similar principles operate. In this review we describe recently identified transmembrane transporters and associated accessory proteins responsible for iron transport at these two sites.

Regulation of transferrin receptor expression in term human cytotrophoblasts

Placental transferrin receptors (TfR's) located at the apical side of syncytiotrophoblast, mediate placental iron uptake. Changes in TfR density on the maternal-fetal exchange area will immediately affect placental iron uptake. Therefore, this could be a major determinant in the regulation of maternal-fetal iron transport. We have studied mechanisms that might influence TfR expression in cultured human term cytotrophoblasts. These cells are notproliferative in vitro. In many proliferating cell types growth factors, like insulin, cause a redistribution of TfR's from cytosolic pools to the cell surface. Our experiments show that addition of insulin to, or withdrawal of serum from the culture medium does not lead to a change in cell surface TfR levels in term cytotrophoblasts, thus suggesting that the redistribution effect in linked to the mitogenic role of growth factors. Addition of extra iron to the culture medium leads to down-regulation of trophoblast TfR levels. This suggests that Iron-Responsive-Elements, operative in many cell types except in macrophages are involved in the regulation of placental iron uptake. Thus, transplacental iron transport can be protected against iron overload and iron deficiency.

Transferrin receptor expression and the regulation of placental iron uptake

Placental transferrin receptors, located at the apical side of syncytiotrophoblast, mediate placental iron uptake. Regulation of transferrin receptors on the fetal-maternal exchange area could be a major determinant in the regulation of trans-placental iron transport. Transferrin receptor expression in cultured human term cytotrophoblasts is on a much lower level than in choriocarcinoma cells, with a higher proportion of receptors located on the cell surface. Differentiation of cells, either due to longer culture periods or to 8-bromo-cAMP treatment does not lead to an increase of transferrin receptor expression. In vitro, the level of expression is largely regulated by the cellular density in the culture dishes. Low cellular occupancy of the dish leads to a high level of transferrin receptors. Treatment with iron-sources results in a down regulation of transferrin receptors. Thus, though the level of transferrin receptors in cultured normal trophoblast is at a constant level, unaffected by differentiation, high levels of maternal transferrin-iron availability can lead to a decrease in placental iron uptake. This feed-back mechanism makes placental iron uptake independent of maternal iron stores.

Regulatory signals in placental iron uptake

Regulatory signals in placental iron uptake

Review article: Regulatory aspects of placental iron transfer — A comparative study

Abstract Receptor-mediated endocytosis is generally assumed to be the process by which the haemochrial placenta takes up iron from transferrin. The involvement of an additional non-endocytic process cannot, however, be excluded. It appears from a study of iron transport mechanisms and of the maturation of the transfer process that placental ferritin is involved in the transfer of iron from mother to fetus. The metabolic relationship between the ferritin pool and the placental transfer pool remains to be elucidated. There is no evidence for short-term regulation of placental transfer capacity in response to changes in the maternal iron supply or to changes in the trophoblastic iron content. This cannot yet be said of fetal feedback control of placental iron uptake because the experiments performed so far do not permit conclusions on this point. The capacity for iron uptake and transfer seems to increase in accordance with the ontogenetically determined placental growth pattern. This does not exclude long-range adaptive modifications of the transfer capacity in response to early maternal or fetal disturbances. The results obtained from studying placental maturation suggest that a possible long-term regulatory interaction between growing placenta and fetus may occur. Clinical evidence so far is inconclusive. The relatively moderate reductions in the fetal iron stores which are generally associated with severe iron-deficient pregnancies might be seen as an argument in favour of long-term placental control. The marked impact of pregnancy on maternal iron metabolism in rodents, as compared to other mammals, is possibly met by means of direct placental control of mucosal iron uptake. In primates, mucosal iron uptake during pregnancy seems to be governed by factors related to systemic iron deficiency only.

Role of the Placenta in Intestinal Absorption of Iron in Pregnant Rats

Intestinal uptake (U) and transport (T) of a 40-mug dose of 59Fe from an isolated duodenal loop has been shown to increase from day 15 of pregnancy until term in the rat. U, 60.4 +/- 4.3%, and T, 44.0 +/- 4.6%, were significantly (P less than 0.01) higher than control values, which were 31.6 +/- 3.6% and 18.9 +/- 1.8%, respectively, and resembled those in nonpregnant iron-deficient rats. Eighteen hours before the increase in absorption there was a rapid fall in the t1/2 of 59Fe in maternal serum to 37.2 +/- 3.4 min (control, 72.1 +/- 2.4 min). Hysterectomy at day 20 to 21 of pregnancy resulted in a rise in t1/2 59Fe within 5 hr to 58.0 +/- 4.7%, followed by a fall in U and T to a degree comparable to that in rats studied 18 hr postpartum. Fetectomy had no significant effect on U, 63.8 +/- 2.7%, T, 34.7 +/- 3.4%, or t1/2 59Fe, 27.8 +/- 2.5 min, when compared with corresponding values in day 20 to 21 pregnant rats. The results indicate the importance of placental iron uptake in the control of iron absorption during the 3rd week of pregnancy.

Studies on the regulation of granulopoiesis. II. Relationship to other differentiation pathways.

Summary. The distribution of 59Fe in maternal, placental and foetal tissues of the rat was determined at intervals of 8, 12, 15, 17, 19, 20 and 21 days of gestation. Large amounts of 59Fe are transferred from maternal plasma to the foetuses in late gestation when foetal development is proceeding at a rapid rate. The deposition of 59Fe in the developing foetus appears governed by erythropoiesis; liver and carcass are the principal sites. 59Fe is rapidly transported across the placenta; there is no indication of a large iron pool within it. Both the allantoic and yolk sac placentae contribute significantly to placental iron uptake during the period of maximum iron transfer. Very little iron is deposited in the uterus during gestation; hence secretions from uterine glands entering the yolk sac cavity are a minor source of foetal iron. There is diminished uptake of 59Fe by the maternal liver and spleen during the period of rapid iron accumulation by the foetuses.

Maternofoetal iron transfer in the rat.

Summary. The distribution of 59Fe in maternal, placental and foetal tissues of the rat was determined at intervals of 8, 12, 15, 17, 19, 20 and 21 days of gestation. Large amounts of 59Fe are transferred from maternal plasma to the foetuses in late gestation when foetal development is proceeding at a rapid rate. The deposition of 59Fe in the developing foetus appears governed by erythropoiesis; liver and carcass are the principal sites. 59Fe is rapidly transported across the placenta; there is no indication of a large iron pool within it. Both the allantoic and yolk sac placentae contribute significantly to placental iron uptake during the period of maximum iron transfer. Very little iron is deposited in the uterus during gestation; hence secretions from uterine glands entering the yolk sac cavity are a minor source of foetal iron. There is diminished uptake of 59Fe by the maternal liver and spleen during the period of rapid iron accumulation by the foetuses.

Regulating factors in the transfer of iron across the rat placenta.

The effect of maternal blood loss on the iron uptake of the foetectomized placenta has been studied. Normal pregnant rats were used as controls. It is suggested that the rate of maternal blood flow and plasma iron concentration primarily controls placental iron uptake independent of the presence of a foetus. Starch gel electrophoresis and fluorescent antibody techniques have been employed to investigate foetal rat synthesis of transferrin. The onset of synthesis at the commencement of the last third of gestation is probably important in creating a viable system for foetal plasma iron turnover which, under the control of the foetal erythroid marrow, is responsible for the high rate of iron transfer from the placenta to the foetus.