Effects of maternal iron status on placental and fetal iron homeostasis
Veena Sangkhae, … , Tomas Ganz, Elizabeta Nemeth
Veena Sangkhae, … , Tomas Ganz, Elizabeta Nemeth
Published October 29, 2019
Citation Information: J Clin Invest. 2020;130(2):625-640. https://doi.org/10.1172/JCI127341.
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Research Article Hematology Reproductive biology

Effects of maternal iron status on placental and fetal iron homeostasis

Abstract

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.

Authors

Veena Sangkhae, Allison L. Fisher, Shirley Wong, Mary Dawn Koenig, Lisa Tussing-Humphreys, Alison Chu, Melisa Lelić, Tomas Ganz, Elizabeta Nemeth

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Figure 3

58Fe transport across the placenta.

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58Fe transport across the placenta. (A) WT C57BL/6 female mice were mai...
(A) WT C57BL/6 female mice were maintained on a standard chow diet or placed on an iron-deficient diet 2 weeks prior to mating and were maintained on an iron-deficient diet throughout gestation. At E17.5, the dams received a single i.v. injection of 58Fe-Tf. The dams were sacrificed 6 hours post injection (p.i.), and placental and embryonic tissues were collected and analyzed using ICP-MS. (B) Placental TFR1 and FPN protein expression was assessed by Western blotting, and quantitation of protein expression relative to β-actin was performed. Total 58Fe content in (C) placentas and (D) fetal livers. Total 56Fe content in (E) placentas and (F) fetal livers. (B–F) Statistical analysis was performed by 2-tailed Student’s t test for normally distributed values and otherwise by Mann-Whitney U rank-sum test (denoted by an asterisk after the P value). The numbers of animals are indicated in the x axes of the box and whisker plots.