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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):e127341. https://doi.org/10.1172/JCI127341.
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Research Article Hematology Reproductive biology Article has an altmetric score of 6

Effects of maternal iron status on placental and fetal iron homeostasis

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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 1

Maternal hepcidin and serum iron levels determine embryo and placental iron status.

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Maternal hepcidin and serum iron levels determine embryo and placental i...
The iron status of WT C57BL/6 female mice was altered using diet or iron dextran injections. (A) Adult females were fed standard chow (185 ppm iron) or a low-iron diet (4 ppm iron) ad libitum 2 weeks prior to and throughout pregnancy, or were injected with 20 mg iron dextran at the time of mating. Pregnant females were analyzed at E12.5, E15.5, and E18.5. Nonpregnant (Non-P) females were subjected to an equivalent iron treatment. (B–F) Maternal measurements of (B) hepcidin (Hamp) mRNA and (C) serum hepcidin. (D) Liver nonheme iron. (E) Serum iron concentration. (F) Hb concentration. Statistical differences between groups was determined by 1-way ANOVA for normally distributed values, or otherwise by 1-way ANOVA on ranks (indicated by a single asterisk after the P value). (G–I) Embryo measurements at E18.5 for (G) serum iron and (H) liver nonheme iron. (I) Hb concentration. (J) Placental nonheme iron levels at E12.5, E15.5, and E18.5. (K) Placental weight at E15.5 and E18.5 (we did not obtain whole placentas at E12.5). Statistical differences between groups was determined by 1-way ANOVA for normally distributed values followed by the Holm-Sidak method for multiple comparisons versus the iron-replete control group (###P < 0.001) or 1-way ANOVA on ranks followed by Dunn’s method for multiple comparisons versus the iron-replete control group (#P < 0.05). The numbers of animals are indicated in the x axes of the box and whisker plots.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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