Sangkhae Veena, Fisher Allison L, Wong Shirley, Koenig Mary Dawn, Tussing-Humphreys Lisa, Chu Alison, Lelić Melisa, Ganz Tomas, Nemeth Elizabeta
Center for Iron Disorders, Department of Medicine, and.
Molecular, Cellular and Integrative Physiology Graduate Program, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
J Clin Invest. 2020 Feb 3;130(2):625-640. doi: 10.1172/JCI127341.
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.
缺铁在全球范围内都很常见，并且与不良妊娠结局相关。孕期不加区分地补充铁剂的现象日益普遍，这也引发了人们对铁过量潜在不良影响的担忧。我们研究了母体铁状态如何影响铁向胎盘和胎儿的输送。通过使用小鼠模型，我们记录了保护胎盘和胎儿免受母体铁过量影响的母体稳态机制。我们确定，在生理条件下或缺铁时，胎儿和胎盘的铁调素并不调节胎儿的铁储备。在母体缺铁的情况下，介导胎盘铁摄取（转铁蛋白受体1 [TFR1]）和输出（铁转运蛋白 [FPN]）的关键转运蛋白受到强烈调节。在小鼠中，不仅TFR1增加，而且令人惊讶的是，FPN减少，以在胎儿缺铁的情况下保存胎盘铁。在轻度缺铁妊娠的人类胎盘中，TFR1增加，但FPN没有变化。然而，在体外对人滋养层细胞诱导更严重的缺铁会导致TFR1和FPN都受到调节，这与在小鼠模型中观察到的情况类似。这种优先考虑胎盘铁的胎盘适应性是由铁调节蛋白1（IRP1）介导的，并且对于维持线粒体呼吸很重要，从而最终保护胎儿免受全身性胎盘功能障碍可能带来的严重后果。
