Erythroferrone and Its Impact on Maternal and Neonatal Iron Homeostasis

全世界近50%的女性在怀孕期间患上贫血，即使在营养良好的美国孕妇中，铁(Fe)缺乏仍然是一个常见的问题。母亲缺铁会增加不良出生结局的风险，并日益被认为会影响新生儿出生时的铁天赋，并可能对胎儿大脑发育造成不可逆转的不利影响。为了预防母亲贫血，建议对所有美国孕妇进行普遍的产前补充，但最近的关注集中在这种做法可能的风险和好处上。为了充分解决母亲补充铁的益处和风险，需要更多地了解孕期铁的调节。母体铁的吸收是通过一种复杂的激素相互作用来调节母体铁的储存的，这些激素包括促红细胞生成素、海普西丁和最近的红血铁酮(ERFe)。ErFe是由红系前体和抑制海普西丁的功能产生的，导致更多的铁可用于红细胞生成。这三种激素结合在一起，根据母亲、胎盘和胎儿对铁的需求，平衡对铁的吸收和释放。2017年，开发了一种新的Erfe检测方法，并得到了Ganz和Nemeth博士的广泛验证。然而，目前还没有关于ERFe在人类怀孕中的数据，关于这种新发现的激素是如何在整个妊娠期间受到调节的，以及关于Erfe如何调节复杂的Fe需求和必须在怀孕期间发生的分配，以响应母亲、胎盘和胎儿的Fe需求。这项拟议的研究将利用在336名孕妇(怀孕青少年和携带多个胎儿的妇女)中获得的现有人类生物样本档案，以评估孕妇在整个孕期和新生儿脐带血中的Erfe与孕产妇和新生儿Fe状况、炎症和另外两种关键调节激素(EPO和海普西丁)之间的关系(目标1)。胎盘ERFe可能是由胎儿红系前体细胞产生的，以调节新生儿铁稳态和红细胞生成。目标1中现有的新生儿胎盘蛋白质和RNA档案将用于研究妊娠25至42周期间Erfe蛋白的表达和转录本的丰度，以确定Erfe的预测因素，及其与出生时胎龄、新生儿和母亲ID和IDA的关系。胎盘-胎儿单位控制新生儿铁稳态的能力将通过评估暴露在相同子宫环境中的兄弟姐妹之间的新生儿ERFE的变异性，并与观察到的无关新生儿之间的变异性进行比较，利用多重数据进行探索(目标2)。最后，将对野生型和缺铁/缺铁的雌性孕妇和缺铁和缺铁的孕妇进行研究，以从机制上探讨缺铁和缺铁对调节孕期红细胞生成和铁稳态的贡献(目标3)。这些数据将提供影响怀孕期间铁利用的母体调节途径的新信息，并将为后续旨在改善怀孕期间母体和胎儿铁状况的研究奠定基础。

Nearly 50% of women worldwide develop anemia during pregnancy, and iron (Fe) deficiency remains a common problem even among otherwise well-nourished US pregnant women. Maternal Fe deficiency increases the risk of adverse birth outcomes and is increasingly recognized to impact the Fe endowment of the neonate at birth and may cause irreversible adverse effects on fetal brain development. To prevent maternal anemia, universal prenatal supplementation is recommended for all pregnant US women but recent concern has been focused on the possible risks and benefits of this practice. In order to fully address the benefits and risk of maternal Fe supplementation, a greater understanding of Fe regulation across gestation is needed. Maternal Fe absorption is regulated in response to maternal Fe stores via a complex interplay of hormones including erythropoietin, hepcidin and most recently erythroferrone (ERFE). ERFE is produced by erythroid precursors and functions to suppress hepcidin, leading to greater Fe availability for erythropoiesis. Together, these three hormones balance Fe absorption and release from stores in relation to maternal, placental and fetal Fe demands. In 2017, a new assay for ERFE was developed and extensively validated by Drs. Ganz and Nemeth. However, at this time there are no data on ERFE in human pregnancies, on how this newly identified hormone is regulated across gestation, and on how ERFE mediates the complex Fe demands and partitioning that must occur across gestation in response to maternal, placental and fetal Fe demands. The proposed research will capitalize on an existing human biospecimen archive obtained in 336 pregnant women (pregnant teens and women carrying multiple fetuses) to evaluate maternal ERFE across gestation and neonatal ERFE in umbilical cord blood in relation to maternal and neonatal Fe status, inflammation and two other key regulatory hormones (EPO and hepcidin) (Aim 1). Placental ERFE may be produced by fetal erythroid precursors to regulate neonatal Fe homeostasis and erythropoiesis. An existing placental protein and RNA archive from the neonates in Aim 1 will be used to investigate ERFE protein expression and transcript abundance between weeks 25 and 42 of gestation to identify predictors of ERFE, its association with gestational age at birth and neonatal and maternal ID and IDA. The ability of the placental-fetal unit to control neonatal Fe homeostasis will be explored using the multiplets data by evaluating variability in neonatal ERFE between siblings exposed to the same uterine environment and compared to variability observed between unrelated neonates (Aim 2). Finally, studies in wild-type and Erfe-/- pregnant females and fetuses from Fe-replete and Fe-deficient pregnancies will be undertaken to mechanistically address the contribution of ERFE to regulating erythropoiesis and Fe homeostasis in pregnancy (Aim 3). These data will provide novel information on the maternal regulatory pathways that impact Fe utilization during pregnancy and will form the basis for subsequent studies designed to improve maternal and fetal Fe status across pregnancy.