Influence of gestational age and fetal iron status on IRP activity and iron transporter protein expression in third-trimester human placenta

Abstract

Placental iron transport during the last trimester of pregnancy determines the iron endowment of the neonate. Iron transport is a function of the major iron transport proteins: transferrin receptor-1 (TfR-1) and ferroportin-1 (FPN-1). The mRNAs for TfR-1 and, potentially, FPN-1 are posttranscriptionally regulated by iron regulatory protein (IRP)-1 and IRP-2. We assessed the effect of gestational age and fetal iron status on IRP-1- and IRP-2-binding activity and on the localization and protein expression of TfR-1 and FPN-1 protein at 24-40 wk of gestation in 21 placentas obtained from iron-sufficient nonanemic mothers. Gestational age had no effect on cord serum ferritin concentration, IRP-2 RNA-binding activity, transporter protein location, and TfR-1 or FPN-1 protein expression. IRP-1 activity remained constant until full term, when it decreased (P = 0.01). Placental ferritin (r = 0.76, P < 0.001) and FPN-1 (r = 0.44, P < 0.05) expression increased with gestational age. Fetal iron status, as indexed by cord serum ferritin concentration, was inversely related to placental IRP-1 (r = -0.66, P < 0.001) and IRP-2 (r = -0.42, P = 0.05) activities. Placental ferritin protein expression correlated better with IRP-1 (r = -0.45, P = 0.04) than with IRP-2 (r = -0.35, P = 0.10) activity. Placental TfR-1 and FPN-1 protein expression was independent of fetal or placental iron status and IRP activities. Iron status had no effect on transport protein localization. We conclude that, toward the end of the third trimester of iron-sufficient human pregnancy, the placenta accumulates ferritin and potentially increases placental-fetal iron delivery through increased FPN-1 expression. IRP-1 may have a more dominant role than IRP-2 activity in regulating ferritin expression.

The Human Placental Methylome

“…These include, for example, up-regulation of System A transporters, which are responsible for transporting amino acids to the fetus (Coan et al 2010;Burton and Fowden 2012), iron transport proteins (Bradley et al 2004), which absorb iron from maternal blood, and placental corticotropin releasing hormone (CRH), which may stimulate maternal glucose production needed to support the growing brain (Gangestad et al 2012). CRH gene promoter DNA methylation has been correlated with its expression in the placenta (Jiang et al 2012); increased gestational age was associated with decreased DNA methylation at CpG sites associated with the CRH gene as well as other cortisol signaling and steroidogenic genes in the placenta (Hogg et al 2013a).…”

Marked Biological Variance in Endocrine and Biochemical Markers in Childhood: Establishment of Pediatric Reference Intervals Using Healthy Community Children from the CALIPER Cohort

“…For ferritin, the high concentrations observed during the first 6 months of life reflect iron stores accumulated during the last trimester of gestation (13 ). Additionally, the increased concentrations observed immediately postnatally may be a consequence of erythrocyte turnover (14 ).…”

Fetal and infantile hemochromatosis

“…12 Ferroportin is highly expressed and colocalizes with HFE in placental trophoblast cells. 13,14 Ferroportin expression increases with gestational age in parallel with the fetus' increasing demand for iron. 13 Fetal hepcidin evidently regulates fetal iron stores.…”

“…13,14 Ferroportin expression increases with gestational age in parallel with the fetus' increasing demand for iron. 13 Fetal hepcidin evidently regulates fetal iron stores. Disruption of the gene encoding for the transcription factor upstream stimulatory factor 2 (Usf2) in the mouse results in complete absence of hepcidin expression and a hemochromatosis phenotype.…”