Fetal iron levels are regulated by maternal and fetal Hfe genotype and dietary iron

Abstract

BackgroundIron metabolism during pregnancy maintains fetal iron levels at the expense of the mother. The mechanism behind this regulation is still not clear despite recent advances. Here we examine the role of maternal and fetal Hfe, its downstream signaling molecule, hepcidin and dietary iron in the regulation of placental iron transfer. Design and MethodsHfe wild-type, knockout and heterozygote dams were fed iron deficient (12.5 ppm), adequate (50 ppm) and replete (150 ppm) iron diets and mated with heterozygote males to produce pups of all genotypes. Dams and pups were sacrificed at Day 18 of gestation; serum, placenta, body and liver iron parameters were measured. Protein and mRNA levels of various iron transporter genes were determined in duodenum, liver and placenta by Western blotting and real time PCR. ResultsMaternal liver iron levels were dependent on both dietary iron intake and Hfe genotype. Increasing iron levels in the maternal diet resulted in increased total iron in the fetus, primarily in the liver. However, fetuses of Hfe-knockout mothers showed further elevation of liver iron levels, concomitant with elevated expression of Tfr1, Dmt1 and Fpn in the placenta. Hfe-knockout fetuses that express low levels of liver hepcidin accumulated more iron in their liver than wild-type fetuses due to increased ferroportin levels in the placenta. ConclusionsMaternal and fetal status, as well as dietary iron, is important in regulating iron transfer across placenta. Maternal Hfe regulates iron transfer by altering gene expression in the placenta. Fetal Hfe is important in regulating placental iron transfer by modulating fetal liver hepcidin expression.

Maternal hemochromatosis gene H63D single-nucleotide polymorphism and lead levels of placental tissue, maternal and umbilical cord blood

“…The effects of C282Y and H63D mutations on HFE protein may be different, and, thus, their effects on placental lead transfer in wild-type and variants was found to be different in Karwowski et al's study and ours. In a previous study by Balesaria et al (2012), it was found that maternal HFE status plays a role in the transfer of iron across the placenta by modulating of gene expressions in the placenta. According to this study, when the mother was a HFE-knockout mouse, the expression of TfR, DMT-1 and ferroportin elevated in the placenta (Balesaria et al, 2012).…”

The placenta: the forgotten essential organ of iron transport

“…Maternal iron stores are generally improved by iron supplementation, with no resultant changes observed in cord ferritin, 114,115 and maternal ferritin exhibits a weak or no relationship with neonatal ferritin levels in small observational studies. In contrast, animal studies consistently show compromised fetal liver iron status in maternal iron deficiency, 102,116,117 suggesting an interdependence between maternal and fetal stores. A recent study in China, which included a large sample of mother-child pairs (n ¼ 3702), detected a strong correlation between maternal and neonatal ferritin in women whose plasma ferritin levels fell below a threshold of depletion, with every unit of decrease in maternal serum ferritin corresponding to a 2.4-unit drop in cord ferritin.…”

Examination of HFE associations with childhood leukemia risk and extension to other iron regulatory genes

“…As previously postulated [9,20], the mechanism of the childhood ALL risk association with HFE variants known to elevate body iron levels may include increased materno-fetal iron transport through placenta. This process is mediated by HFE and TFRC [21,22], and these genetically-mediated alterations in fetal iron homeostasis may also have implications on the developmental origins of health and disease [23].…”