Chang Cao

Pregnancy and iron homeostasis: an update

It has been nearly 15 years since the first review on pregnancy and iron deficiency was published in Nutrition Reviews. Many unresolved issues raised in that seminal review have been addressed. New proteins involved in nonheme and heme iron transport have been identified in the enterocyte, and information on the roles of these proteins in the placenta is evolving. The systemic iron regulatory hormone, hepcidin, has since been identified as a key regulator of iron homeostasis. Additional data on the efficacy and consequences of prenatal iron supplementation are available. Emerging data on developmental changes in iron absorption across early infancy have further emphasized the need to ensure that the iron endowment of the neonate at birth is optimal. This is especially important, given growing evidence linking neonatal iron status with subsequent cognitive and neurobehavioral outcomes. Along with the many advances, new questions and gaps in knowledge have been identified. This review summarizes new data on maternal iron utilization across pregnancy as it impacts the pregnant woman and the iron status of the neonate at birth.

Placental CYP27B1 and CYP24A1 expression in human placental tissue and their association with maternal and neonatal calcitropic hormones.

CONTEXT Placental CYP27B1 may contribute to circulating maternal calcitriol concentrations across gestation, but determinants of CYP27B1 and CYP24A1 expression in term human placental tissue are not well established. OBJECTIVE We hypothesized that higher CYP27B1 protein expression would be associated with increased maternal calcitriol during gestation and that CYP27B1 expression would be impacted by substrate availability. DESIGN This was a prospective, longitudinal study. SETTING The study was completed in an urban, prenatal clinic located in Rochester, New York. PATIENTS The study was undertaken in a cohort of 70 pregnant adolescents (≤18 y of age) and their term neonates. INTERVENTION There was no intervention. MAIN OUTCOMES Protein and mRNA expressions of CYP27B1, CYP24A1, and vitamin D receptor were measured in term placental tissue and related to 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D, PTH, serum total calcium, IL-6, leptin, and osteoprotegerin measured in maternal serum at midgestation and delivery and in umbilical cord serum at birth. RESULTS Placental CYP27B1 protein expression was significantly positively associated with maternal 25(OH)D at both midgestation (n = 68, P = .009) and delivery (n=67, P = .006). Maternal serum 1,25-dihydroxyvitamin D concentrations at midgestation were positively correlated with term placental CYP27B1 mRNA expression (n = 49, P = .002). Significant positive associations were evident between placental CYP27B1 and CYP24A1 protein expression (P = .001, n = 70). Maternal PTH concentrations at midgestation or delivery did not significantly impact placental protein or transcript level of either enzyme. Variability in placental CYP27B1 protein expression was best captured by a model that included maternal midgestation 25(OH)D concentration, placental vitamin D receptor protein expression, and maternal midgestation IL-6 concentrations (P = .002, n = 60, R(2) = 0.22). CONCLUSIONS Higher maternal 25(OH)D during pregnancy was associated with significantly higher placental protein expression of CYP27B1 at term supportive of a link between substrate availability and placental production of calcitriol.

Placental heme receptor LRP1 correlates with the heme exporter FLVCR1 and neonatal iron status

LDL receptor-related protein 1 (LRP1) is a transmembrane receptor highly expressed in human placenta. It was recently found to be the receptor for heme and its plasma-binding protein hemopexin (Hx) and is integral to systemic heme clearance. Little is known about systemic concentrations of Hx during pregnancy and whether maternal Hx and placental LRP1 contributes to fetal iron (Fe) homeostasis during pregnancy. We hypothesized that placental LRP1 would be upregulated in maternal/neonatal Fe insufficiency and would be related to maternal circulating Hx. Placental LRP1 expression was assessed in 57 pregnant adolescents (14-18 years) in relationship with maternal and cord blood Fe status indicators (hemoglobin (Hb), serum ferritin, transferrin receptor), the Fe regulatory hormone hepcidin and serum Hx. Hx at mid-gestation correlated positively with Hb at mid-gestation (r=0.35, P=0.02) and Hx at delivery correlated positively with cord hepcidin (r=0.37, P=0.005). Placental LRP1 protein expression was significantly higher in women who exhibited greater decreases in serum Hx from mid-gestation to term (r=0.28, P=0.04). Significant associations were also found between placental LRP1 protein with cord hepcidin (r=-0.29, P=0.03) and placental heme exporter feline leukemia virus C receptor 1 (r=0.34, P=0.03). Our data are consistent with a role for placental heme Fe utilization in supporting fetal Fe demands.

Prepregnancy Body Mass Index and Gestational Weight Gain Have No Negative Impact on Maternal or Neonatal Iron Status

Objective: To assess the impact of maternal obesity and excessive gestational weight gain (GWG) on maternal and neonatal iron status and to explore the possible mediating role of inflammation on hepcidin. Methods: This analysis included 230 pregnant adolescents (13-18 years) enrolled in either a longitudinal or a cross-sectional study. Prepregnancy body mass index (ppBMI) and GWG were obtained from medical records. Maternal iron status (hemoglobin, serum iron, ferritin, transferrin receptor, total body iron, and hepcidin) and inflammation (interleukin-6 [IL-6] and leptin) were assessed at midgestation (26.2 ± 3.3 weeks) in the longitudinal cohort and at delivery (39.8 ± 1.3 weeks) in both study cohorts. Cord blood was collected in both studies and analyzed for iron indicators. Results: Approximately 40% of the adolescents entered pregnancy overweight or obese. Multivariate analysis identified ppBMI as a negative predictor of serum iron at midgestation (P = .009) and a positive predictor of serum hepcidin at delivery (P = .02). None of the other maternal iron status indicators were significantly associated with ppBMI or GWG. Serum IL-6 was significantly positively associated with hepcidin at delivery (P = .0001) but not at midgestation. There was a positive relationship between ppBMI and cord hemoglobin (P = .03). Conclusion: These results suggest that adiposity-related inflammation does not override the iron-mediated signals that regulate hepcidin production during pregnancy, and in this adolescent cohort, there is no strong evidence for a detrimental effect of maternal obesity and excessive weight gain on iron status in the offspring at birth.

Duodenal Absorption and Tissue Utilization of Dietary Heme and Nonheme Iron Differ in Rats

BACKGROUND Dietary heme contributes to iron intake, yet regulation of heme absorption and tissue utilization of absorbed heme remains undefined. OBJECTIVES In a rat model of iron overload, we used stable iron isotopes to examine heme- and nonheme-iron absorption in relation to liver hepcidin and to compare relative utilization of absorbed heme and nonheme iron by erythroid (RBC) and iron storage tissues (liver and spleen). METHODS Twelve male Sprague-Dawley rats were randomly assigned to groups for injections of either saline or iron dextran (16 or 48 mg Fe over 2 wk). After iron loading, rats were administered oral stable iron in the forms of (57)Fe-ferrous sulfate and (58)Fe-labeled hemoglobin. Expression of liver hepcidin and duodenal iron transporters and tissue stable iron enrichment was determined 10 d postdosing. RESULTS High iron loading increased hepatic hepcidin by 3-fold and reduced duodenal expression of divalent metal transporter 1 (DMT1) by 76%. Nonheme-iron absorption was 2.5 times higher than heme-iron absorption (P = 0.0008). Absorption of both forms of iron was inversely correlated with hepatic hepcidin expression (heme-iron absorption: r = -0.77, P = 0.003; nonheme-iron absorption: r = -0.80, P = 0.002), but hepcidin had a stronger impact on nonheme-iron absorption (P = 0.04). Significantly more (57)Fe was recovered in RBCs (P = 0.02), and more (58)Fe was recovered in the spleen (P = 0.01). CONCLUSIONS Elevated hepcidin significantly decreased heme- and nonheme-iron absorption but had a greater impact on nonheme-iron absorption. Differential tissue utilization of heme vs. nonheme iron was evident between erythroid and iron storage tissues, suggesting that some heme may be exported into the circulation in a form different from that of nonheme iron.

Vitamin D mediates the relationship between placental cathelicidin and group B streptococcus colonization during pregnancy

Vitamin D is thought to modulate innate immune responses, and recent studies have highlighted the autocrine and paracrine functions of vitamin D in the placenta. Our objective was to determine the relationship between maternal vitamin D status and placental antimicrobial peptide (AMP) expression in a group of racially and ethnically diverse pregnant adolescents. In this study, 158 pregnant adolescents were recruited from the Rochester Adolescent Maternity Program (RAMP) in Rochester, NY. Maternal serum concentrations of the vitamin D biomarkers, 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D), were measured at mid-gestation (∼26 weeks) and at delivery. At the placental level, vitamin D regulatory proteins (cubilin, megalin, 1α-hydroxylase (CYP27B1), 24-hydroxylase (CYP24A1), vitamin D receptor (VDR)) and AMPs (cathelicidin and hepcidin) were analyzed using quantitative PCR and western blot techniques. Placental CYP27B1 mRNA expression was significantly positively associated with both placental cathelicidin mRNA expression (P<0.0001) and placental hepcidin mRNA expression (P=0.002). In teens with positive recto-vaginal group B streptococcus (GBS) colonization, placental mRNA expression of cathelicidin (P=0.007), cubilin (P=0.03), and CYP27B1 (P=0.04) were significantly lower compared to those who tested negative for this infection. A mediation analysis showed that the indirect relationship between GBS colonization and placental cathelicidin mRNA expression was mediated by the placental mRNA expression of the vitamin D proteins cubilin and CYP27B1 (P=0.02). Additional research is needed to identify the role and relative contributions of placental and systemic vitamin D metabolites in relation to potentially pathogenic microorganisms which may be present during pregnancy.

The ins and outs of erythroid heme transport

Heme plays critical roles in erythropoiesis not only as a structural component of hemoglobin but also as a regulator of erythroid proliferation by affecting the expression of proteins involved in iron transport and globin synthesis.[1][1] Within the cell, heme is synthesized in the mitochondria and