Erythroferrone Modulates Iron Distribution for Fetal Erythropoiesis

Abstract Erythroferrone (ERFE) is an erythroblast-derived regulator of iron metabolism, and its production increases during stress erythropoiesis. ERFE decreases expression of the iron-regulatory hormone hepcidin to enhance iron availability for erythropoiesis 1. Pregnancy requires a substantial increase in iron availability to sustain a dramatic increase in maternal RBC volume and support fetal development. Whether maternal or fetal ERFE plays a role in regulating iron homeostasis during pregnancy is unknown. In humans, maternal ERFE concentrations were elevated in anemic pregnancies at mid gestation and delivery 2. To define the role of ERFE during iron-replete or iron-deficient pregnancy, we utilized Erfe transgenic (ETg) 3 and Erfe knockout (EKO) 1 mice. Maternal iron status of ETg, WT and EKO mice was altered by placing animals on adequate iron (100ppm) or low iron (4ppm) diet 2 weeks prior to and throughout pregnancy. ETg and WT dams were mated with WT sires to generate ETg and WT embryos while EKO dams were mated with EKO sires to generate EKO embryos. Analysis was performed at embryonic day 18.5. To examine the effect of pregnancy on ERFE expression, we compared non-pregnant females to WT dams at E18.5. Serum ERFE was mildly elevated from 0.01 to 0.2 ng/mL in iron-replete dams, but substantially elevated from 0.01 to 3.1 ng/mL in iron-deficient dams, similarly to human pregnancy 2. We next assessed iron and hematological parameters in pregnant dams with different Erfe genotypes. Under iron-replete conditions, all three groups had similar serum hepcidin, serum iron and hemoglobin concentrations, but ETg dams had 3-fold higher liver iron than WT and EKO dams, presumably because they are mildly iron-overloaded before pregnancy. On iron-deficient diet, maternal hepcidin was decreased in all three genotypes but more so in ETg dams; however, all three Erfe genotypes had similarly depleted liver iron stores, hypoferremia and anemia. MCV was the only parameter that was decreased in EKO compared to WT dams under both iron conditions. Overall, maternal ERFE played a minor role in regulation of maternal erythropoiesis and iron homeostasis, with the lack of ERFE resulting in smaller RBCs but not anemia. Among embryos, we observed a significant effect of Erfe genotype on embryo hepcidin. ETg embryos had significantly lower liver hepcidin compared to WT embryos under both iron-replete and iron-deficient conditions. Conversely, Erfe KO embryos had higher hepcidin compared to WTs under iron-deficient conditions, indicating that embryo ERFE regulates embryo hepcidin during pregnancy. Under iron-replete conditions however, all three embryo genotypes had similar hematologic parameters, and embryo liver iron was dependent on maternal iron levels, with both ETg and WT embryos from ETg dams having increased liver iron concentrations, indicating that embryo ERFE does not regulate placental iron transfer. Under iron-deficient conditions, there was no difference between ETg and WT embryos in hematological or iron parameters, and both genotypes developed iron deficiency and anemia. However, Erfe KO embryos, which had elevated hepcidin, had maldistribution of iron and worse anemia. EKO embryo liver iron concentrations were 6-fold higher compared to WT iron-deficient embryos, whereas hemoglobin was significantly decreased compared to WT iron-deficient embryos. These findings indicate that under iron-limiting conditions, embryo ERFE is important for the suppression of embryo hepcidin to ensure iron redistribution for embryo erythropoiesis. In summary, during iron replete pregnancy, ERFE plays a minor role in maternal and fetal iron homeostasis and erythropoiesis. However, in response to iron-deficiency anemia during pregnancy, ERFE is important for the redistribution of iron within the embryo to support embryo erythropoiesis. 1Kautz L et al, Nat Genet, 2014 2Delaney K et al, Curr Dev Nutr, 2020 3Coffey R et al, Blood, 2020 Disclosures Ganz: Ambys: Consultancy; Sierra Oncology: Consultancy, Research Funding; Rockwell: Consultancy; Pharmacosmos: Consultancy; Ionis: Consultancy; Protagonist: Consultancy; Intrinsic LifeSciences: Consultancy; RallyBio: Consultancy; Silence Therapeutics: Consultancy; Silarus Pharma: Consultancy; Alnylam: Consultancy; American Regent: Consultancy; Disc Medicine: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenecaFibrogen: Consultancy; Global Blood Therapeutics: Consultancy; Gossamer Bio: Consultancy; Akebia: Consultancy, Honoraria. Nemeth: Silarus Pharma: Consultancy; Intrinsic LifeSciences: Consultancy; Protagonist: Consultancy; Vifor: Consultancy; Ionis: Consultancy.

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Maternal iron deficiency alters trophoblast differentiation and placental development in rat pregnancy

Endocrinology ◽

10.1210/endocr/bqab215 ◽

2021 ◽

Author(s):

Hannah Roberts ◽

Andrew G Woodman ◽

Kelly J Baines ◽

Mariyan J Jeyarajah ◽

Stephane L Bourque ◽

...

Keyword(s):

Iron Deficiency ◽

Fetal Growth ◽

Growth And Development ◽

Iron Homeostasis ◽

Junctional Zone ◽

Altered Expression ◽

Expression Of Genes ◽

Iron Deficient ◽

Increased Risk ◽

Maternal Iron

Abstract Iron deficiency occurs when iron demands chronically exceed intake, and is prevalent in pregnant women. Iron deficiency during pregnancy poses major risks for the baby, including fetal growth restriction and long-term health complications. The placenta serves as the interface between a pregnant mother and her baby, and ensures adequate nutrient provisions for the fetus. Thus, maternal iron deficiency may impact fetal growth and development by altering placental function. We used a rat model of diet-induced iron deficiency to investigate changes in placental growth and development. Pregnant Sprague-Dawley rats were fed either a low-iron or iron-replete diet starting two weeks before mating. Compared to controls, both maternal and fetal hemoglobin were reduced in dams fed low-iron diets. Iron deficiency decreased fetal liver and body weight, but not brain, heart or kidney weight. Placental weight was increased in iron deficiency, due primarily to expansion of the placental junctional zone. The stimulatory effect of iron deficiency on junctional zone development was recapitulated in vitro, as exposure of rat trophoblast stem cells to the iron chelator deferoxamine increased differentiation toward junctional zone trophoblast subtypes. Gene expression analysis revealed 464 transcripts changed at least 1.5-fold (P<0.05) in placentas from iron-deficient dams, including altered expression of genes associated with oxygen transport and lipoprotein metabolism. Expression of genes associated with iron homeostasis was unchanged despite differences in levels of their encoded proteins. Our findings reveal robust changes in placentation during maternal iron deficiency, which could contribute to the increased risk of fetal distress in these pregnancies.

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Liver iron sensing and body iron homeostasis

Blood ◽

10.1182/blood-2018-06-815894 ◽

2019 ◽

Vol 133 (1) ◽

pp. 18-29 ◽

Cited By ~ 45

Author(s):

Chia-Yu Wang ◽

Jodie L. Babitt

Keyword(s):

Iron Deficiency ◽

Iron Homeostasis ◽

Inflammatory Diseases ◽

Genetic Disorders ◽

Hereditary Hemochromatosis ◽

Deficiency Anemia ◽

Iron Loading ◽

Liver Iron ◽

Body Iron ◽

Iron Supply

Abstract The liver orchestrates systemic iron balance by producing and secreting hepcidin. Known as the iron hormone, hepcidin induces degradation of the iron exporter ferroportin to control iron entry into the bloodstream from dietary sources, iron recycling macrophages, and body stores. Under physiologic conditions, hepcidin production is reduced by iron deficiency and erythropoietic drive to increase the iron supply when needed to support red blood cell production and other essential functions. Conversely, hepcidin production is induced by iron loading and inflammation to prevent the toxicity of iron excess and limit its availability to pathogens. The inability to appropriately regulate hepcidin production in response to these physiologic cues underlies genetic disorders of iron overload and deficiency, including hereditary hemochromatosis and iron-refractory iron deficiency anemia. Moreover, excess hepcidin suppression in the setting of ineffective erythropoiesis contributes to iron-loading anemias such as β-thalassemia, whereas excess hepcidin induction contributes to iron-restricted erythropoiesis and anemia in chronic inflammatory diseases. These diseases have provided key insights into understanding the mechanisms by which the liver senses plasma and tissue iron levels, the iron demand of erythrocyte precursors, and the presence of potential pathogens and, importantly, how these various signals are integrated to appropriately regulate hepcidin production. This review will focus on recent insights into how the liver senses body iron levels and coordinates this with other signals to regulate hepcidin production and systemic iron homeostasis.

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Iron-deficiency anemia from matriptase-2 inactivation is dependent on the presence of functional Bmp6

Blood ◽

10.1182/blood-2010-07-295147 ◽

2011 ◽

Vol 117 (2) ◽

pp. 647-650 ◽

Cited By ~ 21

Author(s):

Anne Lenoir ◽

Jean-Christophe Deschemin ◽

Léon Kautz ◽

Andrew J. Ramsay ◽

Marie-Paule Roth ◽

...

Keyword(s):

Iron Deficiency ◽

Iron Overload ◽

Serine Protease ◽

Iron Deficiency Anemia ◽

Iron Homeostasis ◽

Deficiency Anemia ◽

Hepatic Iron ◽

Master Regulator ◽

Liver Iron ◽

The Relationship

Abstract Hepcidin is the master regulator of iron homeostasis. In the liver, iron-dependent hepcidin activation is regulated through Bmp6 and its membrane receptor hemojuvelin (Hjv), whereas, in response to iron deficiency, hepcidin repression seems to be controlled by a pathway involving the serine protease matriptase-2 (encoded by Tmprss6). To determine the relationship between Bmp6 and matriptase-2 pathways, Tmprss6−/− mice (characterized by increased hepcidin levels and anemia) and Bmp6−/− mice (exhibiting severe iron overload because of hepcidin deficiency) were intercrossed. We showed that loss of Bmp6 decreased hepcidin levels; increased hepatic iron; and, importantly, corrected hematologic abnormalities in Tmprss6−/− mice. This finding suggests that elevated hepcidin levels in patients with familial iron-refractory, iron-deficiency anemia are the result of excess signaling through the Bmp6/Hjv pathway.

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Fetal liver hepcidin secures iron stores in utero

10.1101/799304 ◽

2019 ◽

Author(s):

Lara Kämmerer ◽

Goran Mohammad ◽

Magda Wolna ◽

Peter A. Robbins ◽

Samira Lakhal-Littleton

Keyword(s):

Iron Overload ◽

Iron Transport ◽

Iron Homeostasis ◽

Iron Absorption ◽

Fetal Liver ◽

In Utero ◽

Liver Iron ◽

Iron Stores ◽

Maternal Iron

AbstractIn the adult, the liver-derived hormone hepcidin (HAMP) controls systemic iron levels by blocking the iron-exporting protein ferroportin (FPN) in the gut and spleen, the sites of iron absorption and recycling respectively. Impaired HAMP expression or FPN responsiveness to HAMP result in iron overload. HAMP is also expressed in the fetal liver but its role in controlling fetal iron stores is not understood. To address this question in a manner that safeguards against the confounding effects of altered maternal iron homeostasis, we generated fetuses harbouring a paternally-inherited ubiquitous knock-in of the HAMP-resistant fpnC326Y. Additionally, to safeguard against any confounding effects of altered placental iron homeostasis, we generated fetuses with a liver-specific knock-in of fpnC326Y or knockout of the hamp gene. These fetuses had reduced liver iron stores, and markedly increased FPN in the liver, but not in the placenta. Thus, in contrast to the adult, fetal liver HAMP operates cell-autonomously to increase fetal liver iron stores. Our findings also suggest that FPN in the placenta is permissive rather than regulatory of iron transport.

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Surface Remodeling vs. Whole-Cell Hemolysis of Reticulocytes Produced With Erythroid Stimulation or Iron Deficiency Anemia

Blood ◽

10.1182/blood.v44.6.817.817 ◽

1974 ◽

Vol 44 (6) ◽

pp. 817-830 ◽

Cited By ~ 22

Author(s):

Steven E. Come ◽

Stephen B. Shohet ◽

Stephen H. Robinson

Keyword(s):

Iron Deficiency ◽

Iron Deficiency Anemia ◽

Deficiency Anemia ◽

Red Cell ◽

Whole Cell ◽

Iron Deficient ◽

Minor Degree ◽

Small Decline ◽

A Minor ◽

Surface Remodeling

Abstract 32P in membrane phosphatidylethanolamine (PE) and red cell 14C, reflecting cytoplasmic hemoglobin, were measured sequentially in rats given transfusions of doubly-labeled reticulocytes. With reticulocytes from normal rats there was a small decline in the levels of both the membrane and the cytoplasmic labels; the changes were almost parellel, although loss of membrane PE-32P exceeded that of 14C to a small extent. By contrast, with "stress reticulocytes" from bled donors, there was a markedly disproportionate loss of the membrane label; this asymmetrical loss of membrane material was diminished when recipients had been splenectomized. With transfusions of doubly-labeled reticulocytes from rats with severe iron deficiency anemia, there was a marked loss of both membrane PE-32P and red cell 14C which was only moderately asymmetrical. The asymmetrical loss of the membrane label found with stress reticulocytes supports the conclusion that these cells undergo a process of surface remodeling during their maturation in the peripheral blood. The spleen is partly responsible for this process. Normal reticulocytes also appear to undergo a minor degree of remodeling. On the other hand, the almost symmetrical loss of membrane and cytoplasmic label observed with reticulocytes from iron deficient rats indicates that many of the cells in this model of ineffective erythropoiesis are hemolyzed in their entirety. These experiments demonstrate that stress reticulocytes differ under different conditions and may lose cellular material by two, possibly interrelated, mechanisms: surface remodeling or whole-cell hemolysis.

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The Serine Protease Tmprss6 Regulates Hepcidin Expression, but Its Loss Does Not Cause Systemic Iron Deficiency In the Fetal and Neonatal Periods

Blood ◽

10.1182/blood.v116.21.4258.4258 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4258-4258

Author(s):

Ramsey M. Wehbe ◽

Rebecca L. Whittlesey ◽

Nancy C. Andrews ◽

Karin E. Finberg

Keyword(s):

Iron Deficiency ◽

Iron Homeostasis ◽

Iron Concentration ◽

Fold Increase ◽

Heme Iron ◽

Hepcidin Expression ◽

Non Heme Iron ◽

Iron Parameters ◽

Maternal Iron ◽

Hepcidin Mrna

Abstract Abstract 4258 Mutations in TMPRSS6 (matriptase-2), a transmembrane serine protease expressed by the liver, result in the clinical phenotype of iron refractory iron deficiency anemia (IRIDA). Additionally, common polymorphisms in TMPRSS6 have been associated with variation in laboratory parameters of iron homeostasis in healthy populations. TMPRSS6 increases iron absorption by reducing expression of the hepatic hormone, hepcidin, via down-regulation of a BMP/SMAD signaling cascade. Hepcidin promotes the internalization and degradation of the duodenal iron transporter, ferroportin, thereby inhibiting iron absorption. Previous studies have demonstrated that adult mice with Tmprss6 deficiency exhibit elevated hepatic hepcidin mRNA levels that are associated with decreased hepatic iron stores. In one study, genetic loss of Tmprss6 was shown to result in significant elevation of hepatic hepcidin expression in mice at birth; however, whether this hepcidin elevation was associated with abnormalities in iron homeostasis was not reported. We therefore asked if the elevated hepcidin levels present in newborn Tmprss6-/- pups correlate with abnormal parameters of iron homeostasis in the fetal or neonatal periods. To answer this question, we intercrossed Tmprss6+/− mice to generate Tmprss6+/+, Tmprss6+/−, and Tmprss6-/- progeny for phenotypic characterization at either gestational day 17.5 (E17.5) or postnatal day 0 (P0). Consistent with prior observations, Tmprss6-/- pups at P0 showed a 4.6-fold increase in hepatic hepcidin mRNA compared to Tmprss6+/+ littermates (p=.006). However, despite this elevation in hepcidin expression, Tmprss6-/- pups were not pale, and they showed no significant differences in body mass or hepatic non-heme iron concentration compared to Tmprss6+/+ and Tmprss6+/− littermates. At E17.5, Tmprss6-/- fetuses showed a 50-fold increase in hepatic hepcidin mRNA compared to Tmprss6+/+ littermates (p=.005). However, Tmprss6-/- fetuses also were not pale, and they showed no significant difference in body mass compared to Tmprss6+/+ and Tmprss6+/− littermates. Surprisingly, hepatic non-heme iron concentration at E17.5 was significantly higher in Tmprss6-/- fetuses than in Tmprss6+/+ fetuses (p=.003). To determine if the increased hepcidin expression of Tmprss6-/- fetuses might affect iron homeostasis in their pregnant mothers, we measured iron parameters in Tmprss6+/− females gestating E17.5 litters that were enriched for either Tmprss6+/+ or Tmprss6-/- fetuses. No significant effects of fetal genotype on maternal iron parameters were observed. In summary, our results demonstrate that Tmprss6 regulates hepcidin expression in the fetal and neonatal periods in mice. However, Tmprss6 deficiency does not appear to be associated with systemic iron deficiency at these stages of development, and fetal Tmprss6 expression does not have a significant effect on maternal iron homeostasis in late gestation. These results may have implications for understanding the maintenance of iron homeostasis in early development, and may provide insight into the evolution of IRIDA as well as other disorders of iron homeostasis. Disclosures: No relevant conflicts of interest to declare.

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Regulation of Iron Uptake by Fine-Tuning the Iron Responsiveness of the Iron Sensor Fur

Applied and Environmental Microbiology ◽

10.1128/aem.03026-18 ◽

2019 ◽

Vol 85 (9) ◽

Cited By ~ 2

Author(s):

Jeongjoon Choi ◽

Sangryeol Ryu

Keyword(s):

Iron Uptake ◽

Metal Ion ◽

Iron Homeostasis ◽

Control Mechanism ◽

Fine Tuning ◽

Ferric Uptake Regulator ◽

Biological Processes ◽

Iron Availability ◽

Fur Protein ◽

Iron Concentrations

ABSTRACTIron is one of most abundant environmental metal ions but is highly limited in organisms. It is an important metal ion as it facilitates various biological processes, including catalysis of metabolic enzymes and DNA biogenesis. In bacteria, the ferric uptake regulator (Fur) protein controls iron uptake by regulating genes coding for iron transporters in response to iron concentration. This iron response is ascribed to Fur’s intrinsic affinity for iron because its binding to iron dictates its regulatory function. However, we now report that the pathogenSalmonellaachieves a proper response of Fur to changes in environmental iron concentrations via EIIANtr(a nitrogen metabolic phosphotransferase system component). We establish that EIIANtrincreases expression of iron transporter-coding genes under low-iron conditions (i.e., nanomolar ranges) in a Fur-dependent manner, which promotesSalmonellagrowth under such conditions. EIIANtrdirectly hampers Fur binding to DNA, thereby inducing expression of those genes. This regulation allowsSalmonellato express Fur-regulated genes under low-iron conditions. Our findings reveal a potentially widespread control mechanism of bacterial iron uptake systems operating in response to iron availability.IMPORTANCEIron is a fundamental metal ion for living organisms as it facilitates various biological processes. The ferric uptake regulator (Fur) protein controls iron homeostasis in various bacterial species. It is believed that Fur’s iron-dependent regulatory action is sufficient for it to function as an iron sensor. However, we now establish that the bacterial pathogenSalmonellaenables Fur to properly reflect changes in surrounding iron availability by fine-tuning its responsiveness to iron. This process requires a protein that hampers Fur DNA binding at low iron concentrations. In this way,Salmonellabroadens the range of iron concentrations that Fur responds to. Our findings reveal a potentially widespread control mechanism of bacterial iron homeostasis.

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Gastrin-Deficient Mice Have Disturbed Hematopoiesis in Response to Iron Deficiency

Endocrinology ◽

10.1210/en.2010-1474 ◽

2011 ◽

Vol 152 (8) ◽

pp. 3062-3073 ◽

Cited By ~ 10

Author(s):

Suzana Kovac ◽

Gregory J. Anderson ◽

Warren S. Alexander ◽

Arthur Shulkes ◽

Graham S. Baldwin

Keyword(s):

Iron Deficiency ◽

Acid Secretion ◽

Gastric Acid Secretion ◽

Gastric Acid ◽

Iron Homeostasis ◽

Transferrin Saturation ◽

Deficient Diet ◽

Direct Role ◽

Iron Deficient

Gastrins are peptide hormones important for gastric acid secretion and growth of the gastrointestinal mucosa. We have previously demonstrated that ferric ions bind to gastrins, that the gastrin-ferric ion complex interacts with the iron transport protein transferrin in vitro, and that circulating gastrin concentrations positively correlate with transferrin saturation in vivo. Here we report the effect of long-term dietary iron modification on gastrin-deficient (Gas−/−) and hypergastrinemic cholecystokinin receptor 2-deficient (Cck2r−/−) mice, both of which have reduced basal gastric acid secretion. Iron homeostasis in both strains appeared normal unless the animals were challenged by iron deficiency. When fed an iron-deficient diet, Gas−/− mice, but not Cck2r−/−mice, developed severe anemia. In iron-deficient Gas−/−mice, massive splenomegaly was also apparent with an increased number of splenic megakaryocytes accompanied by thrombocytosis. The expression of the mRNA encoding the iron-regulatory peptide hepcidin, Hamp, was down-regulated in both Cck2r−/− and Gas−/−mice on a low-iron diet, but, interestingly, the reduction was greater in Cck2r−/− mice and smaller in Gas−/− mice than in the corresponding wild-type strains. These data suggest that gastrins play an important direct role, unrelated to their ability to stimulate acid secretion, in hematopoiesis under conditions of iron deficiency.

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Iron Deficiency in Pulmonary Arterial Hypertension: A Deep Dive into the Mechanisms

Cells ◽

10.3390/cells10020477 ◽

2021 ◽

Vol 10 (2) ◽

pp. 477

Author(s):

Marceau Quatredeniers ◽

Pedro Mendes-Ferreira ◽

Diana Santos-Ribeiro ◽

Morad K. Nakhleh ◽

Maria-Rosa Ghigna ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Iron Deficiency ◽

Arterial Hypertension ◽

Iron Homeostasis ◽

Pulmonary Arteries ◽

Right Heart Failure ◽

Deep Dive ◽

Iron Deficient ◽

Pulmonary Arterial ◽

Progressive Occlusion

Pulmonary arterial hypertension (PAH) is a severe cardiovascular disease that is caused by the progressive occlusion of the distal pulmonary arteries, eventually leading to right heart failure and death. Almost 40% of patients with PAH are iron deficient. Although widely studied, the mechanisms linking between PAH and iron deficiency remain unclear. Here we review the mechanisms regulating iron homeostasis and the preclinical and clinical data available on iron deficiency in PAH. Then we discuss the potential implications of iron deficiency on the development and management of PAH.

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Maternal iron deficiency perturbs embryonic cardiovascular development

10.1101/2020.08.03.230615 ◽

2020 ◽

Author(s):

Jacinta I. Kalisch-Smith ◽

Nikita Ved ◽

Dorota Szumska ◽

Jacob Munro ◽

Michael Troup ◽

...

Keyword(s):

Retinoic Acid ◽

Iron Deficiency ◽

Mouse Model ◽

Iron Deficiency Anaemia ◽

Human Populations ◽

Cardiovascular Development ◽

Deficiency Anaemia ◽

Iron Administration ◽

Iron Deficient ◽

Maternal Iron

AbstractCongenital heart disease (CHD) is the most common type of birth defect, with a global prevalence of 0.9% of live births1. Most research in the last 30 years has focused on finding genetic causes of CHD. However, despite the association of over 100 genes with CHD, mutations in these genes only explain ~30% of cases2. Many of the remaining cases of CHD are caused by in utero exposure to environmental factors3. Here we have identified a completely new environmental teratogen causing CHD: maternal iron deficiency. In humans, iron deficiency anaemia is a major global health problem. 38% of pregnant women worldwide are anaemic4, and at least half of these are due to iron deficiency, the most prevalent micronutrient deficiency. We describe a mouse model of maternal iron deficiency anaemia that causes severe cardiovascular defects in her offspring. We show that these defects likely arise from increased retinoic acid signalling in iron deficient embryos, probably due to reduced activity of the iron-dependent retinoic acid catabolic CYP26 enzymes. The defects can be prevented by maternal iron administration early in pregnancy, and are also greatly reduced in offspring of mothers deficient in both iron and the retinoic acid precursor vitamin A. Finally, one puzzling feature of many genetic forms of CHD in humans is the considerable variation in penetrance and severity of defects. We show that maternal iron deficiency acts as a significant modifier of heart and craniofacial phenotype in a mouse model of Down syndrome. Given the high incidence of maternal iron deficiency, peri-conceptional iron monitoring and supplementation could be a viable strategy to reduce the prevalence and severity of CHD in human populations worldwide.

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