Iron Deficiency in Infancy is Associated with Altered Neural Correlates of Recognition Memory at 10 Years

Congdon, Eliza; Westerlund, Alissa; Algarı́n, Cecilia; Peirano, Patricio; Gregas, Matthew; Lozoff, Betsy; Nelson, Charles A.

doi:10.1016/j.jpeds.2011.12.011

Cited by 132 publications

(114 citation statements)

References 27 publications

(28 reference statements)

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“…These cells are located between the maternal and fetal blood spaces in the labyrinth zone, and express other transporters important for placental nutrient uptake. Decreased in utero iron uptake because of maternal iron deficiency anemia is a common global health problem, and is thought to result in a variety of longterm consequences for the offspring, including cognitive defects (Carter et al, 2010;Congdon et al, 2012). We found that the ZFP36L3-deficient pups contained ∼30% less iron than their WT littermates, a finding confirmed in a second study that compared littermates.…”

Section: Discussionsupporting

confidence: 70%

Deficiency of the placenta- and yolk sac-specific tristetraprolin family member ZFP36L3 identifies likely mRNA targets and an unexpected link to placental iron metabolism

et al. 2016

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The ZFP36L3 protein is a rodent-specific, placenta-and yolk sacspecific member of the tristetraprolin (TTP) family of CCCH tandem zinc finger proteins. These proteins bind to AU-rich elements in target mRNAs, and promote their deadenylation and decay. We addressed the hypotheses that the absence of ZFP36L3 would result in the accumulation of target transcripts in placenta and/or yolk sac, and that some of these would be important for female reproductive physiology and overall fecundity. Mice deficient in ZFP36L3 exhibited decreased neonatal survival rates, but no apparent morphological changes in the placenta or surviving offspring. We found Zfp36l3 to be paternally imprinted, with profound parent-of-origin effects on gene expression. The protein was highly expressed in the syncytiotrophoblast cells of the labyrinth layer of the placenta, and the epithelial cells of the yolk sac. RNA-Seq of placental mRNA from Zfp36l3 knockout (KO) mice revealed many significantly upregulated transcripts, whereas there were few changes in KO yolk sacs. Many of the upregulated placental transcripts exhibited decreased decay rates in differentiated trophoblast stem cells derived from KO blastocysts. Several dozen transcripts were deemed high probability targets of ZFP36L3; these include proteins known to be involved in trophoblast and placenta physiology. Type 1 transferrin receptor mRNA was unexpectedly decreased in KO placentas, despite an increase in its stability in KO stem cells. This receptor is crucial for placental iron uptake, and its decrease was accompanied by decreased iron stores in the KO fetus, suggesting that this intrauterine deficiency might have deleterious consequences in later life.

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Section: Discussionsupporting

confidence: 70%

Deficiency of the placenta- and yolk sac-specific tristetraprolin family member ZFP36L3 identifies likely mRNA targets and an unexpected link to placental iron metabolism

et al. 2016

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“…However, the data in Matak et al (6), in combination with other studies, create a biological basis for understanding the relationship between body iron status and neurocognitive function in early childhood. In addition to this study, it has been shown that infants who have abnormally low serum ferritin concentrations, an indicator of severe iron deficiency, have defective auditory recognition memory and neurocognitive development (21,22). Low serum ferritin is often seen in infants born to severely anemic mothers (23).…”

mentioning

confidence: 63%

A role for iron deficiency in dopaminergic neurodegeneration

Yien

Paw

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Together, these data demonstrate that intestinal iron absorption via DMT-1 is critical for adequate levels of iron in breast milk and intestinal iron absorption from breast milk. Perinatal iron deficiency in neonates has been consistently associated with cognitive dysfunction in infants and young adults (34,35). Due to a lack of animal models of perinatal anemia, prior studies have been unable to determine if iron deficiency predisposes neonates to neuronal dysfunction.…”

Section: Neonatal Iron Stores Are Rapidly Depleted In the Absence Of mentioning

confidence: 99%

Maternal intestinal HIF-2α is necessary for sensing iron demands of lactation in mice

Ramakrishnan

Anderson

Martin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The mechanisms that are essential for the maintenance of nutrient status in breast milk are unclear. Our data demonstrate that the intestine via hypoxia-inducible factor (HIF)-2α is an essential regulatory mechanism for maintaining the quality of breast milk. During lactation, intestinal HIF-2α is highly increased, leading to an adaptive induction of apical and basolateral iron transport genes. Disruption of intestinal HIF-2α (but not HIF-1α) or the downstream target gene divalent metal transporter (DMT)-1 in lactating mothers did not alter systemic iron homeostasis in the mothers, but led to anemia, decreased growth, and truncal alopecia in pups which was restored following weaning. Moreover, pups born from mothers with a disruption of intestinal HIF-2α led to long-term cognitive defects. Cross-fostering experiments and micronutrient profiling of breast milk demonstrated that the defects observed were due to decreased maternal iron delivery via milk. Increasing intestinal iron absorption by activation of HIF-2α or parenteral administration of iron-dextran in HIF-2α knockout mothers ameliorated anemia and restored neonatal development and adult cognitive functions. The present work details the importance of breast milk iron in neonatal development and uncovers an unexpected molecular mechanism for the regulation of nutritional status of breast milk through intestinal HIF-2α.iron homeostasis | anemia | HIF-2α | pregnancy | lactation I ron is the most abundant trace element involved in numerous biological processes such as oxygen delivery, mitochondrial respiration, and metabolism. Under normal circumstances, dietary iron provides 1-3% of the systemic iron requirement, due to an efficient recycling of iron from senesced red blood cells (1). During conditions of high iron demand, iron homeostasis relies on intestinal iron absorption (2, 3). A major systemic regulator of intestinal iron absorption is the liver-derived peptide hormone hepcidin. Hepcidin expression is regulated by systemic iron levels and in turn can regulate the only known iron exporter ferroportin (FPN) (4). This adaptive mechanism is essential for systemic iron homeostasis as evidenced in patients with iron-related disorders exhibiting decreased hepcidin expression or function (5). Moreover, mouse models with disruption of hepcidin expression, intestine specific disruption of FPN, or mice with a specific mutation of FPN with decreased hepcidin binding results in robust iron-related disorders, detailing the importance of the hepcidin-FPN axis in iron homeostasis (6-8).During pregnancy, the systemic iron requirement increase by 10-fold to support placental and fetal growth (9). Fetal and neonatal iron deficiency results in decreased growth, immunological dysfunction, anemia, and irreversible cognitive defects (10). Iron supplementation is highly recommended to prevent iron deficiency anemia during pregnancy (11). The increase in iron demand during pregnancy is met by an adaptive decrease in maternal hepcidin levels leading to enhanced iron absorption...

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Iron Deficiency in Infancy is Associated with Altered Neural Correlates of Recognition Memory at 10 Years

Cited by 132 publications

References 27 publications

Deficiency of the placenta- and yolk sac-specific tristetraprolin family member ZFP36L3 identifies likely mRNA targets and an unexpected link to placental iron metabolism

Deficiency of the placenta- and yolk sac-specific tristetraprolin family member ZFP36L3 identifies likely mRNA targets and an unexpected link to placental iron metabolism

A role for iron deficiency in dopaminergic neurodegeneration

Maternal intestinal HIF-2α is necessary for sensing iron demands of lactation in mice

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