Quantitative Proteomic Analyses of Cerebrospinal Fluid Using iTRAQ in a Primate Model of Iron Deficiency Anemia

Patton, Stephanie M.; Coe, Christopher L.; Lubach, Gabriele R.; Connor, James R.

doi:10.1159/000341919

Cited by 29 publications

(20 citation statements)

References 140 publications

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“…There is a large literature describing the negative consequences of early-life iron deficiency on both infant and adult learning and memory in humans [3–5,43]. Data from a non-human primate model suggests that abnormally patterned neural connectivity from early in life likely contributes to these abnormalities [33]. Our study may provide some of the specifically hippocampal cellular mechanisms for these observations.…”

Section: Discussionmentioning

confidence: 66%

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Early-Life Iron Deficiency Anemia Alters the Development and Long-Term Expression of Parvalbumin and Perineuronal Nets in the Rat Hippocampus

et al. 2013

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Early-life iron deficiency anemia (IDA) alters the expression of critical genes involved in neuronal dendritic structural plasticity of the hippocampus, thus contributing to delayed maturation of electrophysiology, and learning and memory behavior in rats. Structural maturity in multiple cortical regions is characterized by the appearance of parvalbumin-positive (PV⁺) GABAergic interneurons and perineuronal nets (PNNs). Appearance of PV⁺ interneurons and PNNs can serve as cellular markers for the beginning and end of a critical developmental period, respectively. During this period, the system progresses from an immature yet highly plastic condition, to a more mature and efficient state that is however less flexible and may exhibit poorer potential for recovery from injury. To test if fetal-neonatal IDA alters parvalbumin (PV) mRNA expression, protein levels, and the number of PV⁺ interneurons and PNNs in the male rat hippocampus, pregnant dams were given an iron-deficient (ID) diet (3 mg iron/kg chow) from gestational day 2 to postnatal day (P) 7 and then placed on an iron-sufficient (IS) diet (198 mg/kg) for the remainder of the experiment. On this regimen, formerly ID animals become fully iron-replete by P56. Minimal levels of PV (mRNA and protein), PV⁺ interneurons, and PNNs were found in IS and ID P7 rats. By P15, and continuing through P30 and P65, ID rats had reduced PV mRNA expression and protein levels compared to IS controls. While there were no differences in the number of PV⁺ neurons at either P30 or P65, the percentage of PV⁺ cells surrounded by PNNs was slightly greater in ID rats as compared to IS controls. The lower levels of these acknowledged critical period biomarkers in the ID group are consistent with studies that demonstrate later maturation of the acutely ID hippocampus and lower plasticity in the adult formerly ID hippocampus. The findings provide additional potential cellular bases for previously described electrophysiologic and behavioral abnormalities found during and following early-life IDA.

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Section: Discussionmentioning

confidence: 66%

“…A recent study in formerly iron deficient anemic monkeys indicates that these long-term functional changes relate to developmental alterations in proteins that are important for establishing and maintaining normal neuronal connectivity [33]. …”

Section: Discussionmentioning

confidence: 99%

Early-Life Iron Deficiency Anemia Alters the Development and Long-Term Expression of Parvalbumin and Perineuronal Nets in the Rat Hippocampus

et al. 2013

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“…Failure to accumulate iron results in irreversible low iron levels in brain and associated motor, behavioral, and cognitive defects in adulthood, independent of improvement in peripheral hematological parameters in rodents and primates (56,57). Cognitive defects persisted in pups nursing from Hif-2α…”

Section: Discussionmentioning

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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“…A similar etiology of ID is also seen in human infants with rapid postnatal growth [24], particularly in those born with low iron stores [25]. Previous studies using this primate model of IDA have demonstrated altered CSF levels of several proteins using proteomic methods and abnormal levels of monoamine neurotransmitters (e.g., dopamine and norepinephrine) via HPLC analysis [26–28]. These changes in critical proteins may also be indexed by changes in CNS metabolism that would reflect a more generalized disturbance in brain function in IDA.…”

Section: Introductionmentioning

confidence: 88%

Metabolomic Analysis of Cerebrospinal Fluid Indicates Iron Deficiency Compromises Cerebral Energy Metabolism in the Infant Monkey

et al. 2012

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Iron deficiency anemia affects many pregnant women and young infants worldwide. The health impact is significant, given iron’s known role in many body functions, including oxidative and lipid metabolism, protein synthesis and brain neurochemistry. The following research determined if 1H NMR spectroscopy-based metabolomic analysis of cerebrospinal fluid (CSF) could detect the adverse influence of early life iron deficiency on the central nervous system. Using a controlled dietary model in 43 infant primates, distinct differences were found in spectra acquired at 600 MHz from the CSF of anemic monkeys. Three metabolite ratios, citrate/pyruvate, citrate/lactate and pyruvate/glutamine ratios, differed significantly in the iron deficient infant and then normalized following the consumption of dietary iron and improvement of clinical indices of anemia in the heme compartment. This distinctive metabolomic profile associated with anemia in the young infant indicates that CSF can be employed to track the neurological effects of iron deficiency and benefits of iron supplementation.

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Quantitative Proteomic Analyses of Cerebrospinal Fluid Using iTRAQ in a Primate Model of Iron Deficiency Anemia

Cited by 29 publications

References 140 publications

Early-Life Iron Deficiency Anemia Alters the Development and Long-Term Expression of Parvalbumin and Perineuronal Nets in the Rat Hippocampus

Early-Life Iron Deficiency Anemia Alters the Development and Long-Term Expression of Parvalbumin and Perineuronal Nets in the Rat Hippocampus

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

Metabolomic Analysis of Cerebrospinal Fluid Indicates Iron Deficiency Compromises Cerebral Energy Metabolism in the Infant Monkey

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