Iron Deficiency and Brain Development

doi:10.1016/j.spen.2006.08.004

Seminars in Pediatric Neurology

Volume 13, Issue 3, September 2006, Pages 158-165

https://doi.org/10.1016/j.spen.2006.08.004 Get rights and content

Iron deficiency (ID) is common in pregnant women and infants worldwide. Rodent models show that ID during gestation/lactation alters neurometabolism, neurotransmitters, myelination, and gene/protein profiles before and after iron repletion at weaning. Human infants with iron deficiency anemia test lower in cognitive, motor, social-emotional, and neurophysiologic development than comparison group infants. Iron therapy does not consistently improve developmental outcome, with long-term differences observed. Poorer outcome has also been shown in human and monkey infants with fetal/neonatal ID. Recent randomized trials of infant iron supplementation show benefits, indicating that adverse effects can be prevented and/or reversed with iron earlier in development or before ID becomes severe or chronic. This body of research emphasizes the importance of protecting the developing brain from ID.

Section snippets

Animal Models of Early Iron Deficiency

Animal models offer the possibility of studying effects of ID while controlling environmental conditions that so often complicate ID in the human. ID can also be experimentally induced in animal models at different stages of development, carefully matched to specific aspects of human brain development.⁶ Many important developing processes such as myelination, dendritogenesis, synaptogenesis, and neurotransmission are highly dependent on iron-containing enzymes and hemoproteins.⁷ ID disrupts

Iron Deficiency in Infants and Toddlers: Global Effects

Most studies on developmental/behavioral effects of ID focus on the infancy period of peak prevalence, which is 6 to 24 months. At least 16 studies around the world found poorer cognitive, motor, and/or social/emotional functioning in IDA infants, compared with those without.12, 36, 37 Of studies with reassessments after iron therapy, most reported persisting differences even after [ge]3 months of treatment, although improvements were dramatic in a few studies. There are 9 follow-up reports of

Summary and Conclusion

Rodent models provide convincing evidence that early ID alters metabolism and neurotransmission in major brain structures, such as the basal ganglia and hippocampus, and disrupts 1 brainwide process—myelination. New research also shows altered gene and protein profiles. For all these systems, differences are found before and after iron repletion when ID is induced during gestation and/or lactation (brain growth spurt). However, iron repletion at the equivalent of the human third trimester

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Cited by (513)

Identification of Genes Responding to Iron or Choline Treatment for Early-Life Iron Deficiency in the Male Rat Hippocampal Transcriptomes
2024, Journal of Nutrition
Developmental iron deficiency (ID) is associated with long-term cognitive and affective behavioral impairments in humans. Preclinical studies have shown that developmental ID has short- and long-term effects on gene regulation. Prenatal choline supplementation partially rescues early-life ID-induced cognitive deficits in adult male rats.
To identify acute and long-term changes in biological processes regulated by developmental ID and modifiable by choline.
This study compares the hippocampal transcriptomes of postnatal day (P) 15 iron-deficient (acute) and P65 formerly ID (persistent) rats with or without prenatal choline treatment. Pregnant rats were fed an ID (4 mg/kg Fe) or iron-sufficient (IS) (200 mg/kg Fe) diet from gestational day (G) 2 to P7 with or without choline supplementation (5 g/kg choline) from G11 to G18. Hippocampi were collected from P15 or P65 offspring and analyzed for gene expression by RNA sequencing.
Developmental ID-induced changes suggested modified activity of oxidative phosphorylation and fatty acid metabolism. Prenatal choline supplementation induced robust changes in gene expression, particularly in iron-deficient animals, where it partially mitigated the early-life ID-dysregulated genes. Choline supplementation also altered the hippocampal transcriptome in the IS rats, with indications for both beneficial and adverse effects.
This study provided global assessments of gene expression regulated by iron and choline. Our new findings highlight genes responding to iron or choline treatments, including a potentially novel choline-regulated transporter (IPO7), with shared effects on neuroinflammation in the male rat hippocampus.
Prognostic Performance of Hematological and Serum Iron and Metabolite Indices for Detection of Early Iron Deficiency Induced Metabolic Brain Dysfunction in Infant Rhesus Monkeys
2024, Journal of Nutrition
The current pediatric practice of monitoring for infantile iron deficiency (ID) via hemoglobin (Hgb) screening at one y of age does not identify preanemic ID nor protect against later neurocognitive deficits.
To identify biomarkers of iron-related metabolic alterations in the serum and brain and determine the sensitivity of conventional iron and heme indices for predicting risk of brain metabolic dysfunction using a nonhuman primate model of infantile ID.
Simultaneous serum iron and RBC indices, and serum and cerebrospinal fluid (CSF) metabolomic profiles were determined in 20 rhesus infants, comparing iron sufficient (IS; N = 10) and ID (N = 10) infants at 2 and 4 mo of age.
Reticulocyte hemoglobin (RET-He) was lower at 2 wk in the ID group. Significant IS compared with ID differences in serum iron indices were present at 2 mo, but Hgb and RBC indices differed only at 4 mo (P < 0.05). Serum and CSF metabolomic profiles of the ID and IS groups differed at 2 and 4 mo (P < 0.05). Key metabolites, including homostachydrine and stachydrine (4-5-fold lower at 4 mo in ID group, P < 0.05), were altered in both serum and CSF. Iron indices and RET-He at 2 mo, but not Hgb or other RBC indices, were correlated with altered CSF metabolic profile at 4 mo and had comparable predictive accuracy (area under the receiver operating characteristic curve scores, 0.75–0.80).
Preanemic ID at 2 mo was associated with metabolic alterations in serum and CSF in infant monkeys. Among the RBC indices, only RET-He predicted the future risk of abnormal CSF metabolic profile with a predictive accuracy comparable to serum iron indices. The concordance of homostachydrine and stachydrine changes in serum and CSF indicates their potential use as early biomarkers of brain metabolic dysfunction in infantile ID.
Maternal selenium dietary supplementation alters sociability and reinforcement learning deficits induced by in utero exposure to maternal immune activation in mice
2024, Brain, Behavior, and Immunity
Maternal immune activation (MIA) during pregnancy increases the risk for the unborn foetus to develop neurodevelopmental conditions such as autism spectrum disorder and schizophrenia later in life. MIA mouse models recapitulate behavioural and biological phenotypes relevant to both conditions, and are valuable models to test novel treatment approaches. Selenium (Se) has potent anti-inflammatory properties suggesting it may be an effective prophylactic treatment against MIA. The aim of this study was to determine if Se supplementation during pregnancy can prevent adverse effects of MIA on offspring brain and behaviour in a mouse model.
Selenium was administered via drinking water (1.5 ppm) to pregnant dams from gestational day (GD) 9 to birth, and MIA was induced at GD17 using polyinosinic:polycytidylic acid (poly-I:C, 20 mg/kg via intraperitoneal injection). Foetal placenta and brain cytokine levels were assessed using a Luminex assay and brain elemental nutrients assessed using inductively coupled plasma- mass spectrometry. Adult offspring were behaviourally assessed using a reinforcement learning paradigm, the three-chamber sociability test and the open field test. MIA elevated placental IL-1β and IL-17, and Se supplementation successfully prevented this elevation. MIA caused an increase in foetal brain calcium, which was prevented by Se supplement. MIA caused in offspring a female-specific reduction in sociability, which was recovered by Se, and a male-specific reduction in social memory, which was not recovered by Se. Exposure to poly-I:C or selenium, but not both, reduced performance in the reinforcement learning task. Computational modelling indicated that this was predominantly due to increased exploratory behaviour, rather than reduced rate of learning the location of the food reward.
This study demonstrates that while Se may be beneficial in ameliorating sociability deficits caused by MIA, it may have negative effects in other behavioural domains. Caution in the use of Se supplementation during pregnancy is therefore warranted.
Blood Levels of Environmental Heavy Metals are Associated with Poorer Iron Status in Ugandan Children: A Cross-Sectional Study
2023, Journal of Nutrition
Iron deficiency (ID) and environmental exposure to metals frequently co-occur among Ugandan children, but little is known about their associations, although iron and other divalent metals share the same intestinal absorption transporter, divalent metal transporter 1 (DMT1).
We examined associations between iron status and blood concentrations of lead, manganese (Mn), cobalt (Co), and cadmium, both singly and as a mixture.
We used data on sociodemographic status, iron biomarkers, and blood concentrations of heavy metals collected from a cross-sectional survey of 100 children aged 6–59 mo in Kampala, Uganda. We compared blood concentrations of metals in ID with iron-sufficient children. We examined associations between a metal mixture and iron biomarkers using multiple linear regression and weighted quintile sum regression.
The median (interquartile range) blood Mn (μg/L) was higher in ID children defined by soluble transferrin receptor (sTfR) and ferritin (ID compared with iron-sufficient children): (sTfR [21.3 {15.1, 28.8}, 11.2 {8.6, 18.5}], ferritin [19.5 {15.0, 27.2}, 11.2 {8.8, 19.6}]; P < 0.001 for both). Similarly, the median (interquartile range) blood Co (μg/L) was higher in ID children by ferritin ([0.5 {0.4, 0.9}, 0.4 {0.3, 0.5}], P = 0.05). Based on the multiple linear regression results, higher blood Co and Mn were associated with poorer iron status (defined by all 4 iron indicators for Co and by sTfR for Mn). The weighted quintile sum regression result showed that higher blood concentrations of a metal mixture were associated with poorer iron status represented by sTfR, ferritin, and hepcidin, mainly driven by Co and Mn.
Our study findings suggest that poorer iron status is associated with overall heavy metal burden, predominantly Co and Mn, among Ugandan children. Further prospective studies should confirm our primary findings and investigate the combined effects of coexposures to neurotoxicants on the neurodevelopment of young children.
Convergent imaging-transcriptomic evidence for disturbed iron homeostasis in Gilles de la Tourette syndrome
2023, Neurobiology of Disease
Gilles de la Tourette syndrome (GTS) is a neuropsychiatric movement disorder with reported abnormalities in various neurotransmitter systems. Considering the integral role of iron in neurotransmitter synthesis and transport, it is hypothesized that iron exhibits a role in GTS pathophysiology. As a surrogate measure of brain iron, quantitative susceptibility mapping (QSM) was performed in 28 patients with GTS and 26 matched controls. Significant susceptibility reductions in the patients, consistent with reduced local iron content, were obtained in subcortical regions known to be implicated in GTS. Regression analysis revealed a significant negative association of tic scores and striatal susceptibility. To interrogate genetic mechanisms that may drive these reductions, spatially specific relationships between susceptibility and gene-expression patterns from the Allen Human Brain Atlas were assessed. Correlations in the striatum were enriched for excitatory, inhibitory, and modulatory neurochemical signaling mechanisms in the motor regions, mitochondrial processes driving ATP production and iron‑sulfur cluster biogenesis in the executive subdivision, and phosphorylation-related mechanisms affecting receptor expression and long-term potentiation in the limbic subdivision. This link between susceptibility reductions and normative transcriptional profiles suggests that disruptions in iron regulatory mechanisms are involved in GTS pathophysiology and may lead to pervasive abnormalities in mechanisms regulated by iron-containing enzymes.
Antibiotics augment the impact of iron deficiency on metabolism in a piglet model
2023, Journal of Nutritional Biochemistry
Infancy and childhood represent a high-risk period for developing iron deficiency (ID) and is a period of increased susceptibility to infectious disease. Antibiotic use is high in children from low-, middle-, and high-income countries, and thus we sought to determine the impact of antibiotics in the context of ID. In this study, a piglet model was used to assess the impact of ID and antibiotics on systemic metabolism. ID was induced by withholding a ferrous sulfate injection after birth to piglets in the ID group and providing an iron deficient diet upon weaning on postnatal day (PD) 25. Antibiotics (gentamicin and spectinomycin) were administered on PD34-36 to a set of control (Con*+Abx) and ID piglets (ID+Abx) after weaning. Blood was analyzed on PD30 (before antibiotic administration) and PD43 (7 days after antibiotic administration). All ID piglets exhibited growth faltering and had lower hemoglobin and hematocrit compared to control (Con) and Con*+Abx throughout. The metabolome of ID piglets at weaning and sacrifice exhibited elevated markers of oxidative stress, ketosis, and ureagenesis compared to Con. The impact of antibiotics on Con*+Abx piglets did not result in significant changes to the serum metabolome 7-days after treatment; however, the impact of antibiotics on ID+Abx piglets resulted in the same metabolic changes observed in ID piglets, but with a greater magnitude when compared to Con. These results suggest that antibiotic administration in the context of ID exacerbates the negative metabolic impacts of ID and may have long lasting impacts on development.

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: Supported in part by grants from NICHD (P01 HD39386, Brain and Behavior in Early Iron Deficiency, Betsy Lozoff, Principal Investigator, and R01 HD29421, Newborn Iron Deficiency, Michael Georgieff, Principal Investigator).

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Iron Deficiency and Brain Development

Section snippets

Animal Models of Early Iron Deficiency

Iron Deficiency in Infants and Toddlers: Global Effects

Summary and Conclusion

J Nutr

Am J Clin Nutr

J Nutr

Brain Behav Res

Behav Brain Res

J Nutr

J Nutr

J Nutr

J Nutr

Am J Clin Nutr

J Nutr

J Nutr

Am J Clin Nutr

J Pediatr

J Pediatr

Am J Clin Nutr

Am J Clin Nutr

Am J Clin Nutr

Pediatr Neurol

Early Hum Dev

Am J Clin Nutr

J Pediatr

J Pediatr

J Pediatr

J Pediatr

Am J Obstet Gynecol

J Pediatr

J Pediatr

Lancet

J Nutr

Lancet

Global Database on Child Growth and Malnutrition

Fourth Report on the World Nutrition Situation

Iron deficiency anaemia

Iron deficiency, prolonged bottle-feeding, and racial/ethnic disparities in young children

Arch Pediatr Adolesc Med

An integrative, multidisciplinary approach to the study of brain-behavior relations in the context of typical and atypical development

Dev Psychopathol

Iron dependent enzymes in the brain

Brain iron: Persistent deficiency following short-term iron deprivation in the young rat

Br J Haematol

Perinatal iron deficiency decreases cytochrome c oxidase (CytOx) activity in selected regions of neonatal rat brain

Pediatr Res

Long-lasting neural and behavioral effects of iron deficiency in infancy

Nutr Rev