Exploring the association between haematological markers of iron and general movements in 4-month-old infants exposed to anaemia in-utero.

BACKGROUND: Iron is a vital micronutrient for brain development, influencing myelination, neurotransmitter balance, and the maturation of specific brain cells. Hence iron insufficiency in the foetal, neonatal and infancy period has the potential to influence the neuromotor development. AIMS: We aimed to describe haematological markers of iron at 4 months of age in infants exposed to prenatal anaemia and explore the association with their quality of general movements. STUDY DESIGN: Cross sectional study nested within the RAPIDIRON-KIDS trial. SUBJECTS: All infants whose mothers were part of RAPIDIRON-KIDS trial, were eligible to participate in this study when the infants were 4 months old. Children suffering from fever or acute illness on the day of assessment, or with a history of either surgery, or admission to hospital in the first month were excluded. OUTCOME MEASURES: Haematological markers of iron (Haemoglobin and Ferritin level) and quality of general movements in infants at 4 months of age. RESULTS: 120 infants were assessed with mean birth weight of 2685.5 g (±384.5) and median gestational age of 39 weeks [Q1, Q3:38,40]. There was no significant association between haemoglobin or ferritin levels with fidgety movements (p = 0.18 and p = 0.27, respectively). The combined effect of haemoglobin and ferritin estimates also did not show any significant association with the study groups (p = 0.21). CONCLUSION: A majority of infants still had low iron indices at 4 months of age and this was not associated with the quality of general movements. A prospective longitudinal study needs to be considered in infants exposed to prenatal anaemia rather than assessing the outcomes at a single time point.

Chromatin accessibility and H3K9me3 landscapes reveal long-term epigenetic effects of fetal-neonatal iron deficiency in rat hippocampus.

BACKGROUND: Iron deficiency (ID) during the fetal-neonatal period results in long-term neurodevelopmental impairments associated with pervasive hippocampal gene dysregulation. Prenatal choline supplementation partially normalizes these effects, suggesting an interaction between iron and choline in hippocampal transcriptome regulation. To understand the regulatory mechanisms, we investigated epigenetic marks of genes with altered chromatin accessibility (ATAC-seq) or poised to be repressed (H3K9me3 ChIP-seq) in iron-repleted adult rats having experienced fetal-neonatal ID exposure with or without prenatal choline supplementation. RESULTS: Fetal-neonatal ID was induced by limiting maternal iron intake from gestational day (G) 2 through postnatal day (P) 7. Half of the pregnant dams were given supplemental choline (5.0 g/kg) from G11-18. This resulted in 4 groups at P65 (Iron-sufficient [IS], Formerly Iron-deficient [FID], IS with choline [ISch], and FID with choline [FIDch]). Hippocampi were collected from P65 iron-repleted male offspring and analyzed for chromatin accessibility and H3K9me3 enrichment. 22% and 24% of differentially transcribed genes in FID- and FIDch-groups, respectively, exhibited significant differences in chromatin accessibility, whereas 1.7% and 13% exhibited significant differences in H3K9me3 enrichment. These changes mapped onto gene networks regulating synaptic plasticity, neuroinflammation, and reward circuits. Motif analysis of differentially modified genomic sites revealed significantly stronger choline effects than early-life ID and identified multiple epigenetically modified transcription factor binding sites. CONCLUSIONS: This study reveals genome-wide, stable epigenetic changes and epigenetically modifiable gene networks associated with specific chromatin marks in the hippocampus, and lays a foundation to further elucidate iron-dependent epigenetic mechanisms that underlie the long-term effects of fetal-neonatal ID, choline, and their interactions.

Identification of Genes Responding to Iron or Choline Treatment for Early-Life Iron Deficiency in the Male Rat Hippocampal Transcriptomes.

BACKGROUND: 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. OBJECTIVES: To identify acute and long-term changes in biological processes regulated by developmental ID and modifiable by choline. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Cellular Iron Deficiency Disrupts Thyroid Hormone Regulated Gene Expression in Developing Hippocampal Neurons.

BACKGROUND: Developing neurons have high thyroid hormone and iron requirements to support their metabolically demanding growth. Early-life iron and thyroid-hormone deficiencies are prevalent and often coexist, and each independently increases risk of permanently impaired neurobehavioral function in children. Early-life dietary iron deficiency reduces thyroid-hormone concentrations and impairs thyroid hormone-responsive gene expression in the neonatal rat brain, but it is unclear whether the effect is cell-intrinsic. OBJECTIVES: This study determined whether neuronal-specific iron deficiency alters thyroid hormone-regulated gene expression in developing neurons. METHODS: Iron deficiency was induced in primary mouse embryonic hippocampal neuron cultures with the iron chelator deferoxamine (DFO) beginning at 3 d in vitro (DIV). At 11DIV and 18DIV, thyroid hormone-regulated gene messenger ribonucleic acid (mRNA)concentrations indexing thyroid hormone homeostasis (Hairless, mu-crystallin, Type II deiodinase, solute carrier family member 1c1, and solute carrier family member 16a2) and neurodevelopment (neurogranin, Parvalbumin, and Krüppel-like factor 9) were quantified. To assess the effect of iron repletion, DFO was removed at 14DIV from a subset of DFO-treated cultures, and gene expression and adenosine 5'-triphosphate (ATP) concentrations were quantified at 21DIV. RESULTS: At 11DIV and 18DIV, neuronal iron deficiency decreased neurogranin, Parvalbumin, and mu-crystallin, and by 18DIV, solute carrier family member 16a2, solute carrier family member 1c1, Type II deiodinase, and Hairless were increased, suggesting cellular sensing of a functionally abnormal thyroid hormone state. Dimensionality reduction with Principal component analysis reveals that thyroid hormone homeostatic genes strongly correlate with and predict iron status. Iron repletion from 14-21DIV did not restore ATP concentration, and Principal component analysis suggests that, after iron repletion, cultures maintain a gene expression signature indicative of previous iron deficiency. CONCLUSIONS: These novel findings suggest there is an intracellular mechanism coordinating cellular iron/thyroid hormone activities. We speculate this is a part of the homeostatic response to acutely match neuronal energy production and growth signaling. However, the adaptation to iron deficiency may cause permanent deficits in thyroid hormone-dependent neurodevelopmental processes even after recovery from iron deficiency.

Prognostic Performance of Hematological and Serum Iron and Metabolite Indices for Detection of Early Iron Deficiency Induced Metabolic Brain Dysfunction in Infant Rhesus Monkeys.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Anemia, Iron Supplementation, and the Brain.

The developing brain is particularly vulnerable to extrinsic environmental events such as anemia and iron deficiency during periods of rapid development. Studies of infants with postnatal iron deficiency and iron deficiency anemia clearly demonstrated negative effects on short-term and long-term brain development and function. Randomized interventional trials studied erythropoiesis-stimulating agents and hemoglobin-based red blood cell transfusion thresholds to determine how they affect preterm infant neurodevelopment. Studies of red blood cell transfusion components are limited in preterm neonates. A biomarker strategy measuring brain iron status and health in the preanemic period is desirable to evaluate treatment options and brain response.

The Interaction between Psychological Stress and Iron Status on Early-Life Neurodevelopmental Outcomes.

This review presents evidence from animal and human studies demonstrating the possible connection and significant impact of poor iron status and psychological distress on neurocognitive development during pregnancy and the neonatal period, with implications for long-term cognition. Stress and iron deficiency are independently prevalent and thus are frequently comorbid. While iron deficiency and early-life stress independently contribute to long-term neurodevelopmental alterations, their combined effects remain underexplored. Psychological stress responses may engage similar pathways as infectious stress, which alters fundamental iron metabolism processes and cause functional tissue-level iron deficiency. Psychological stress, analogous to but to a lesser degree than infectious stress, activates the hypothalamic-pituitary-adrenocortical (HPA) axis and increases proinflammatory cytokines. Chronic or severe stress is associated with dysregulated HPA axis functioning and a proinflammatory state. This dysregulation may disrupt iron absorption and utilization, likely mediated by the IL-6 activation of hepcidin, a molecule that impedes iron absorption and redistributes total body iron. This narrative review highlights suggestive studies investigating the relationship between psychological stress and iron status and outlines hypothesized mechanistic pathways connecting psychological stress exposure and iron metabolism. We examine findings regarding the overlapping impacts of early stress exposure to iron deficiency and children's neurocognitive development. We propose that studying the influence of psychological stress on iron metabolism is crucial for comprehending neurocognitive development in children exposed to prenatal and early postnatal stressors and for children at risk of early iron insufficiency. We recommend future directions for dual-exposure studies exploring iron as a potential mediating pathway between early stress and offspring neurodevelopment, offering opportunities for targeted interventions.

Blood Levels of Environmental Heavy Metals are Associated with Poorer Iron Status in Ugandan Children: A Cross-Sectional Study.

BACKGROUND: 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). OBJECTIVES: We examined associations between iron status and blood concentrations of lead, manganese (Mn), cobalt (Co), and cadmium, both singly and as a mixture. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

The importance of iron deficiency in pregnancy on fetal, neonatal, and infant neurodevelopmental outcomes.

The role of iron in neurodevelopment has long been recognized, and the adverse effects of early-life iron deficiency on brain development and subsequent function across the lifespan continue to be a subject of research. A greater appreciation of the contribution of maternal preconceptional iron status and fetal iron accretion to offspring, postnatal iron status, and brain health across the lifespan has occurred over the past decade. This paradigm shift in thinking links two previously relatively siloed literatures: neonatal iron deficiency and postnatal iron deficiency. The understanding that iron accretion during the fetal period strongly influences postnatal iron balance has led to an appreciation of the importance and value of ensuring proper fetal iron loading. This article reviews the dynamics of fetal iron metabolism, the role of iron in the developing fetal brain, the short- and long-term neurobehavioral consequences of fetal iron underloading, and the potential mechanisms that account for the long-term effects of fetal/neonatal iron deficiency.

Maternal gestational iron status and infant haematological and neurodevelopmental outcomes.

Prevention of iron deficiency (ID), the most common micronutrient deficiency in infants and children, begins prenatally by ensuring adequate fetal loading. Adequate intrauterine iron status is crucial for normal fetal brain development, postnatal brain performance and prevention of early postnatal iron deficiency, particularly in infants fed exclusively human milk. Adequate fetal loading may be achieved in some cases through adequate maternal iron levels prior to pregnancy and oral iron supplementation during pregnancy. However, because so many women are iron-deficient leading up to pregnancy, coupled with the negative iron balance induced by pregnancy, a large number of women remain iron-deficient during pregnancy. More consistent iron-specific early screening and more effective iron delivery approaches are needed to solve this global problem.

Cellular Iron Deficiency Disrupts Thyroid Hormone Regulated Gene Expression in Developing Hippocampal Neurons.

Background: Developing neurons have high thyroid hormone and iron requirements to support their metabolism and growth. Early-life iron and thyroid hormone deficiencies are prevalent, often coexist, and increase the risk of permanently impaired neurobehavioral function in children. Early-life dietary iron deficiency reduces thyroid hormone levels and impairs thyroid hormone-responsive gene expression in the neonatal rat brain. Objective: This study determined whether neuronal-specific iron deficiency alters thyroid hormone-regulated gene expression in developing neurons. Methods: Iron deficiency was induced in primary mouse embryonic hippocampal neuron cultures with the iron chelator deferoxamine (DFO) beginning at 3 days in vitro (DIV). At 11DIV and 18DIV, mRNA levels for thyroid hormone-regulated genes indexing thyroid hormone homeostasis (Hr, Crym, Dio2, Slco1c1, Slc16a2) and neurodevelopment (Nrgn, Pvalb, Klf9) were quantified. To assess the effect of iron repletion, DFO was removed at 14DIV from a subset of DFO-treated cultures and gene expression and ATP levels were quantified at 21DIV. Results: At 11DIV and 18DIV, neuronal iron deficiency decreased Nrgn, Pvalb, and Crym, and by 18DIV, Slc16a2, Slco1c1, Dio2, and Hr were increased; collectively suggesting cellular sensing of a functionally abnormal thyroid hormone state. Dimensionality reduction with Principal Component Analysis (PCA) reveals that thyroid hormone homeostatic genes strongly correlate with and predict iron status (Tfr1 mRNA). Iron repletion from 14-21DIV restored neurodevelopmental genes, but not all thyroid hormone homeostatic genes, and ATP concentrations remained significantly altered. PCA clustering suggests that cultures replete with iron maintain a gene expression signature indicative of previous iron deficiency. Conclusions: These novel findings suggest there is an intracellular mechanism coordinating cellular iron/thyroid hormone activities. We speculate this is a part of homeostatic response to match neuronal energy production and growth signaling for these important metabolic regulators. However, iron deficiency may cause permanent deficits in thyroid hormone-dependent neurodevelopmental processes even after recovery from iron deficiency.

Development of Iron Status Measures during Youth: Associations with Sex, Neighborhood Socioeconomic Status, Cognitive Performance, and Brain Structure.

BACKGROUND: Iron is essential to brain function, and iron deficiency during youth may adversely impact neurodevelopment. Understanding the developmental time course of iron status and its association with neurocognitive functioning is important for identifying windows for intervention. OBJECTIVES: This study aimed to characterize developmental change in iron status and understand its association with cognitive performance and brain structure during adolescence using data from a large pediatric health network. METHODS: This study included a cross-sectional sample of 4899 participants (2178 males; aged 8-22 y at the time of participation, M [SD] = 14.24 [3.7]) who were recruited from the Children's Hospital of Philadelphia network. Prospectively collected research data were enriched with electronic medical record data that included hematological measures related to iron status, including serum hemoglobin, ferritin, and transferrin (33,015 total samples). At the time of participation, cognitive performance was assessed using the Penn Computerized Neurocognitive Battery, and brain white matter integrity was assessed using diffusion-weighted MRI in a subset of individuals. RESULTS: Developmental trajectories were characterized for all metrics and revealed that sex differences emerged after menarche such that females had reduced iron status relative to males [all R2partial > 0.008; all false discovery rates (FDRs) < 0.05]. Higher socioeconomic status was associated with higher hemoglobin concentrations throughout development (R2partial = 0.005; FDR < 0.001), and the association was greatest during adolescence. Higher hemoglobin concentrations were associated with better cognitive performance during adolescence (R2partial = 0.02; FDR < 0.001) and mediated the association between sex and cognition (mediation effect = -0.107; 95% CI: -0.191, -0.02). Higher hemoglobin concentration was also associated with greater brain white matter integrity in the neuroimaging subsample (R2partial = 0.06, FDR = 0.028). CONCLUSIONS: Iron status evolves during youth and is lowest in females and individuals of low socioeconomic status during adolescence. Diminished iron status during adolescence has consequences for neurocognition, suggesting that this critical period of neurodevelopment may be an important window for intervention that has the potential to reduce health disparities in at-risk populations.

Sex-Specific Effects of Early-Life Iron Deficiency and Prenatal Choline Treatment on Adult Rat Hippocampal Transcriptome.

BACKGROUND: Fetal-neonatal iron deficiency (ID) causes long-term neurocognitive and affective dysfunctions. Clinical and preclinical studies have shown that early-life ID produces sex-specific effects. However, little is known about the molecular mechanisms underlying these early-life ID-induced sex-specific effects on neural gene regulation. OBJECTIVE: To illustrate sex-specific transcriptome alterations in adult rat hippocampus induced by fetal-neonatal ID and prenatal choline treatment. METHODS: Pregnant rats were fed an iron-deficient (4 mg/kg Fe) or iron-sufficient (200 mg/kg Fe) diet from gestational day (G) 2 to postnatal day (P) 7 with or without choline supplementation (5 g/kg choline) from G11-18. Hippocampi were collected from P65 offspring of both sexes and analyzed for changes in gene expression. RESULTS: Both early-life ID and choline treatment induced transcriptional changes in adult female and male rat hippocampi. Both sexes showed ID-induced alterations in gene networks leading to enhanced neuroinflammation. In females, ID-induced changes indicated enhanced activity of oxidative phosphorylation and fatty acid metabolism, which were contrary to the ID effects in males. Prenatal choline supplementation induced the most robust changes in gene expression, particularly in iron-deficient animals where it partially rescued ID-induced dysregulation. Choline supplementation also altered hippocampal transcriptome in iron-sufficient rats with indications for both beneficial and adverse effects. CONCLUSIONS: This study provided unbiased global assessments of gene expression regulated by iron and choline in a sex-specific manner, with greater effects in female than male rats. Our new findings highlight potential sex-specific gene networks regulated by iron and choline for further investigation.

Reticulocyte Hemoglobin Equivalent has Comparable Predictive Accuracy as Conventional Serum Iron Indices for Predicting Iron Deficiency and Anemia in a Nonhuman Primate model of Infantile Iron Deficiency.

BACKGROUND: Infantile iron deficiency (ID) causes anemia and compromises neurodevelopment. Current screening relies on hemoglobin (Hgb) determination at 1 year of age, which lacks sensitivity and specificity for timely detection of infantile ID. Low reticulocyte Hgb equivalent (RET-He) indicates ID, but its predictive accuracy relative to conventional serum iron indices is unknown. OBJECTIVES: The objective was to compare diagnostic accuracies of iron indices, red blood cell (RBC) indices, and RET-He for predicting the risk of ID and IDA in a nonhuman primate model of infantile ID. METHODS: Serum iron, total iron binding capacity, unsaturated iron binding capacity, transferrin saturation (TSAT), Hgb, RET-He, and other RBC indices were determined at 2 wk and 2, 4, and 6 mo in breastfed male and female rhesus infants (N = 54). The diagnostic accuracies of RET-He, iron, and RBC indices for predicting the development of ID (TSAT < 20%) and IDA (Hgb < 10 g/dL + TSAT < 20%) were determined using t tests, area under the receiver operating characteristic curve (AUC) analysis, and multiple regression models. RESULTS: Twenty-three (42.6%) infants developed ID and 16 (29.6%) progressed to IDA. All 4 iron indices and RET-He, but not Hgb or RBC indices, predicted future risk of ID and IDA (P < 0.001). The predictive accuracy of RET-He (AUC = 0.78, SE = 0.07; P = 0.003) for IDA was comparable to that of the iron indices (AUC = 0.77-0.83, SE = 0.07; P ≤ 0.002). A RET-He threshold of 25.5 pg strongly correlated with TSAT < 20% and correctly predicted IDA in 10 of 16 infants (sensitivity: 62.5%) and falsely predicted possibility of IDA in only 4 of 38 unaffected infants (specificity: 89.5%). CONCLUSIONS: RET-He is a biomarker of impending ID/IDA in rhesus infants and can be used as a hematological parameter to screen for infantile ID.

Quantitative omics analyses of NCOA4 deficiency reveal an integral role of ferritinophagy in iron homeostasis of hippocampal neuronal HT22 cells.

Introduction: Neurons require iron to support their metabolism, growth, and differentiation, but are also susceptible to iron-induced oxidative stress and cytotoxicity. Ferritin, a cytosolic iron storage unit, mediates cellular adaptation to fluctuations in iron delivery. NCOA4 has been characterized as a selective autophagic cargo receptor facilitating the mobilization of intracellular iron from ferritin. This process named ferritinophagy results in the degradation of ferritin and the consequent release of iron into the cytosol. Methods: Here we demonstrate that NCOA4 is important for the adaptation of the HT22 mouse hippocampal neuronal cell line to cellular iron restriction. Additionally, we determined the pathophysiological implications of impaired ferritinophagy via functional analysis of the omics profile of HT22 cells deficient in NCOA4. Results: NCOA4 silencing impaired ferritin turnover and was cytotoxic when cells were restricted of iron. Quantitative proteomics identified IRP2 accumulation among the most prominent protein responses produced by NCOA4 depletion in HT22 cells, which is indicative of functional iron deficiency. Additionally, proteins of apoptotic signaling pathway were enriched by those responsive to NCOA4 deficiency. Transcriptome profiles of NCOA4 depletion revealed neuronal cell death, differentiation of neurons, and development of neurons as potential diseases and bio functions affected by impaired ferritinophagy, particularly, when iron was restricted. Discussion: These findings identify an integral role of NCOA4-mediated ferritinophagy in the maintenance of iron homeostasis by HT22 cells, and its potential implications in controlling genetic pathways of neurodevelopment and neurodegenerative diseases.

Iron supplementation and the risk of bronchopulmonary dysplasia in extremely low gestational age newborns.

BACKGROUND: The aim of this study was to determine the relationship between iron exposure and the development of bronchopulmonary dysplasia (BPD). METHODS: A secondary analysis of the PENUT Trial dataset was conducted. The primary outcome was BPD at 36 weeks gestational age and primary exposures of interest were cumulative iron exposures in the first 28 days and through 36 weeks' gestation. Descriptive statistics were calculated for study cohort characteristics with analysis adjusted for the factors used to stratify randomization. RESULTS: Of the 941 patients, 821 (87.2%) survived to BPD evaluation at 36 weeks, with 332 (40.4%) diagnosed with BPD. The median cohort gestational age was 26 weeks and birth weight 810 g. In the first 28 days, 76% of infants received enteral iron and 55% parenteral iron. The median supplemental cumulative enteral and parenteral iron intakes at 28 days were 58.5 and 3.1 mg/kg, respectively, and through 36 weeks' 235.8 and 3.56 mg/kg, respectively. We found lower volume of red blood cell transfusions in the first 28 days after birth and higher enteral iron exposure in the first 28 days after birth to be associated with lower rates of BPD. CONCLUSIONS: We find no support for an increased risk of BPD with iron supplementation. TRIAL REGISTRATION NUMBER: NCT01378273. https://clinicaltrials.gov/ct2/show/NCT01378273 IMPACT: Prior studies and biologic plausibility raise the possibility that iron administration could contribute to the pathophysiology of oxidant-induced lung injury and thus bronchopulmonary dysplasia in preterm infants. For 24-27-week premature infants, this study finds no association between total cumulative enteral iron supplementation at either 28-day or 36-week postmenstrual age and the risk for developing bronchopulmonary dysplasia.

Effect of Malaria and Malaria Chemoprevention Regimens in Pregnancy and Childhood on Neurodevelopmental and Behavioral Outcomes in Children at 12, 24, and 36 Months: A Randomized Clinical Trial.

BACKGROUND: Malaria in pregnancy has been associated with worse cognitive outcomes in children, but its association with behavioral outcomes and the effectiveness of malaria chemoprevention on child neurodevelopment are not well characterized. METHODS: To determine if more effective malaria chemoprevention in mothers and their children results in better neurodevelopment, 305 pregnant women were randomly assigned to 3 doses of sulfadoxine-pyrimethamine, 3 doses of dihydroartemisinin-piperaquine (DP), or monthly DP during pregnancy, and their 293 children were assigned to DP every 3 months or monthly DP from 2 to 24 months of age. Cognition, language, and motor function were assessed at 12, 24. and 36 months of age, and attention, memory, behavior, and executive function were assessed at 24 and 36 months of age. RESULTS: Children of mothers with versus without malaria in pregnancy had worse scores on cognitive, behavioral, and executive function outcomes at 24 months. Clinical malaria in children within the first 12 months was similarly associated with poorer scores in behavior and executive function at 24 months, language at 24 and 36 months, and motor function scores at 36 months. However, more effective malaria chemoprevention in the mothers and children was not associated with better outcomes. CONCLUSIONS: Malaria in pregnancy was associated with worse cognitive, behavioral, and executive function scores in affected children, but more effective malaria chemoprevention measures did not result in better outcomes. Malaria chemoprevention prior to and early in gestation and with even higher efficacy in mothers and children may be required to prevent neurodevelopmental impairment in children. Clinical Trials Registration. NCT02557425.

Effects of chronic Helicobacter pylori strain PMSS1 infection on whole brain and gastric iron homeostasis in male INS-GAS mice.

Iron deficiency, the most common micronutrient deficiency in humans, is associated with long-term deficits in cognition and memory if left untreated. Infection with the gastric pathogen Helicobacter pylori has been linked to iron deficiency anemia (IDA). The H. pylori virulence factor cytotoxin-associated gene A (cagA) is proposed to be especially pertinent in iron deficiency. Male INS-GAS/FVB mice were infected with the CagA+ strain pre-murine Sydney strain 1 (PMSS1) for 12-13 or 27-29 weeks to investigate the role of chronic H. pylori infection in iron deficiency and neurological sequelae. Mice at both timepoints demonstrated significantly elevated gastric histopathology scores and inflammatory cytokines compared to sham-dosed controls. However, only mice at 27-29 weeks post infection had changes in hematological parameters, with significantly decreased erythrocyte count, hematocrit, serum hemoglobin, and increased serum total iron binding capacity. Gastric transcription of iron-regulatory genes Hamp and Bmp4 were significantly downregulated at both timepoints. In the brain, iron-dependent myelingergic and synaptic markers were significantly downregulated at 27-29 weeks. These results indicated that long-term infection of the CagA + PMSS1 strain of H. pylori in this study caused anemia, altered gastric iron homeostasis, and neurological changes similar to those reported in other rodent H. pylori CagA- strain infection models.

Early life nutrition and brain development: breakthroughs, challenges and new horizons.

The role of early life nutrition's impact on relevant health outcomes across the lifespan laid the foundation for the field titled the developmental origins of health and disease. Studies in this area initially concentrated on nutrition and the risk of adverse cardio-metabolic and cancer outcomes. More recently the role of nutrition in early brain development and the subsequent influence of later mental health has become more evident. Scientific breakthroughs have elucidated two mechanisms behind long-term nutrient effects on the brain, including the existence of critical periods for certain nutrients during brain development and nutrient-driven epigenetic modifications of chromatin. While multiple nutrients and nutritional conditions have the potential to modify brain development, iron can serve as a paradigm to understand both mechanisms. New horizons in nutritional medicine include leveraging the mechanistic knowledge of nutrient-brain interactions to propose novel nutritional approaches that protect the developing brain through better timing of nutrient delivery and potential reversal of negative epigenetic marks. The main challenge in the field is detecting whether a change in nutritional status truly affects the brain's development and performance in human subjects. To that end, a strong case can be made to develop and utilise bioindicators of a nutrient's effect on the developing brain instead of relying exclusively on biomarkers of the nutrient's status.

Tandem mass tag proteomic and untargeted metabolomic profiling reveals altered serum and CSF biochemical datasets in iron deficient monkeys.

The effects of early-life iron deficiency anemia (IDA) extend past the blood and include both short- and long-term adverse effects on many tissues including the brain. Prior to IDA, iron deficiency (ID) can cause similar tissue effects, but a sensitive biomarker of iron-dependent brain health is lacking. To determine serum and CSF biomarkers of ID-induced metabolic dysfunction we performed proteomic and metabolomic analysis of serum and CSF at 4- and 6- months from a nonhuman primate model of infantile IDA. LC/MS/MS analyses identified a total of 227 metabolites and 205 proteins in serum. In CSF, we measured 210 metabolites and 1,560 proteins. Data were either processed from a Q-Exactive (Thermo Scientific, Waltham, MA) through Progenesis QI with accurate mass and retention time comparisons to a proprietary small molecule database and Metlin or with raw files imported directly from a Fusion Orbitrap (Thermo Scientific, Waltham, MA) through Sequest in Proteome Discoverer 2.4.0.305 (Thermo Scientific, Waltham, MA) with peptide matches through the latest Rhesus Macaque HMDB database. Metabolite and protein identifiers, p-values, and q-values were utilized for molecular pathway analysis with Ingenuity Pathways Analysis (IPA). We applied multiway distance weighted discrimination (DWD) to identify a weighted sum of the features (proteins or metabolites) that distinguish ID from IS at 4-months (pre-anemic period) and 6-months of age (anemic).