Perinatal Brain Iron Deficiency Predisposes the Rat Hippocampus to Long-term Damage following Hypoxic-ischemic Insult • 1566

Early-life iron deficiency (ID) causes long-term neurocognitive impairments and gene dysregulation that can be partially mitigated by prenatal choline supplementation. The long-term gene dysregulation is hypothesized to underlie cognitive dysfunction. However, mechanisms by which iron and choline mediate long-term gene dysregulation remain unknown. In the present study, using a well-established rat model of fetal-neonatal ID, we demonstrated that ID downregulated hippocampal expression of the gene encoding JmjC-ARID domain-containing protein 1B (JARID1B), an iron-dependent histone H3K4 demethylase, associated with a higher histone deacetylase 1 (HDAC1) enrichment and a lower enrichment of acetylated histone H3K9 (H3K9ac) and phosphorylated cAMP response element-binding protein (pCREB). Likewise, ID reduced transcriptional capacity of the gene encoding brain-derived neurotrophic factor (BDNF), a target of JARID1B, associated with repressive histone modifications such as lower H3K9ac and pCREB enrichments at the Bdnf promoters in the adult rat hippocampus. Prenatal choline supplementation did not prevent the ID-induced chromatin modifications at these loci but induced long-lasting repressive chromatin modifications in the iron-sufficient adult rats. Collectively, these findings demonstrated that the iron-dependent epigenetic mechanism mediated by JARID1B accounted for long-term Bdnf dysregulation by early-life ID. Choline supplementation utilized a separate mechanism to rescue the effect of ID on neural gene regulation. The negative epigenetic effects of choline supplementation in the iron-sufficient rat hippocampus necessitate additional investigations prior to its use as an adjunctive therapeutic agent.

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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

Developmental Neuroscience ◽

10.1159/000354178 ◽

2013 ◽

Vol 35 (5) ◽

pp. 427-436 ◽

Cited By ~ 23

Author(s):

Liam S.N. Callahan ◽

Kathryn A. Thibert ◽

Jane D. Wobken ◽

Michael K. Georgieff

Keyword(s):

Iron Deficiency ◽

Iron Deficiency Anemia ◽

Early Life ◽

Rat Hippocampus ◽

Deficiency Anemia ◽

Perineuronal Nets

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Dysregulation of Neuronal Genes by Fetal-Neonatal Iron Deficiency Anemia Is Associated with Altered DNA Methylation in the Rat Hippocampus

Nutrients ◽

10.3390/nu11051191 ◽

2019 ◽

Vol 11 (5) ◽

pp. 1191 ◽

Cited By ~ 5

Author(s):

Yu-Chin Lien ◽

David E Condon ◽

Michael K Georgieff ◽

Rebecca A Simmons ◽

Phu V Tran

Keyword(s):

Dna Methylation ◽

Iron Deficiency ◽

Early Life ◽

Rat Hippocampus ◽

Epigenetic Mechanism ◽

Deficiency Anemia ◽

Gene Dysregulation ◽

Iron Deficient ◽

Neuronal Genes

Early-life iron deficiency results in long-term abnormalities in cognitive function and affective behavior in adulthood. In preclinical models, these effects have been associated with long-term dysregulation of key neuronal genes. While limited evidence suggests histone methylation as an epigenetic mechanism underlying gene dysregulation, the role of DNA methylation remains unknown. To determine whether DNA methylation is a potential mechanism by which early-life iron deficiency induces gene dysregulation, we performed whole genome bisulfite sequencing to identify loci with altered DNA methylation in the postnatal day (P) 15 iron-deficient (ID) rat hippocampus, a time point at which the highest level of hippocampal iron deficiency is concurrent with peak iron demand for axonal and dendritic growth. We identified 229 differentially methylated loci and they were mapped within 108 genes. Among them, 63 and 45 genes showed significantly increased and decreased DNA methylation in the P15 ID hippocampus, respectively. To establish a correlation between differentially methylated loci and gene dysregulation, the methylome data were compared to our published P15 hippocampal transcriptome. Both datasets showed alteration of similar functional networks regulating nervous system development and cell-to-cell signaling that are critical for learning and behavior. Collectively, the present findings support a role for DNA methylation in neural gene dysregulation following early-life iron deficiency.

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Long-Term Effectiveness of Oral Ferric Maltol vs Intravenous Ferric Carboxymaltose for the Treatment of Iron-Deficiency Anemia in Patients With Inflammatory Bowel Disease: A Randomized Controlled Noninferiority Trial

Inflammatory Bowel Diseases ◽

10.1093/ibd/izab073 ◽

2021 ◽

Author(s):

Stefanie Howaldt ◽

Eugeni Domènech ◽

Nicholas Martinez ◽

Carsten Schmidt ◽

Bernd Bokemeyer

Keyword(s):

Inflammatory Bowel Disease ◽

Iron Deficiency ◽

Iron Deficiency Anemia ◽

Primary Endpoint ◽

Bowel Disease ◽

Deficiency Anemia ◽

Ferric Carboxymaltose ◽

Inflammatory Bowel ◽

Intent To Treat

Abstract Background Iron-deficiency anemia is common in inflammatory bowel disease, requiring oral or intravenous iron replacement therapy. Treatment with standard oral irons is limited by poor absorption and gastrointestinal toxicity. Ferric maltol is an oral iron designed for improved absorption and tolerability. Methods In this open-label, phase 3b trial (EudraCT 2015-002496-26 and NCT02680756), adults with nonseverely active inflammatory bowel disease and iron-deficiency anemia (hemoglobin, 8.0-11.0/12.0 g/dL [women/men]; ferritin, <30 ng/mL/<100 ng/mL with transferrin saturation <20%) were randomized to oral ferric maltol 30 mg twice daily or intravenous ferric carboxymaltose given according to each center’s standard practice. The primary endpoint was a hemoglobin responder rate (≥2 g/dL increase or normalization) at week 12, with a 20% noninferiority limit in the intent-to-treat and per-protocol populations. Results For the intent-to-treat (ferric maltol, n = 125/ferric carboxymaltose, n = 125) and per-protocol (n = 78/88) analyses, week 12 responder rates were 67% and 68%, respectively, for ferric maltol vs 84% and 85%, respectively, for ferric carboxymaltose. As the confidence intervals crossed the noninferiority margin, the primary endpoint was not met. Mean hemoglobin increases at weeks 12, 24, and 52 were 2.5 vs 3.0 g/dL, 2.9 vs 2.8 g/dL, and 2.7 vs 2.8 g/dL with ferric maltol vs ferric carboxymaltose. Treatment-emergent adverse events occurred in 59% and 36% of patients, respectively, and resulted in treatment discontinuation in 10% and 3% of patients, respectively. Conclusions Ferric maltol achieved clinically relevant increases in hemoglobin but did not show noninferiority vs ferric carboxymaltose at week 12. Both treatments had comparable long-term effectiveness for hemoglobin and ferritin over 52 weeks and were well tolerated.

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Wnt pathway regulation by long-term moderate exercise in rat hippocampus

Brain Research ◽

10.1016/j.brainres.2013.10.048 ◽

2014 ◽

Vol 1543 ◽

pp. 38-48 ◽

Cited By ~ 28

Author(s):

S. Bayod ◽

I. Menella ◽

S. Sanchez-Roige ◽

J.F. Lalanza ◽

R.M. Escorihuela ◽

...

Keyword(s):

Wnt Pathway ◽

Rat Hippocampus ◽

Moderate Exercise ◽

Pathway Regulation

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Ferric Citrate Dosing in Iron Deficiency Anemia in Nondialysis-Dependent Chronic Kidney Disease

American Journal of Nephrology ◽

10.1159/000516012 ◽

2021 ◽

pp. 1-10

Author(s):

Pablo E. Pergola ◽

Diogo Belo ◽

Paul Crawford ◽

Moustafa Moustafa ◽

Wenli Luo ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Iron Deficiency ◽

Iron Deficiency Anemia ◽

Ferric Citrate ◽

Deficiency Anemia ◽

Open Label ◽

Starting Dose ◽

Dosing Regimens

Introduction: Ferric citrate (FC) is indicated as an oral iron replacement for iron deficiency anemia in adult patients with chronic kidney disease (CKD) not on dialysis. The recommended starting dose is one 1-g tablet three times daily (TID). This study investigated long-term efficacy and safety of different FC dosing regimens for treating anemia in nondialysis-dependent CKD (NDD-CKD). Methods: In this phase 4, randomized, open-label, multicenter study, patients with anemia with NDD-CKD (estimated glomerular filtration rate, ≥20 mL/min and <60 mL/min) were randomized 1:1 to one FC tablet (1-g equivalent to 210 mg ferric iron) TID (3 g/day) or 2 tablets twice daily (BID; 4 g/day). At week 12, dosage was increased to 2 tablets TID (6 g/day) or 3 tablets BID (6 g/day) in patients whose hemoglobin (Hb) levels increased <0.5 g/dL or were <10 g/dL. Primary endpoint was mean change in Hb from baseline to week 24. Results: Of 484 patients screened, 206 were randomized and 205 received FC. Mean (standard deviation) changes from baseline in Hb at week 24 were 0.77 (0.84) g/dL with FC TID 3 g/day and 0.70 (0.98) g/dL with FC BID 4 g/day. Discussion/Conclusions: FC administered BID and TID for 48 weeks was safe and effective for treating anemia in this population, supporting potentially increased dosing flexibility.

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Maternal Iron Status in Pregnancy and Child Health Outcomes after Birth: A Systematic Review and Meta-Analysis

Nutrients ◽

10.3390/nu13072221 ◽

2021 ◽

Vol 13 (7) ◽

pp. 2221

Author(s):

Hugo G. Quezada-Pinedo ◽

Florian Cassel ◽

Liesbeth Duijts ◽

Martina U. Muckenthaler ◽

Max Gassmann ◽

...

Keyword(s):

Systematic Review ◽

Iron Deficiency ◽

Child Health ◽

Methodological Quality ◽

Iron Status ◽

Meta Analysis ◽

Child Health Outcomes ◽

Maternal Iron ◽

In Pregnancy

In pregnancy, iron deficiency and iron overload increase the risk for adverse pregnancy outcomes, but the effects of maternal iron status on long-term child health are poorly understood. The aim of the study was to systematically review and analyze the literature on maternal iron status in pregnancy and long-term outcomes in the offspring after birth. We report a systematic review on maternal iron status during pregnancy in relation to child health outcomes after birth, from database inception until 21 January 2021, with methodological quality rating (Newcastle-Ottawa tool) and random-effect meta-analysis. (PROSPERO, CRD42020162202). The search identified 8139 studies, of which 44 were included, describing 12,7849 mother–child pairs. Heterogeneity amongst the studies was strong. Methodological quality was predominantly moderate to high. Iron status was measured usually late in pregnancy. The majority of studies compared categories based on maternal ferritin, however, definitions of iron deficiency differed across studies. The follow-up period was predominantly limited to infancy. Fifteen studies reported outcomes on child iron status or hemoglobin, 20 on neurodevelopmental outcomes, and the remainder on a variety of other outcomes. In half of the studies, low maternal iron status or iron deficiency was associated with adverse outcomes in children. Meta-analyses showed an association of maternal ferritin with child soluble transferrin receptor concentrations, though child ferritin, transferrin saturation, or hemoglobin values showed no consistent association. Studies on maternal iron status above normal, or iron excess, suggest deleterious effects on infant growth, cognition, and childhood Type 1 diabetes. Maternal iron status in pregnancy was not consistently associated with child iron status after birth. The very heterogeneous set of studies suggests detrimental effects of iron deficiency, and possibly also of overload, on other outcomes including child neurodevelopment. Studies are needed to determine clinically meaningful definitions of iron deficiency and overload in pregnancy.

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