Early Development of Parvalbumin-, Somatostatin-, and Cholecystokinin-Expressing Neurons in Rat Brain following Prenatal Immune Activation and Maternal Iron Deficiency

2016 ◽  
Vol 38 (5) ◽  
pp. 342-353 ◽  
Author(s):  
Patricia Boksa ◽  
Ying Zhang ◽  
Dominique Nouel ◽  
Alice Wong ◽  
Tak Pan Wong
Keyword(s):  
Iron Deficiency ◽  
Early Development ◽  
Immune Activation ◽  
Brain Regions ◽  
Neuron Density ◽  
Ventral Subiculum ◽  
Iron Deficient ◽  
Medial Pfc ◽  
Maternal Iron

Prenatal maternal infection and maternal iron deficiency during pregnancy are 2 early environmental insults associated with increased risk for schizophrenia in offspring. Substantial evidence suggests that abnormalities in inhibitory γ-aminobutyric acid (GABA) interneuron function, especially in the parvalbumin subtype of GABA interneuron, both developmentally and in adulthood, may contribute mechanistically to cognitive deficits and psychotic symptoms in schizophrenia. This study used a rat model to test whether prenatal immune activation with lipopolysaccharide (LPS; at gestation days, GD, 15 and 16) or maternal iron deficiency (from GD2 to postnatal day P7) or the combination of both insults alters major subtypes of GABAergic interneurons (parvalbumin, somatostatin, cholecystokinin) in brain regions relevant to schizophrenia (medial and dorsolateral prefrontal cortex [PFC], hippocampal CA1 and dentate gyrus, ventral subiculum) in offspring at P14 or P28. Prenatal LPS treatment significantly increased the density of parvalbumin-immunoreactive neurons at P14 in the medial PFC, dorsolateral PFC, and ventral subiculum of offspring born from iron-sufficient but not iron-deficient dams. Prenatal LPS also increased cholecystokinin neuron density in the medial PFC at P28, under both iron-sufficient and iron-deficient conditions. We observed a large increase in parvalbumin neuron density from P14 to P28 in the medial PFC and subiculum across all birth groups, that was not observed in other brain regions, and significant decreases in somatostatin neuron density from P14 to P28 in all brain regions examined across all birth groups, indicating differential developmental trajectories for parvalbumin and somatostatin neurons in various brain regions during this early postnatal period. Thus, it appears that the medial PFC and ventral subiculum, brain regions involved in circuitry modulating ventral tegmental dopamine and nucleus accumbens activities, may be regions vulnerable to effects of prenatal LPS on specific subpopulations of interneurons. It is known that the timing of maturation and expansion of parvalbumin neurons in early development provides threshold levels of inhibition that trigger critical periods for cortical plasticity, leading to long-term circuit consolidation. Thus, our finding of increased parvalbumin neuron density at early developmental times might suggest a mechanism by which an acute prenatal insult like LPS exposure could produce long-term changes in prefrontal cortical or subicular function.

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

Nutrients ◽  
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.

Maternal iron deficiency alters trophoblast differentiation and placental development in rat pregnancy

Endocrinology ◽  
2021 ◽  
Author(s):  
Hannah Roberts ◽  
Andrew G Woodman ◽  
Kelly J Baines ◽  
Mariyan J Jeyarajah ◽  
Stephane L Bourque ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Fetal Growth ◽  
Growth And Development ◽  
Iron Homeostasis ◽  
Junctional Zone ◽  
Altered Expression ◽  
Expression Of Genes ◽  
Iron Deficient ◽  
Increased Risk ◽  
Maternal Iron

Abstract Iron deficiency occurs when iron demands chronically exceed intake, and is prevalent in pregnant women. Iron deficiency during pregnancy poses major risks for the baby, including fetal growth restriction and long-term health complications. The placenta serves as the interface between a pregnant mother and her baby, and ensures adequate nutrient provisions for the fetus. Thus, maternal iron deficiency may impact fetal growth and development by altering placental function. We used a rat model of diet-induced iron deficiency to investigate changes in placental growth and development. Pregnant Sprague-Dawley rats were fed either a low-iron or iron-replete diet starting two weeks before mating. Compared to controls, both maternal and fetal hemoglobin were reduced in dams fed low-iron diets. Iron deficiency decreased fetal liver and body weight, but not brain, heart or kidney weight. Placental weight was increased in iron deficiency, due primarily to expansion of the placental junctional zone. The stimulatory effect of iron deficiency on junctional zone development was recapitulated in vitro, as exposure of rat trophoblast stem cells to the iron chelator deferoxamine increased differentiation toward junctional zone trophoblast subtypes. Gene expression analysis revealed 464 transcripts changed at least 1.5-fold (P<0.05) in placentas from iron-deficient dams, including altered expression of genes associated with oxygen transport and lipoprotein metabolism. Expression of genes associated with iron homeostasis was unchanged despite differences in levels of their encoded proteins. Our findings reveal robust changes in placentation during maternal iron deficiency, which could contribute to the increased risk of fetal distress in these pregnancies.

scholarly journals Long-lasting behavioural consequences of neonatal iron deficiency in high-risk children

2020 ◽  
Vol 79 (OCE2) ◽  
Author(s):  
Elaine McCarthy ◽  
Deirdre Murray ◽  
Louise Kenny ◽  
Jonathan Hourihane ◽  
Alan Irvine ◽  
...  
Keyword(s):  
High Risk ◽  
Iron Deficiency ◽  
Birth Cohort ◽  
Multiple Pregnancy ◽  
Cumulative Risk ◽  
Total Problem ◽  
Iron Deficient ◽  
Infant Birth ◽  
Neonatal Iron Deficiency

AbstractLittle consideration has been given to the long-term consequences of iron deficiency in new-born infants. Fetal iron accretion is compromised by multiple pregnancy complications including preterm birth, gestational diabetes mellitus and fetal growth restriction, while our work has identified increased risks from maternal lifestyle factors such as smoking and obesity for low iron stores at birth. Early-life events, including C-section delivery, also add to this cumulative risk of neonatal iron deficiency, predisposing infants to iron deficiency later in infancy and early childhood. This study aimed to investigate the effect of neonatal iron deficiency on neurological development up to 5 years of age in term-born participants of a maternal-infant birth cohort in Ireland. In the Cork BASELINE Birth Cohort, 697 maternal-infant dyads with prospectively collected lifestyle and clinical data from 15 weeks’ gestation had umbilical cord serum ferritin concentrations measured. Neurological assessments were performed at 2 (Bayley Scales of Infant Development and Child Behaviour Checklist [CBCL]) and 5 (Kaufman Brief Intelligence Test and CBCL) years of age. In the cohort, median [IQR] cord ferritin concentrations were 200.9 [139.0,265.8] μg/L; 7.5% had neonatal iron deficiency (< 76μg/L). Using the risk factors for neonatal iron deficiency that we previously identified (smoking, obesity, C-section delivery, SGA) in this cohort, as selection criteria, we conducted an a priori sensitivity analysis in 306 children. Of the 306 children identified as high-risk, 12.4% had neonatal iron deficiency. Those with neonatal iron deficiency had higher median [IQR] CBCL internal (9.0 [5.3,12.0] vs. 5.0 [3.0,10.0]), external (7.5 [4.0,14.8] vs. 5.0 [2.0,10.0]) and total problem (24.5 [15.3,40.8] vs. 16.0 [10.0,30.0], all P < 0.05) scores at 5 years compared to those without neonatal deficiency. This adverse effect was especially apparent in children of obese mothers (n = 85) who were iron deficient at birth, with a total problem score at 5 years of 42.0 [24.5,54.5] compared to 16.0 [8.8,29.3] in those not deficient (P = 0.008). Associations were robust to adjustment for confounding factors. No effect on cognition or intelligence at 2 or 5 years was observed in this cohort. This study has identified behavioural consequences of neonatal iron deficiency. Interventions targeting the fetal/neonatal period could, therefore, represent a key opportunity for prevention of iron deficiency and its associated long-term neurological consequences. A dual approach is required, comprising public health strategies targeting prevention, through improving nutrition and health in women, and the development of screening strategies for early detection of iron deficiency in new-borns.

scholarly journals Erythroferrone Modulates Iron Distribution for Fetal Erythropoiesis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 757-757
Author(s):  
Veena Sangkhae ◽  
Vivian Yu ◽  
Richard Coffey ◽  
Tomas Ganz ◽  
Elizabeta Nemeth
Keyword(s):  
Iron Deficiency ◽  
Iron Homeostasis ◽  
Minor Role ◽  
Iron Availability ◽  
Liver Iron ◽  
Iron Deficient ◽  
Embryo Liver ◽  
A Minor ◽  
Maternal Iron ◽  
Iron Concentrations

Abstract Erythroferrone (ERFE) is an erythroblast-derived regulator of iron metabolism, and its production increases during stress erythropoiesis. ERFE decreases expression of the iron-regulatory hormone hepcidin to enhance iron availability for erythropoiesis 1. Pregnancy requires a substantial increase in iron availability to sustain a dramatic increase in maternal RBC volume and support fetal development. Whether maternal or fetal ERFE plays a role in regulating iron homeostasis during pregnancy is unknown. In humans, maternal ERFE concentrations were elevated in anemic pregnancies at mid gestation and delivery 2. To define the role of ERFE during iron-replete or iron-deficient pregnancy, we utilized Erfe transgenic (ETg) 3 and Erfe knockout (EKO) 1 mice. Maternal iron status of ETg, WT and EKO mice was altered by placing animals on adequate iron (100ppm) or low iron (4ppm) diet 2 weeks prior to and throughout pregnancy. ETg and WT dams were mated with WT sires to generate ETg and WT embryos while EKO dams were mated with EKO sires to generate EKO embryos. Analysis was performed at embryonic day 18.5. To examine the effect of pregnancy on ERFE expression, we compared non-pregnant females to WT dams at E18.5. Serum ERFE was mildly elevated from 0.01 to 0.2 ng/mL in iron-replete dams, but substantially elevated from 0.01 to 3.1 ng/mL in iron-deficient dams, similarly to human pregnancy 2. We next assessed iron and hematological parameters in pregnant dams with different Erfe genotypes. Under iron-replete conditions, all three groups had similar serum hepcidin, serum iron and hemoglobin concentrations, but ETg dams had 3-fold higher liver iron than WT and EKO dams, presumably because they are mildly iron-overloaded before pregnancy. On iron-deficient diet, maternal hepcidin was decreased in all three genotypes but more so in ETg dams; however, all three Erfe genotypes had similarly depleted liver iron stores, hypoferremia and anemia. MCV was the only parameter that was decreased in EKO compared to WT dams under both iron conditions. Overall, maternal ERFE played a minor role in regulation of maternal erythropoiesis and iron homeostasis, with the lack of ERFE resulting in smaller RBCs but not anemia. Among embryos, we observed a significant effect of Erfe genotype on embryo hepcidin. ETg embryos had significantly lower liver hepcidin compared to WT embryos under both iron-replete and iron-deficient conditions. Conversely, Erfe KO embryos had higher hepcidin compared to WTs under iron-deficient conditions, indicating that embryo ERFE regulates embryo hepcidin during pregnancy. Under iron-replete conditions however, all three embryo genotypes had similar hematologic parameters, and embryo liver iron was dependent on maternal iron levels, with both ETg and WT embryos from ETg dams having increased liver iron concentrations, indicating that embryo ERFE does not regulate placental iron transfer. Under iron-deficient conditions, there was no difference between ETg and WT embryos in hematological or iron parameters, and both genotypes developed iron deficiency and anemia. However, Erfe KO embryos, which had elevated hepcidin, had maldistribution of iron and worse anemia. EKO embryo liver iron concentrations were 6-fold higher compared to WT iron-deficient embryos, whereas hemoglobin was significantly decreased compared to WT iron-deficient embryos. These findings indicate that under iron-limiting conditions, embryo ERFE is important for the suppression of embryo hepcidin to ensure iron redistribution for embryo erythropoiesis. In summary, during iron replete pregnancy, ERFE plays a minor role in maternal and fetal iron homeostasis and erythropoiesis. However, in response to iron-deficiency anemia during pregnancy, ERFE is important for the redistribution of iron within the embryo to support embryo erythropoiesis. 1Kautz L et al, Nat Genet, 2014 2Delaney K et al, Curr Dev Nutr, 2020 3Coffey R et al, Blood, 2020 Disclosures Ganz: Ambys: Consultancy; Sierra Oncology: Consultancy, Research Funding; Rockwell: Consultancy; Pharmacosmos: Consultancy; Ionis: Consultancy; Protagonist: Consultancy; Intrinsic LifeSciences: Consultancy; RallyBio: Consultancy; Silence Therapeutics: Consultancy; Silarus Pharma: Consultancy; Alnylam: Consultancy; American Regent: Consultancy; Disc Medicine: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenecaFibrogen: Consultancy; Global Blood Therapeutics: Consultancy; Gossamer Bio: Consultancy; Akebia: Consultancy, Honoraria. Nemeth: Silarus Pharma: Consultancy; Intrinsic LifeSciences: Consultancy; Protagonist: Consultancy; Vifor: Consultancy; Ionis: Consultancy.

scholarly journals Maternal iron deficiency perturbs embryonic cardiovascular development

2020 ◽  
Author(s):  
Jacinta I. Kalisch-Smith ◽  
Nikita Ved ◽  
Dorota Szumska ◽  
Jacob Munro ◽  
Michael Troup ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Iron Deficiency ◽  
Mouse Model ◽  
Iron Deficiency Anaemia ◽  
Human Populations ◽  
Cardiovascular Development ◽  
Deficiency Anaemia ◽  
Iron Administration ◽  
Iron Deficient ◽  
Maternal Iron

AbstractCongenital heart disease (CHD) is the most common type of birth defect, with a global prevalence of 0.9% of live births1. Most research in the last 30 years has focused on finding genetic causes of CHD. However, despite the association of over 100 genes with CHD, mutations in these genes only explain ~30% of cases2. Many of the remaining cases of CHD are caused by in utero exposure to environmental factors3. Here we have identified a completely new environmental teratogen causing CHD: maternal iron deficiency. In humans, iron deficiency anaemia is a major global health problem. 38% of pregnant women worldwide are anaemic4, and at least half of these are due to iron deficiency, the most prevalent micronutrient deficiency. We describe a mouse model of maternal iron deficiency anaemia that causes severe cardiovascular defects in her offspring. We show that these defects likely arise from increased retinoic acid signalling in iron deficient embryos, probably due to reduced activity of the iron-dependent retinoic acid catabolic CYP26 enzymes. The defects can be prevented by maternal iron administration early in pregnancy, and are also greatly reduced in offspring of mothers deficient in both iron and the retinoic acid precursor vitamin A. Finally, one puzzling feature of many genetic forms of CHD in humans is the considerable variation in penetrance and severity of defects. We show that maternal iron deficiency acts as a significant modifier of heart and craniofacial phenotype in a mouse model of Down syndrome. Given the high incidence of maternal iron deficiency, peri-conceptional iron monitoring and supplementation could be a viable strategy to reduce the prevalence and severity of CHD in human populations worldwide.

scholarly journals Iron-Dependent Mechanism of Neuronal Bdnf Suppression by Cellular Iron Deficiency

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1278-1278
Author(s):  
Phu Tran ◽  
Montana Beeson ◽  
Michael Georgieff
Keyword(s):  
Iron Deficiency ◽  
Neuronal Cell ◽  
Epigenetic Modifications ◽  
Similar Degree ◽  
Bdnf Expression ◽  
In Vivo Models ◽  
Iron Deficient

Abstract Objectives Iron deficiency (ID) during neural development is associated with long-term neurocognitive dysfunction. In rodent models, the cognitive deficit is associated with reduced hippocampal brain-derived neurotrophic factor (Bdnf) expression in adulthood despite early iron treatment. Since a previous study suggested a role of epigenetic modifications at the Bdnf locus, we assessed whether an iron-dependent signaling pathway from ID → HIF1α → JARID1B (Fe-containing histone demethylase) → Bdnf is responsible for Bdnf suppression in iron-deficient neurons. The objective is to determine the effect of ID on the HIF1α/JARID1B/Bdnf pathway in vitro and in vivo. Methods A hippocampal neuronal cell line HT-22 (n = 3/group) was used to assess cellular changes following deferoxamine (10 μM) induced-ID. In parallel, timed pregnant Sprague-Dawley rats were fed a purified iron deficient diet (ID, 4 mg Fe/kg) from gestational day (G)2 to through postnatal day (P)7 to induce a similar degree of neuronal ID. At P7, nursing dams where switched to a purified-iron sufficient diet (IS, 200 mg Fe/kg). Control dams were fed IS diet. Hippocampi (n = 6/group) were collected from P15 ID and IS rats. Enrichment of HIF1α, JARID1B, USF1, histone H3 methylation at the Bdnf promoter in both models was determined using ChIP-qPCR. Results were analyzed using t-test for pairwise comparison and α ≤ 0.05. Results ID increased nuclear HIF1α in HT-22 cells (P = 0.03), suggesting less hydroxylated-HIF1α due to reduced Fe-dependent prolyl hydroxylase (PHD) activity. Increased nuclear HIF1α led to increased binding and transactivation at the VEGF (positive control, P = 0.03)) and JARID1B promoters (P = 0.04), which in turns reduced Bdnf expression in HT-22 cells (P = 0.02). Similar effects were observed in iron-deficient P15 hippocampus. Conclusions This is the first evidence that ID directly regulates long-term neural gene expression through the cellular PHD/HIF1α/JARID1B pathway to induce epigenetic modifications both in vitro and in vivo models. Funding Sources 1R01NS099178.

Functional iron deficiency markers are absent during pregnancy despite evidence of low iron stores

2019 ◽  
Vol 56 (4) ◽  
pp. 450-456 ◽  
Author(s):  
Martijn WHJ Demmers ◽  
Marijke Niens ◽  
Gerrie van der Haar ◽  
Hester J van der Zaag-Loonen ◽  
Johannes JML Hoffmann ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Pregnant Women ◽  
Univariate Analysis ◽  
Mean Cell Volume ◽  
Functional Iron Deficiency ◽  
Iron Stores ◽  
Iron Deficient ◽  
Haemoglobin Content ◽  
Maternal Iron ◽  
Reticulocyte Haemoglobin Content

Introduction Functional iron deficiency parameters predict iron-restricted erythropoiesis more precisely than ferritin. Ferritin and erythropoiesis can be affected by inflammation and hormonal alterations. We hypothesize that the association between low ferritin concentrations and iron-restricted erythropoiesis is not comparable between pregnant and non-pregnant women. Materials and methods Pregnant women ( n = 926) were included at week 12 of gestation. Ferritin concentrations, %hypochromic erythrocytes (%HYPO), %microcytic erythrocytes (%MICRO), reticulocyte haemoglobin content (MCHr), mean cell volume (MCV) and mean cell haemoglobin (MCH) were analysed. Data were compared with non-pregnant women ( n = 1302). Results Functional iron deficiency parameters (%HYPO, %MICRO, MCHr) were present in, respectively, 3.9%, 14.3% and 2.3% off all pregnant women. Univariate analysis of low ferritin (<20 μg/L) showed significant differences between non-pregnant versus pregnant women; %HYPO (10.92% vs. 0.92%), increased %MICRO (4.33% vs. 1.00%) and decreased MCHr (24.9 pg vs. 29.5 pg), respectively. In the logistic regression analysis, MCHr, %MICRO and MCV were independently associated with low ferritin concentrations in pregnant women, while %HYPO and %MICRO were independently associated variables in non-pregnant women with low ferritin concentrations. Discussion Functional iron deficiency is significantly less frequent in pregnant women compared with iron-deficient non-pregnant women. During pregnancy, iron metabolism might be differentially regulated for optimal fetal growth and development despite low maternal iron stores.

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

Nutrients ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 1191 ◽  
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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