Developmental iron deficiency dysregulates TET activity and DNA hydroxymethylation in the rat hippocampus and cerebellum

2022 ◽  
Author(s):  
Amanda K. Barks ◽  
Montana M. Beeson ◽  
Timothy C. Hallstrom ◽  
Michael K. Georgieff ◽  
Phu V. Tran
Keyword(s):  
Iron Deficiency ◽  
Neural Circuit ◽  
Epigenetic Modification ◽  
Rat Hippocampus ◽  
Dietary Iron ◽  
Deficient Diet ◽  
Dna Hydroxymethylation ◽  
Iron Treatment ◽  
Iron Deficient ◽  
Increased Risk

Iron deficiency (ID) during neurodevelopment is associated with lasting cognitive and socioemotional deficits, and increased risk for neuropsychiatric disease throughout the lifespan. These neurophenotypical changes are underlain by gene dysregulation in the brain that outlasts the period of ID; however, the mechanisms by which ID establishes and maintains gene expression changes are incompletely understood. The epigenetic modification 5-hydroxymethylcytosine (5hmC), or DNA hydroxymethylation, is one candidate mechanism because of its dependence on iron-containing TET enzymes. The aim of the present study was to determine the effect of fetal-neonatal ID on regional brain TET activity, Tet expression, and 5hmC in the developing rat hippocampus and cerebellum, and to determine whether changes are reversible with dietary iron treatment. Timed pregnant Sprague-Dawley rats were fed iron deficient diet (ID; 4 mg/kg Fe) from gestational day (G)2 to generate iron deficient anemic (IDA) offspring. Control dams were fed iron sufficient diet (IS; 200 mg/kg Fe). At postnatal day (P)7, a subset of ID-fed litters was randomized to IS diet, generating treated IDA (TIDA) offspring. At P15, hippocampus and cerebellum were isolated for subsequent analysis. TET activity was quantified by ELISA from nuclear proteins. Expression of Tet1, Tet2, and Tet3 was quantified by qPCR from total RNA. Global %5hmC was quantified by ELISA from genomic DNA. ID increased DNA hydroxymethylation (p=0.0105), with a corresponding increase in TET activity (p<0.0001) and Tet3 expression (p<0.0001) in the P15 hippocampus. In contrast, ID reduced TET activity (p=0.0016) in the P15 cerebellum, with minimal effect on DNA hydroxymethylation. Neonatal dietary iron treatment resulted in partial normalization of these changes in both brain regions. These results demonstrate that the TET/DNA hydroxymethylation system is disrupted by developmental ID in a brain region-specific manner. Differential regional disruption of this epigenetic system may contribute to the lasting neural circuit dysfunction and neurobehavioral dysfunction associated with developmental ID.

Dietary iron-deficient anemia induces a variety of metabolic changes and even apoptosis in rat liver: a DNA microarray study

2010 ◽  
Vol 42 (2) ◽  
pp. 149-156 ◽  
Author(s):  
Asuka Kamei ◽  
Yuki Watanabe ◽  
Tomoko Ishijima ◽  
Mariko Uehara ◽  
Soichi Arai ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Iron Deficiency ◽  
Dna Microarray ◽  
Global Analysis ◽  
Control Diet ◽  
Diet Group ◽  
Iron Level ◽  
Dietary Iron ◽  
Deficient Diet ◽  
Iron Deficient

Anemia can be induced by dietary iron deficiency, as well as by hemorrhagia. It may also be associated with changes in lipid metabolism. However, no global analysis detailing the consequences of iron deficiency in the liver has yet been conducted. Since the liver is a metabolically important organ and also a major iron-storing organ, we performed a comprehensive transcriptome analysis to determine the effects of iron deficiency on hepatic gene expression. Four-week-old rats were fed an iron-deficient diet, ∼3 ppm iron, ad libitum for 16 days. These rats were compared with similar rats pair-fed a control diet with a normal iron level, 48 ppm iron. The 16-day iron-deficient diet apparently induced anemia. On day 17, the rats were killed under anesthesia, and their livers were dissected for DNA microarray analysis. We identified 600 upregulated and 500 downregulated probe sets that characterized the iron-deficient diet group. In the upregulated probe sets, genes involved in cholesterol, amino acid, and glucose metabolism were significantly enriched, while genes related to lipid metabolism were significantly enriched in the downregulated probe sets. We also found that genes for caspases 3 and 12, which mediate endoplasmic reticulum (ER)-specific apoptosis, were upregulated in the iron-deficient group. Combined, these results suggest that iron deficiency exerts various influences, not only on nutrient metabolism but also on apoptosis, as a consequence of ER stress in the liver.

Ceruloplasmin Is Essential for the Mobilization of Tissue Iron Stores.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3581-3581
Author(s):  
Seth Rivera ◽  
Miguel Lopez ◽  
Dina Farshidi ◽  
Victoria Gabayan ◽  
Tomas Ganz
Keyword(s):  
Iron Deficiency ◽  
Serum Iron ◽  
Iron Homeostasis ◽  
Extracellular Fluid ◽  
Deficiency Anemia ◽  
Dietary Iron ◽  
Deficient Diet ◽  
Iron Stores ◽  
High Iron ◽  
Iron Deficient

Abstract In extracellular fluid, iron is in the ferric (oxidized form) but the intracellular form is ferrous iron (reduced). The outflow of iron from cells is dependent on oxidase activity that converts ferrous to ferric iron. Iron-absorbing enterocytes possess a unique iron oxidase, hephaestin. It is presumed that the circulating hephaestin paralog ceruloplasmin fulfils this role in hepatocytes and macrophages. The DiSnA mouse lacks ceruloplasmin. We hypothesized that iron homeostasis in this mouse would be unusually dependent on dietary iron because the mouse would not be able to mobilize iron from tissue stores in hepatocytes and macrophages. We fed 4-week-old DiSnA and wildtype (WT) mice a high iron (1%) diet for 4 weeks to load tissue stores. We then switched them to an iron-deficient diet and analyzed them weekly to measure iron and hemoglobin concentrations. Even on the high iron diet, DiSnA mice had lower serum iron concentrations than WT control (32.9±17.9 vs. 53.5±17.6 μM, p=0.05) but after two weeks on the iron deficient diet, the DiSnA mice had almost undetectable serum iron (4.2±1.8 μM) whereas the WT controls had only declined slightly (43.2±9.6 μM, p&lt;0.001). Iron saturation followed a similar trend. Neither WT nor DiSnA mice were anemic at baseline (Hgb = 13.9±0.3 and 13.9±1.1 g/dL, respectively; p=0.994) but by the end of two weeks, the DiSnA mice had developed anemia whereas the WT mice had not (Hgb = 10.4±0.5 vs. 12.6±0.5 g/dL; p&lt;0.001). The difference in hemoglobin concentrations persisted to the 6-week timepoint (Hgb = 8.4±0.5 vs. 12.6±1.4; p&lt;0.001). After 6-weeks on a low iron diet, iron was still present in livers and spleens of both groups. Ceruloplasmin is essential for the mobilization of iron stores to protect against iron deficiency anemia in response to periods of dietary iron deficiency.

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&lt;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 The Treatment of Iron Deficiency Anemia

Blood ◽  
1955 ◽  
Vol 10 (6) ◽  
pp. 567-581 ◽  
Author(s):  
DANIEL H. COLEMAN ◽  
ALEXANDER R. STEVENS ◽  
CLEMENT A. FINCH
Keyword(s):  
Iron Deficiency ◽  
Gastrointestinal Symptoms ◽  
The Body ◽  
Deficiency Anemia ◽  
Deficient Diet ◽  
Significant Group ◽  
Body Iron ◽  
Iron Stores ◽  
Iron Deficient ◽  
Full Complement

Abstract In the normal individual the amount of iron absorbed and lost from the body each day is exceedingly small. There are certain periods during life when body iron requirements are increased; the most important of these is infancy. Here, existing iron stores are rapidly depleted, and a deficient diet can soon produce iron deficiency. Once a full complement of body iron has been accrued, the adult is independent of iron intake and becomes iron deficient only through blood loss. In the production of iron deficiency, iron stores are exhausted before anemia appears. If any question in diagnosis from usual laboratory tests exists, the direct. examination of marrow for hemosiderin will establish the diagnosis. It is of obvious importance to confirm the diagnosis by specific therapy and to determine the cause of the iron depletion. Response to oral iron is highly predictable and failure of response usually in dictates a mistaken diagnosis. In a small but significant group of patients, either unable to take iron because of gastrointestinal symptoms, unable to absorb iron, or in need of iron reserves, parenteral administration of iron has distinct advantages. The saccharated oxide of iron is an effective preparation for this purpose.

scholarly journals Adverse Outcome Prediction of Iron Deficiency in Patients with Acute Coronary Syndrome

Biomolecules ◽  
2018 ◽  
Vol 8 (3) ◽  
pp. 60 ◽  
Author(s):  
Tanja Zeller ◽  
Christoph Waldeyer ◽  
Francisco Ojeda ◽  
Renate Schnabel ◽  
Sarina Schäfer ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Acute Coronary Syndrome ◽  
Iron Deficiency ◽  
Cardiovascular Mortality ◽  
Adverse Outcome ◽  
Smoking Status ◽  
Coronary Syndrome ◽  
Iron Deficient ◽  
Increased Risk

Acute myocardial infarction remains a leading cause of morbidity and mortality. While iron deficient heart failure patients are at increased risk of future cardiovascular events and see improvement with intravenous supplementation, the clinical relevance of iron deficiency in acute coronary syndrome remains unclear. We aimed to evaluate the prognostic value of iron deficiency in the acute coronary syndrome (ACS). Levels of ferritin, iron, and transferrin were measured at baseline in 836 patients with ACS. A total of 29.1% was categorized as iron deficient. The prevalence of iron deficiency was clearly higher in women (42.8%), and in patients with anemia (42.5%). During a median follow-up of 4.0 years, 111 subjects (13.3%) experienced non-fatal myocardial infarction (MI) and cardiovascular mortality as combined endpoint. Iron deficiency strongly predicted non-fatal MI and cardiovascular mortality with a hazard ratio (HR) of 1.52 (95% confidence interval (CI) 1.03-2.26; p = 0.037) adjusted for age, sex, hypertension, smoking status, diabetes, hyperlipidemia, body-mass-index (BMI) This association remained significant (HR 1.73 (95% CI 1.07–2.81; p = 0.026)) after an additional adjustment for surrogates of cardiac function and heart failure severity (N-terminal pro B-type natriuretic peptide, NT-proBNP), for the size of myocardial necrosis (troponin), and for anemia (hemoglobin). Survival analyses for cardiovascular mortality and MI provided further evidence for the prognostic relevance of iron deficiency (HR 1.50 (95% CI 1.02–2.20)). Our data showed that iron deficiency is strongly associated with adverse outcome in acute coronary syndrome.

Identification of differentially expressed genes in response to dietary iron deprivation in rat duodenum

2005 ◽  
Vol 288 (5) ◽  
pp. G964-G971 ◽  
Author(s):  
James F. Collins ◽  
Christina A. Franck ◽  
Kris V. Kowdley ◽  
Fayez K. Ghishan
Keyword(s):  
Iron Deficiency ◽  
Real Time ◽  
Real Time Pcr ◽  
Iron Transport ◽  
Dietary Iron ◽  
Cancer Resistance ◽  
Novel Genes ◽  
Copper Absorption ◽  
Iron Deprivation ◽  
Iron Deficient

We sought to identify novel genes involved in intestinal iron absorption by inducing iron deficiency in rats during postnatal development from the suckling period through adulthood. We then performed comparative gene chip analyses (RAE230A and RAE230B chips; Affymetrix) with cRNA derived from duodenal mucosa. Real-time PCR was used to confirm changes in gene expression. Genes encoding the apical iron transport-related proteins [ divalent metal transporter 1 (DMT1) and duodenal cytochrome b] were strongly induced at all ages studied, whereas increases in mRNA encoding the basolateral proteins iron-regulated gene 1 and hephaestin were observed only by real-time PCR. In addition, transferrin receptor 1 and heme oxygenase 1 were induced. We also identified induction of novel genes not previously associated with intestinal iron transport. The Menkes copper ATPase (ATP7a) and metallothionein were strongly induced at all ages studied, suggesting increased copper absorption by enterocytes during iron deficiency. We also found significantly increased liver copper levels in 7- to 12-wk-old iron-deficient rats. Also upregulated at most ages examined were the sodium-dependent vitamin C transporter, tripartite motif protein 27, aquaporin 4, lipocalin-interacting membrane receptor, and the breast cancer-resistance protein (ABCG2). Some genes also showed decreased expression with iron deprivation, including several membrane transporters, metabolic enzymes, and genes involved in the oxidative stress response. We speculate that dietary iron deprivation leads to increased intestinal copper absorption via DMT1 on the brush-border membrane and the Menkes copper ATPase on the basolateral membrane. These findings may thus explain copper loading in the iron-deficient state. We also demonstrate that many other novel genes may be differentially regulated in the setting of iron deprivation.

The Mask Mutation Identifies TMPRSS6 as an Essential Suppressor of Hepcidin Gene Expression, Required for Normal Uptake of Dietary Iron.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3-3 ◽  
Author(s):  
Ernest Beutler ◽  
Pauline Lee ◽  
Terri Gelbart ◽  
Xin Du ◽  
Bruce Beutler
Keyword(s):  
Iron Deficiency ◽  
Serine Protease ◽  
Positional Cloning ◽  
Negative Regulator ◽  
Mrna Levels ◽  
Dietary Iron ◽  
Iron Deficient ◽  
Total Body ◽  
Hepcidin Gene ◽  
Hepcidin Mrna

Abstract Hepcidin, the central negative regulator of iron absorption and iron release from macrophages, is upregulated by iron. Mutations in hemojuvelin, Hfe, transferrin receptor 2, and SMAD4 are known to prevent upregulation. Additionally, the bone morphogenetic proteins (BMPs), and the inflammatory cytokines IL-1 and IL-6 stimulate hepcidin gene activation. Downregulation of hepcidin is effected by anemia and hypoxia, but nothing is known of the mechanism through which this occurs. Here we describe the recessive ENU-induced phenotype Mask, so called because affected homozygotes developed regional alopecia in which truncal hair was shed while facial hair was retained. The Mask phenotype was found to be a manifestation of iron deficiency, and was eliminated by correcting the iron deficiency. When fed an iron deficient diet, mutant mice absorbed less iron than controls, as measured by total body 59Fe counting. After reaching a plateau total body counts stabilized, indicating that blood loss did not play a role in the iron deficiency. The level of liver hepcidin mRNA of iron deficient mice is normally greatly decreased; in contrast, the Mask mouse had high liver hepcidin mRNA levels. By positional cloning, we were able to ascribe the Mask phenotype to a splicing error in the Tmprss6 gene, which encodes a membrane-bound serine protease of previously unknown function. The mutation truncates the protein, eliminating the serine protease domain. Transfecting HepG2 cells to express the wildtype TMPRSS6 protein decreased baseline hepcidin reporter activity and almost entirely blunted the hepcidin inducing effect of IL-6, IL-1, hemojuvelin, and the BMPs. A construct encoding the Mask truncation mutant had diminished activity. Thus, TMPRSS6 powerfully down-regulates hepcidin gene transcription in the baseline state and prevents its upregulation by all known stimulators. TMPRSS6 is a non-redundant component of a hepcidin suppression pathway that exerts dominant effect over all known hepcidin inducing pathways, and is required for normal absorption of dietary iron.

scholarly journals An Analysis of the Etiology of Anemia and Iron Deficiency in Young Women of Low Socioeconomic Status in Bangalore, India

2007 ◽  
Vol 28 (3) ◽  
pp. 328-336 ◽  
Author(s):  
Prashanth Thankachan ◽  
Sumithra Muthayya ◽  
Thomas Walczyk ◽  
Anura V. Kurpad ◽  
Richard F. Hurrell
Keyword(s):  
Socioeconomic Status ◽  
Iron Deficiency ◽  
Dietary Intake ◽  
Serum Ferritin ◽  
Young Women ◽  
Low Socioeconomic Status ◽  
Dietary Iron ◽  
Low Socioeconomic ◽  
Blood Hemoglobin ◽  
Iron Deficient

Background Anemia and iron deficiency are significant public health problems in India, particularly among women and children. Recent figures suggest that nearly 50% of young Indian women are anemic. Objectives Few studies have comprehensively assessed etiologic factors contributing to anemia and iron deficiency in India. Hence, this study assessed the relative importance of various factors contributing to these problems in young women of low socioeconomic status in Bangalore, India. Methods A random sample of 100 nonpregnant, nonlactating women 18 to 35 years of age, selected from among 511 women living in a poor urban settlement, participated in this study. Data were obtained on demography, socioeconomic status, anthropometry, three-day dietary intake, blood hemoglobin, hemoglobinopathies, serum ferritin, serum C-reactive protein, and stool parasites. Results The prevalence rates of anemia and iron deficiency were 39% and 62%, respectively; 95% of the anemic women were iron deficient. The mean dietary iron intake was 9.5 mg per day, predominantly from the consumption of cereals, pulses, and vegetables (77%). The estimated bioavailability of nonheme iron in this diet was 2.8%. Dietary intakes were suboptimal for several nutrients. Blood hemoglobin was significantly correlated with dietary intake of fat, riboflavin, milk and yogurt, and coffee. Serum ferritin was significantly correlated with intake of niacin, vitamin B12, and selenium. Parasitic infestation was low. Conclusions An inadequate intake of dietary iron, its poor bioavailability, and concurrent inadequate intake of dietary micronutrients appear to be the primary factors responsible for the high prevalence of anemia and iron deficiency in this population.

scholarly journals How I treat anemia in pregnancy: iron, cobalamin, and folate

Blood ◽  
2017 ◽  
Vol 129 (8) ◽  
pp. 940-949 ◽  
Author(s):  
Maureen M. Achebe ◽  
Anat Gafter-Gvili
Keyword(s):  
Iron Deficiency ◽  
First Trimester ◽  
Cobalamin Deficiency ◽  
Iron Treatment ◽  
Iron Deficient ◽  
Iv Iron ◽  
Anemia In Pregnancy ◽  
Surgery Rates ◽  
Global Health Problem ◽  
In Pregnancy

AbstractAnemia of pregnancy, an important risk factor for fetal and maternal morbidity, is considered a global health problem, affecting almost 50% of pregnant women. In this article, diagnosis and management of iron, cobalamin, and folate deficiencies, the most frequent causes of anemia in pregnancy, are discussed. Three clinical cases are considered. Iron deficiency is the most common cause. Laboratory tests defining iron deficiency, the recognition of developmental delays and cognitive abnormalities in iron-deficient neonates, and literature addressing the efficacy and safety of IV iron in pregnancy are reviewed. An algorithm is proposed to help clinicians diagnose and treat iron deficiency, recommending oral iron in the first trimester and IV iron later. Association of folate deficiency with neural tube defects and impact of fortification programs are discussed. With increased obesity and bariatric surgery rates, prevalence of cobalamin deficiency in pregnancy is rising. Low maternal cobalamin may be associated with fetal growth retardation, fetal insulin resistance, and excess adiposity. The importance of treating cobalamin deficiency in pregnancy is considered. A case of malarial anemia emphasizes the complex relationship between iron deficiency, iron treatment, and malaria infection in endemic areas; the heightened impact of combined etiologies on anemia severity is highlighted.

scholarly journals Diurnal Rhythm rather than Dietary Iron Mediates Daily Hepcidin Variations

2013 ◽  
Vol 59 (3) ◽  
pp. 527-535 ◽  
Author(s):  
Charlotte CM Schaap ◽  
Jan CM Hendriks ◽  
Guus AM Kortman ◽  
Siem M Klaver ◽  
Joyce JC Kroot ◽  
...  
Keyword(s):  
Diurnal Rhythm ◽  
Mixed Model ◽  
Linear Mixed Model ◽  
Transferrin Saturation ◽  
Dietary Iron ◽  
Deficient Diet ◽  
Iron Deficient ◽  
Sampling Protocols ◽  
Baseline Values ◽  
The Mean

BACKGROUND The iron-regulating hormone hepcidin is a promising biomarker in the diagnosis of iron disorders. Concentrations of hepcidin have been shown to increase during the day in individuals who are following a regular diet. It is currently unknown whether these increases are determined by an innate rhythm or by other factors. We aimed to assess the effect of dietary iron on hepcidin concentrations during the day. METHODS Within a 7-day interval, 32 volunteers received an iron-deficient diet on 1 day and the same diet supplemented with 65 mg ferrous fumarate at 0815 and 1145 on another day. Blood was drawn to assess ferritin, hepcidin-25, and transferrin saturation (TS) throughout both days at 4 time points between 0800 (fasted) and 1600. A linear mixed model for repeated data was used to analyze the effect of iron intake on TS and hepcidin concentrations. RESULTS Baseline values of hepcidin at 0800 correlated significantly with ferritin (r = 0.61). During the day of an iron-deficient diet the mean TS was similar both in men and in women, whereas hepcidin increased. During the day with iron supplementation the mean TS was significantly higher both in men and in women, and the mean hepcidin was moderately but significantly higher in women (1.0 nmol/L, 95% CI, 0.2–1.8) but not in men (0.0 nmol/L, 95% CI, −0.8 to 0.8). CONCLUSIONS Our data demonstrate that ferritin sets the basal hepcidin concentrations and suggest that innate diurnal rhythm rather than dietary iron mediates the daily hepcidin variations. These findings will be useful for optimizing sampling protocols and will facilitate the interpretation of hepcidin as an iron biomarker.

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