Dataset Information

Early-Life Neuronal-Specific Iron Deficiency Alters the Adult Mouse Hippocampal Transcriptome.

ABSTRACT:

Background

Iron deficiency (ID) compromises the developing nervous system, including the hippocampus, resulting in later-life deficits despite iron repletion. The iron-dependent molecular changes driving these lasting deficits, and the effect of early iron repletion, are incompletely understood. Previous studies have utilized dietary models of maternal-fetal ID anemia (IDA) to address these questions; however, concurrent anemia prevents delineation of the specific role of iron.

Objective

The aim of the study was to isolate the effects of developmental ID on adult hippocampal gene expression and to determine if iron repletion reverses these effects in a mouse model of nonanemic hippocampal neuronal ID.

Methods

Nonanemic, hippocampus-specific neuronal ID was generated by using a Tet-OFF dominant negative transferrin receptor (DN-TFR1) mouse model that impairs cellular iron uptake. Hippocampal ID was reversed with doxycycline at postnatal day 21 (P21) in a subset of mice to create 2 experimental groups, chronically iron-deficient and formerly iron-deficient mice, which were compared with their respective doxycycline-treated and untreated iron-sufficient controls. RNA from adult male hippocampi was sequenced. Paired-end reads were analyzed for differential expression. Differentially expressed genes were analyzed in Ingenuity Pathway Analysis.

Results

A total of 346 genes were differentially expressed in adult, chronically iron-deficient hippocampi compared with controls. ID dysregulated genes in critical neurodevelopmental pathways, including axonal guidance, CDK5, Ephrin receptor, Rac, and Neurotrophin/Trk signaling. Iron repletion at P21 normalized adult hippocampal expression of 198 genes; however, genes involved in cAMP response element-binding protein (CREB) signaling, neurocognition, and neurologic disease remained dysregulated in adulthood.

Conclusions

Chronic ID during development, independent of anemia, alters the adult mouse hippocampal transcriptome. Restoring iron status during a known critical period of hippocampal neurodevelopment incompletely normalized these changes, suggesting a need for additional studies to identify the most effective timeline for iron therapy, and adjunctive treatments that can fully restore ID-induced molecular changes, particularly in human populations in whom chronic ID is endemic.

SUBMITTER: Barks A

PROVIDER: S-EPMC6258792 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundEarly-life iron deficiency (ID) impairs hippocampal energy production. Whether there are changes in glucose transporter (GLUT) expression is not known.ObjectiveThe aim of this study was to investigate whether early-life ID and the treatment iron dose alter brain regional GLUT expression in adult rats and mice.MethodsIn Study 1, ID was induced in male and female Sprague Dawley rat pups by feeding dams a 3-mg/kg iron diet during gestation and the first postnatal week, followed by treatment using low-iron [3-10 mg/kg; formerly iron-deficient (FID)-10 group], standard-iron (40-mg/kg; FID-40 group), or high-iron (400-mg/kg; FID-400 group) diets until weaning. The control group received the 40 mg/kg iron diet. GLUT1, GLUT3, hypoxia-inducible factor (HIF)-1α, and prolyl-hydroxylase-2 (PHD2) mRNA and protein expression in the cerebral cortex, hippocampus, striatum, cerebellum, and hypothalamus were determined at adulthood. In Study 2, the role of hippocampal ID in GLUT expression was examined by comparing the Glut1, Glut3, Hif1α, and Phd2 mRNA expression in adult male and female wild-type (WT) and nonanemic hippocampal iron-deficient and iron-replete dominant negative transferrin receptor 1 (DNTfR1-/-) transgenic mice.ResultsIn Study 1, Glut1, Glut3, and Hif1α mRNA, and GLUT1 55-kDa protein expression was upregulated 20-33% in the hippocampus of the FID-10 group but not the FID-40 group, relative to the control group. Hippocampal Glut1 mRNA (-39%) and GLUT1 protein (-30%) expression was suppressed in the FID-400 group, relative to the control group. Glut1 and Glut3 mRNA expression was not altered in the other brain regions in the 3 FID groups. In Study 2, hippocampal Glut1 (+14%) and Hif1α (+147%) expression was upregulated in the iron-deficient DNTfR1-/- mice, but not in the iron-replete DNTfR1-/- mice, relative to the WT mice (P < 0.05, all).ConclusionsEarly-life ID is associated with altered hippocampal GLUT1 expression in adult rodents. The mouse study suggests that tissue ID is potentially responsible.

Project description:Background: Iron deficiency is the most prevalent micronutrient deficiency worldwide, affecting over two billion people. Early-life iron deficiency may alter the developing microbiota, which may or may not be reversible with subsequent dietary iron repletion. Thus, the aim of this study was to determine whether early-life iron deficiency and subsequent repletion alter colonic microbial composition and fermentation end-product concentrations in pigs. Methods: Forty-two male pigs received either control (CONT, 21.3 mg Fe/L) or iron-deficient (ID, 2.72 mg Fe/L) milk replacer treatments from postnatal day (PND) 2 to 32. Subsequently, 20 pigs continued through a series of age-appropriate, iron-adequate diets from PND 33 to 61. Contents from the ascending colon (AC) and rectum (feces) were collected at PND 32 and/or 61. Assessments included microbiota composition by 16S rRNA sequencing and volatile fatty acid (VFA) concentrations by gas chromatography methods. Data were analyzed using a 1-way ANOVA and PERMANOVA to assess the main effects of early-life iron status on all outcomes. Results: In AC samples, 15 genera differed (P < 0.05) between ID and CONT pigs, while 27 genera differed (P < 0.05) in fecal samples at PND 32. Early-life ID pigs had higher (P = 0.012) relative abundance of Lactobacillus in AC samples compared with CONT pigs. In feces, ID pigs had lower (P < 0.05) relative abundances of Bacteroides and Clostridium from the families of Clostridiaceae, Lachnospiraceae, and Ruminococcaceae. At PND 61, only two genera differed between treatment groups in AC samples, with ID pigs having a higher (P = 0.043) relative abundance of Bifidobacterium and lower (P = 0.047) relative abundance of Prevotella. Beta diversity differed at PND 32 in both AC and feces between CONT and ID pigs but no differences remained at PND 61. At PND 32, the total VFA concentration was higher in ID pigs compared with CONT pigs in both AC (P = 0.003) and feces (P = 0.001), but no differences in VFA concentrations persisted to PND 61. Conclusion: Early-life iron status influenced microbial composition and VFA concentrations within the large intestine, but these differences were largely normalized following subsequent dietary iron repletion.

Project description:Background/objectiveIron deficiency (ID) is the most common nutrient deficiency, affecting two billion people worldwide, including about 30% of pregnant women. During gestation, the brain is particularly vulnerable to environmental insults, which can irrevocably impair critical developmental processes. Consequently, detrimental consequences of early-life ID for offspring brain structure and function have been described. Although early life ID has been associated with an increased long-term risk for several neuropsychiatric disorders, the effect on depressive disorders has remained unresolved.Materials and methodsA mouse model of moderate foetal and neonatal ID was established by keeping pregnant dams on an iron-deficient diet throughout gestation until postnatal day 10. The ensuing significant decrease of iron content in the offspring brain, as well as the impact on maternal behaviour and offspring vocalization was determined in the first postnatal week. The consequences of early-life ID for depression- and anxiety-like behaviour in adulthood were revealed employing dedicated behavioural assays. miRNA sequencing of hippocampal tissue of offspring revealed specific miRNAs signatures accompanying the behavioural deficits of foetal and neonatal ID in the adult brain.ResultsMothers receiving iron-deficient food during pregnancy and lactation exhibited significantly less licking and grooming behaviour, while active pup retrieval and pup ultrasonic vocalizations were unaltered. Adult offspring with a history of foetal and neonatal ID showed an increase in depression- and anxiety-like behaviour, paralleled by a deranged miRNA expression profile in the hippocampus, specifically levels of miR200a and miR200b.ConclusionID during the foetal and neonatal periods has life-long consequences for affective behaviour in mice and leaves a specific and persistent mark on the expression of miRNAs in the brain. Foetal and neonatal ID needs to be further considered as risk factor for the development of depression and anxiety disorders later in life.Key MessagesMarginal reduction of gestational alimentary iron intake decreases brain iron content of the juvenile offspring.Early-life ID is associated with increased depression- and anxiety-like behaviour in adulthood.Reduction of maternal alimentary iron intake during pregnancy is reflected in an alteration of miRNA signatures in the adult offspring brain.