Postweaning Iron Deficiency in Male Rats Leads to Long-Term Hyperactivity and Decreased Reelin Gene Expression in the Nucleus Accumbens

Nishikura, Noriko; Hino, Kodai; Kimura, Tomoko; Uchimura, Yasuhiro; Hino, Shinjiro; Nakao, Mitsuyoshi; Maruo, Yoshihiro; Udagawa, Jun

doi:10.1093/jn/nxz237

Cited by 3 publications

(1 citation statement)

References 56 publications

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“…Iron deficiency can trigger epigenetic changes that lead to altered expression levels of key proteins (e.g., brain-derived neurotrophic factor, reelin, and cofilin) causing long-term consequences affecting brain development, learning, memory, and plasticity [28,[148][149][150][151]154,[200][201][202][203]. Plasticity is critical for normal brain development, as well as throughout life, e.g., evolving synaptic connections associated with learning and mem-ory [204].…”

Section: Shared Consequences Of a Functional Iron Deficiency In Lysos...mentioning

confidence: 99%

Examining the Role of a Functional Deficiency of Iron in Lysosomal Storage Disorders with Translational Relevance to Alzheimer’s Disease

LeVine

2023

Cells

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The recently presented Azalea Hypothesis for Alzheimer’s disease asserts that iron becomes sequestered, leading to a functional iron deficiency that contributes to neurodegeneration. Iron sequestration can occur by iron being bound to protein aggregates, such as amyloid β and tau, iron-rich structures not undergoing recycling (e.g., due to disrupted ferritinophagy and impaired mitophagy), and diminished delivery of iron from the lysosome to the cytosol. Reduced iron availability for biochemical reactions causes cells to respond to acquire additional iron, resulting in an elevation in the total iron level within affected brain regions. As the amount of unavailable iron increases, the level of available iron decreases until eventually it is unable to meet cellular demands, which leads to a functional iron deficiency. Normally, the lysosome plays an integral role in cellular iron homeostasis by facilitating both the delivery of iron to the cytosol (e.g., after endocytosis of the iron–transferrin–transferrin receptor complex) and the cellular recycling of iron. During a lysosomal storage disorder, an enzyme deficiency causes undigested substrates to accumulate, causing a sequelae of pathogenic events that may include cellular iron dyshomeostasis. Thus, a functional deficiency of iron may be a pathogenic mechanism occurring within several lysosomal storage diseases and Alzheimer’s disease.

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Section: Shared Consequences Of a Functional Iron Deficiency In Lysos...mentioning

confidence: 99%

Examining the Role of a Functional Deficiency of Iron in Lysosomal Storage Disorders with Translational Relevance to Alzheimer’s Disease

LeVine

2023

Cells

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Iron and n-3 fatty acid depletion, alone and in combination, during early development provoke neurochemical changes, anhedonia, anxiety and social dysfunction in rats

Kemp,

Zandberg,

Harvey

et al. 2023

Nutritional Neuroscience

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

Liu,

Ramakrishnan,

Shen

et al. 2024

BMC Genomics

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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.

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Postweaning Iron Deficiency in Male Rats Leads to Long-Term Hyperactivity and Decreased Reelin Gene Expression in the Nucleus Accumbens

Cited by 3 publications

References 56 publications

Examining the Role of a Functional Deficiency of Iron in Lysosomal Storage Disorders with Translational Relevance to Alzheimer’s Disease

Examining the Role of a Functional Deficiency of Iron in Lysosomal Storage Disorders with Translational Relevance to Alzheimer’s Disease

Iron and n-3 fatty acid depletion, alone and in combination, during early development provoke neurochemical changes, anhedonia, anxiety and social dysfunction in rats

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

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