Fetal-neonatal iron deficiency (ID) has a lasting negative impact on neurodevelopment, resulting in significant cognitive, socio-emotional, and learning and memory deficits in adulthood. Given that ID is the most common micronutrient deficiency worldwide, and that pregnant women and young children are disproportionately affected, it presents a significant public health concern. Preclinical models have demonstrated that the developing hippocampus is particularly affected by ID, and that the deleterious neurodevelopmental and behavioral outcomes that follow are associated with dysregulation of hippocampal gene expression. Affected genes include many that are important for neurodevelopment and synaptic plasticity such as Bdnf, Dlg4 (PSD- 95), and Vamp1. If developmental ID is corrected by iron repletion within a critical period, correction of these deficits is possible. However, if iron repletion occurs outside of the critical period, the phenotypic and gene expression changes persist into adulthood despite correction of the deficiency. While changes in gene expression can be understood as the proximate cause of the ID neurocognitive phenotype, it is still unclear what the ultimate cause is. As such, there is a gap in our understanding of how developmental ID drives hippocampal gene expression changes. A potential mechanism by which iron could enact these changes is through Ten-Eleven Translocation (TET) proteins, a family of iron-dependent hydroxylases that generate the epigenetic modification 5-hydroxymethylcytosine. Epigenetic modifications such as DNA hydroxymethylation have the ability to stably influence gene expression throughout the lifespan, and are known to be labile to environmental influences. Of particular relevance, 5-hydroxyethylcytosine is more abundant in the brain than any other tissue type, and it increases in enrichment as neurodevelopment progresses, particularly in genes critical for neuronal development and function. The central hypothesis of this proposal is that dysregulation of TET protein activity and DNA hydroxymethylation by ID drive gene expression changes in hippocampal neurons that contribute to the long-term neurocognitive phenotype of developmental ID. To test this hypothesis, the following specific aims are proposed: 1) Determine how ID alters TET activity and hydroxymethylation of neurons in an in vitro model of hippocampal neurodevelopment, and 2) Determine the effect of developmental ID and subsequent iron repletion on hydroxymethylation in the developing mouse hippocampus. Completion of these aims will contribute to our long-term goal of understanding the cellular and molecular underpinnings of hippocampal dysfunction following developmental ID. Because the standard therapy of iron repletion incompletely rescues the neurodevelopmental phenotype of ID, there is a need for better therapeutic options. By better understanding the underlying mechanisms of ID-related hippocampal dysfunction, it may be possible to identify new therapeutic targets for more effective treatment of iron deficiency.

Public Health Relevance

Iron deficiency (ID) is the most common micronutrient deficiency worldwide, affecting an estimated 40-50% of pregnant women and preschool-aged children. ID during fetal and early childhood periods results in poor neurodevelopmental outcomes that can last throughout the lifetime; this is the true public health burden of early life ID. Because the biological mechanism underlying these permanent deficits is still not known, the present proposal investigates TET proteins and DNA hydroxymethylation as an iron-dependent mechanism by which these changes might occur, and has the potential to uncover new targets for more effective treatment of childhood iron deficiency.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Bremer, Andrew
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University of Minnesota Twin Cities
Schools of Medicine
United States
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Barks, Amanda; Hall, Anne M; Tran, Phu V et al. (2018) Iron as a model nutrient for understanding the nutritional origins of neuropsychiatric disease. Pediatr Res :