Iron deficiency (ID) anemia is the foremost micronutrient deficiency worldwide, affecting around 40% of pregnant women and young children. ID during the prenatal and early postnatal periods has a pronounced effect on neurodevelopment, resulting in long-term effects such as cognitive impairment and increased risk for neuropsychiatric disorders. Treatment of ID has been complicated as it does not always resolve the long-lasting neurodevelopmental deficits. A better understanding of the underlying molecular mechanisms is needed in order to develop more effective treatments.
1. Introduction
Iron deficiency (ID), which affects 40–50% of pregnant women and preschool-aged children and is the most common micronutrient deficiency worldwide [3,4]. Given the prevalence of this early-life nutritional exposure, it is important to understand its effect on long-term health outcomes, and the biological basis underlying these effects. ID during the fetal and early childhood periods has a significant effect on neurodevelopment, resulting in cognitive, socio-emotional, and learning and memory deficits that last into early adulthood [5,6]. ID also carries long-term health risks, including increased risk for neuropsychiatric disorders such as autism and schizophrenia [7,8]. Parallel studies in pre-clinical models have shown that early-life ID results in abnormal hippocampal structure, function, and gene expression acutely during the period of rapid neurodevelopment and persistently into adulthood despite prompt iron therapy after diagnosis [9,10,11,12,13,14,15,16,17,18]. The persistent gene dysregulation likely drives the adult neurobehavioral abnormalities of early-life or developmental ID. However, specific iron-dependent mechanisms by which early-life ID alters gene expression across the lifespan are unknown.
2. Early-Life Iron Deficiency Modifies Gene Regulation and Epigenetic Landscape in the Adult Rat Hippocampus
Understanding the biology behind the association of maternal and early postnatal ID with neurocognitive impairments and psychopathology risks is a prerequisite for developing effective prevention and treatment strategies. Based on a series of observational studies, two hypotheses are formulated to explicate the poor long-term neurodevelopmental outcomes. The structural defects hypothesis posits that developmental ID causes abnormalities ranging from gross structures (e.g., brain and white matter volumes) to fine ultrastructures (e.g., dendrite branching and synaptic spines) that persist despite later iron reconstitution [
13,
15,
50]. The gene dysregulation hypothesis postulates that early-life ID reprograms gene regulation, which in turn contributes to subsequent phenotypic changes [
18,
51,
52,
53,
54]. These two hypotheses are not mutually exclusive, and their interactions likely drive abnormal structure during neurodevelopment and function throughout the lifetime, accounting for the risk of psychopathology in later life. The structural hypothesis is discussed elsewhere [
55]. This review focuses on the gene dysregulation hypothesis and the potential underlying mechanisms.
3. Early-Life Iron Deficiency Reprograms Gene Regulation
Extensive gene dysregulation has been demonstrated in both rodent and porcine models of fetal-neonatal ID acutely during ID [
10,
56] and persistently in adulthood following iron repletion [
18,
54]. The dysregulated genes implicate abnormal neurodevelopment and increased propensity of neuropsychiatric disorders [
10,
18,
54,
56]. These widespread and lasting effects implicate global and stable changes in gene regulatory mechanisms such as epigenetic regulation. Epigenetic regulation refers to covalent modifications of DNA and histones to alter gene transcriptional activity and phenotype without changes in the genetic code. Importantly, DNA and histone modifications can be altered depending on environmental exposures such as stress [
57,
58], toxicants [
59,
60,
61], and nutrients [
24,
51,
52,
53,
62,
63]. Thus, epigenetic regulation can be a mechanism by which ID alters gene regulation during critical windows of the nervous system development, contributing to poor long-term neuropsychiatric outcomes.
4. Prenatal Choline Supplementation and Iron Deficiency Interact to Regulate the Rat Hippocampal Epigenomic Landscape
Given the beneficial effects of prenatal choline supplementation in reversing the repression and epigenetic modifications of the hippocampal
Bdnf gene, an important mediator of neuronal differentiation and plasticity, by early-life ID [
24], it is enticing to use choline as a prevention (prenatal period) or treatment (children diagnosed with ID anemia) in clinical studies [
83]. However, there are several caveats to the use of such a potential epigenetic modulator in the treatment of ID. First, given multiple epigenetic modifications by ID, the therapeutic efficacy of modulating any single modification is unclear. Our recent genome-wide analysis reveals that prenatal choline supplementation produces a distinct epigenomic effect from early-life ID, where choline modifies specifically histone H3K9me3 landscape. Second, the efficacy of epigenetic regulators has to be considered in the context of critical periods of neurodevelopment. For example, once the process of dendrite outgrowth is complete, altering gene expression by treatment with an epigenetic modulator cannot reverse the structural damage caused by ID since the critical period is closed. Therefore, appropriate timing of choline use in the context of neurodevelopment is crucial for its efficacy. Since the brain is not developmentally homogeneous, certain brain regions may be affected more or less than others depending on whether they are or are not in a rapid developmental period. Finally, potential adverse effects of inappropriate use of epigenetic modulators such as choline remain possible. We found little and even negative effects in our control iron-sufficient rats with prenatal supplementation from gestational day 11 through 18 [
18,
29]. These observations indicate the need to continue to study appropriate choline dosing, timing, and duration of supplementation to avoid potential long-term adverse consequences.
This entry is adapted from the peer-reviewed paper 10.3390/nu13113857
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