Iron as a model nutrient for understanding the nutritional origins of neuropsychiatric disease

Abstract

Adequate nutrition during the pre- and early-postnatal periods plays a critical role in programming early neurodevelopment. Disruption of neurodevelopment by nutritional deficiencies can result not only in lasting functional deficits, but increased risk of neuropsychiatric disease in adulthood. Historical periods of famine such as the Dutch Hunger Winter and the Chinese Famine have provided foundational evidence for the long-term effects of developmental malnutrition on neuropsychiatric outcomes. Because neurodevelopment is a complex process that consists of many nutrient- and brain-region-specific critical periods, subsequent clinical and pre-clinical studies have aimed to elucidate the specific roles of individual macro- and micronutrient deficiencies in neurodevelopment and neuropsychiatric pathologies. This review will discuss developmental iron deficiency (ID), the most common micronutrient deficiency worldwide, as a paradigm for understanding the role of early-life nutrition in neurodevelopment and risk of neuropsychiatric disease. We will review the epidemiologic data linking ID to neuropsychiatric dysfunction, as well as the underlying structural, cellular, and molecular mechanisms that are thought to underlie these lasting effects. Understanding the mechanisms driving lasting dysfunction and disease risk is critical for development and implementation of nutritional policies aimed at preventing nutritional deficiencies and their long-term sequelae.

Figure 1.. Epigenetic modifications of DNA and chromatin are sensitive to nutritional status.

Two major categories of epigenetic modification, DNA methylation (left) and histone modification, specifically histone methylation (right), are both modified by iron deficiency. DNA methylation consists of cytosine bases with a covalently added methyl group. Active DNA demethylation is performed by TET methylcytosine dioxygenases, which require iron for their enzymatic conversion of methylcytosine to hydroxymethylcytosine and its derivatives. Lysine residues of histone tails can undergo mono-, di-, or trimethylation. JARID histone demethylases enzymatically remove methyl groups from di- or trimethylated lysine residues, and also require iron for their enzymatic activity. C: Cytosine; hME: Hydroxymethyl; K: Lysine; Me: Methyl.