Newborn Iron Deficiency

ABSTRACT: Early-life iron deficiency (ID) is prevalent throughout the world, affecting 40-50% of pregnant women, fetuses, and children. ID impairs cognition in children, causes persistent cognitive impairments and increases risk of neuropsychiatric disorders despite postnatal iron treatment. The long-term effects of early-life ID are the real cost to society because of lost education and job potential and their association with transgenerational racial health disparities. In mice, hippocampal neuron-specific ID causes long-term learning/memory neurocircuit dysfunction despite postnatal iron repletion, demonstrating the long-term effects are due to neuronal iron loss during development. Thus, dysregulation of early-life neuronal iron-requiring activities set neuronal functional capacity across the lifespan. The fetal/neonatal brain is highly metabolic, accounting for 60% of total body oxygen consumption. The hippocampus has one of the highest regional metabolic rates in the neonatal brain. Iron provides the catalytic component for enzymes required for mitochondrial electron transport and energy production. Mitochondrial quality control mechanisms (e.g., redox balance, fusion/fission, and mitophagy) maintain mitochondrial structure and energetic homeostasis and prevent long-term mitochondrial damage and dysfunction. Early-life ID acutely disrupts these processes, impairing dendrite and synapse formation. Postnatal iron repletion does not rescue ID-induced mitochondrial energetic impairments in the adult brain, suggesting a permanent reprogramming. The cellular mechanisms of how developmental ID causes long-term neuronal structural and functional deficits and whether these can be prevented with iron treatment alone are unclear. We will test the overall hypothesis that permanently impaired hippocampal mitochondrial energetic capacity and quality control is programmed during early life, directly contributes to the compromised neurocircuitry that persists after recovery from early-life ID and that prenatal maternal iron repletion is required to prevent this. In Aim 1, we will utilize a unique in vitro model of chronic fetal-neonatal hippocampal neuronal ID to test the timing and dose of iron repletion during development in order to prevent programming of long-term mitochondrial neuronal structural deficits. We will treat iron-deficient hippocampal neuron cultures with moderate or high dose iron at neuron developmental stages equivalent to human 2nd trimester, birth, and 6-12 months. Recovery of mitochondrial quality control mechanisms and synapse formation will be assessed as outcome measures. Aim 2 uses an in vivo rat model of dietary fetal-neonatal ID to test whether fetal iron treatment is necessary and sufficient to prevent permanent abnormalities in hippocampal mitochondrial structure/function, epigenetics, neuron structure and neurocognitive behavior in adulthood. This proposal is highly significant because it will provide neurobiologically-based mechanistic evidence to delineate accurate timing and dosing of iron repletion and inform adjunct therapy strategies to reduce the lifelong consequences of fetal-neonatal ID.