| Iron deficiency is the most prevalent nutritional disorder in the world, affecting 25% of the world's infants. In the U.S. it has been estimated that 35-58% of healthy women show some degree of iron deficiency, with a higher prevalence during pregnancy. Reduced iron availability during brain development leads to blood brain barrier alterations, cognitive abnormalities, learning impairments, and behavioral defects that are often associated with hypomyelination. It has also been reported that iron deficient, anemic infants exhibit slower auditory nerve conduction velocities compared to non-anemic infants, and the abnormal ABR patterns were attributed to impaired myelination associated to iron deficiency.;Interestingly, human and animal studies have revealed that postnatal iron supplementation cannot correct the brain iron concentrations, behavioral alterations and myelination defects generated during severe perinatal iron deficiency. This lack of repair suggests that the role of iron in oligodendrocyte development and myelin synthesis and maintenance is more complex than appreciated. We recently discovered that glial restricted precursor cell function is disrupted by iron deficiency during embryogenesis as early as E13.5. This developmental window had not been considered in previous studies investigating possible causes of hypomyelination associated with iron deficiency. These observations suggest that hypomyelination resulting from gestational iron deficiency might be a precursor cell disease. We therefore concentrated on determining the role of iron during early stages of gliogenesis and oligodendrocyte generation.;For our analysis we first established the use of genetic and nutritional animal models for studying embryonic iron deficiency. Belgrade rats represent animals with a genetic defect in the major iron transporter DMT1. The nutritional model is based on a low iron diet provided two weeks prior to conception. Secondly, we focused on the impact of both animal models on glial lineage progression, by analyzing the effects of iron restriction on fundamental biological properties (survival, proliferation and differentiation) of glial restricted precursor cells during early glial development. Our data shows a global decrease of myelin proteins expression in the offspring in a number of different brain regions due to gestational iron deficiency during glial development. We demonstrate for the first time a direct correlation between the reduced myelination and the abnormally elevated ABR (P2-P1) interpeak latencies consistently observed in iron deficient animals. These results emphasize a direct causal relationship between the embryonic CNS tissue iron depletion and disrupted myelination at later stages leading to slower conduction velocity through the auditory pathway. Our findings also suggest that peripheral myelin is not affected by maternal iron deficiency.;Finally, using defined feeding regimens to induce embryonic CNS iron deficiency and the Auditory Brainstem Responses measurements as readout for functional myelination deficit, we identified the windows of vulnerability during embryonic development when gestational iron deficiency has the greatest impact on glial precursor cells and the developing CNS. This study facilitates the identification of time points relevant for therapeutic interventions or preventive iron strategies. |
