Behavior and Monoamine Deficits in Prenatal and Perinatal Iron Deficiency Are Not Corrected by Early Postnatal Moderate-Iron or High-Iron Diets in Rats,

Abstract

Developmental iron deficiency anemia (IDA) causes brain and behavioral deficits in rodent models, which cannot be reversed when treated at periods equivalent to later infancy in humans. This study sought to determine whether earlier iron treatment can normalize deficits of IDA in rats and what iron dose is optimal. The offspring of dams with IDA during gestation were cross-fostered at postnatal d (P) 8 to dams receiving diets with 1 of 3 iron concentrations until weaning (P21): 0.003-0.01 g/kg [totally iron deficient (TID)]; 0.04 g/kg [formerly iron deficient (FID-40)]; or 0.4 g/kg (FID-400). Always iron-sufficient control dams (CN-40) received a 0.04-g/kg iron diet. At P21, TID pups received a 0.01 g iron/kg diet; all others received a 0.04 g iron/kg diet. Hematocrit and brain iron and monoamine concentrations were assessed at P21 and P100. Pup growth, development, activity, object recognition, hesitancy, and watermaze performance were evaluated. Regional brain iron was restored by iron treatment. Regional monoamine and metabolite concentrations were elevated in FID-40 rats and reduced in FID-400 and TID rats compared with CN-40 rats. FID-40 offspring had motor delays similar to TID during lactation and FID-400 rats had elevated thigmotaxis similar to TID rats at P25 and P100 in the spatial watermaze. In conclusion, iron treatment at P8 in rats did not normalize all monoamine or behavioral measures after early IDA. Moderate iron treatment improved adult behavior, but higher iron treatment caused brain and behavioral patterns similar to TID in the short and long term.

Is early-life iron exposure critical in neurodegeneration?

“…56 One curiosity among the literature is why lower levels of iron fortification that more closely resemble the levels in breast milk have not been included in clinical studies of the possible health benefits of iron supplementation, particularly when some evidence suggests that moderate iron supplementation is sufficient (and even preferable) for the correction of behavioural deficits that arise from iron deficiency. 57 If, as the ESPGHAN reported, iron fortification is only beneficial to infants who are preterm and have anaemia, the lack of acute health effects that arise from overexposure to iron should not exclude modest supplementation from further study. We believe that a priority in paediatric research is the rigorous determination of iron supplementation needs of infants according to their individual iron status.…”

Fetal iron deficiency alters the proteome of adult rat hippocampal synaptosomes

“…Previous studies in humans and animal models of fetal and early postnatal life iron deficiency demonstrate long-lasting impairments in learning and memory and socio-emotional behaviors (18,20,35,60,71), as well as increased risk for depression and schizophrenia (27,37). The long-term biobehavioral deficits occur despite treatment with iron and have been ascribed in part to persistence of abnormalities in monoamine signaling, myelination, neural metabolism, and expression of neuroplasticity-associated proteins into adulthood ( systematically analyzing the long-term effect of early-life iron deficiency specifically on proteins expressed in adult hippocampal synapses and addresses the persistent defect of learning and memory and sensory-motor gating.…”

“…These deficits have been replicated in rodent models of fetal-neonatal iron deficiency (35). Of relevance to the present study, hippocampal-dependent learning and memory as well as prepulse inhibition, an index of sensory-motor gating linked to the schizophrenia endophenotype, were abnormal in the rat model (10,20,35,53,67,71).…”

“…These deficits have been replicated in rodent models of fetal-neonatal iron deficiency (35). Of relevance to the present study, hippocampal-dependent learning and memory as well as prepulse inhibition, an index of sensory-motor gating linked to the schizophrenia endophenotype, were abnormal in the rat model (10,20,35,53,67,71).The developing fetal brain is extremely susceptible to iron deficiency (44) in part because of the growth spurt that occurs during the late fetal-neonatal period (1, 54) and because fetal iron is prioritized over the brain for red blood cell production (21). Rodent models of maternal-fetal iron deficiency result in a 50% reduction in brain iron concentration by postnatal day (P) 7 (57), a time point that approximates full-term human newborn in terms of brain development (1) and recapitulates the degree of iron deficiency found in newborns (52).…”

Iron deficiency during pregnancy: the consequences for placental function and fetal outcome

“…Most of these experiments have used rodents, but more recently, studies in human subjects have shown that changes in the cognitive function of babies can be related to maternal iron status (4,21,22) .…”