Research reportModerate iron deficiency in infancy: Biology and behavior in young rats☆
Introduction
Iron deficiency and anemia during infancy have been associated with poorer performance on mental and motor measures and altered social–emotional behavior [18], [49]. Despite iron treatment, developmental alterations persisted in infancy [29], [36], [45] and may continue into adolescence [28]. The neurobiological alterations that account for these findings are not fully delineated or clearly identified in a causal model [5].
Investigators have explored central nervous system (CNS) effects of iron deficiency anemia (IDA) in rodent models for several decades [18], [50] utilizing research designs that incorporate both the pre-weaning and post-weaning effects of iron deficiency [37], [47], [50]. Brain regions particularly iron rich in adulthood (striatum, substantia nigra and deep cerebellar nuclei) are not particularly rich in iron in early development, as the process of regional acquisition of iron appears to be developmentally bound [35]. Thus, dietary iron restriction during early periods of growth and development results in a very different profile of regional brain iron deficits than does iron deficiency during later periods of life. Indeed, our working hypothesis is that a significant portion of the consequences of iron restriction to the brain is likely to be related directly to the developmental biology occurring at the time of this nutrient deficiency.
The direct and indirect effects of iron deficiency are not clear, but likely include effects on cell growth and differentiation [22], cellular bioenergetics [9] and biochemistry [5], [37]. Previous studies identified manifestations of iron deficiency in neurotransmitter systems [8], [11], [12], [30], [50], [51], myelin biology [6], [31], [52], and behavior [6], [10], [11], [13], [34]. Recently, new observations regarding metabolism and dendritic arborization in the hippocampus document lasting effects of pre- and post-natal iron deficiency on brain morphology [22], [37]. Changes in monoamine metabolism can be used as a marker of developmental brain pathology or compensatory reorganization in the forebrain involving other neurotransmitters and cellular and molecular events [32], [38], [41]. Recently published studies indicate that relatively mild early iron deficiency in human infants result in delays in achievement of both short term and long-term developmental milestones [3]. The observations of a paucity of motor movements while iron deficient as infants and poorer executive functioning years later as adolescents may both be explained, in part, by alterations in the monoamergic systems.
Most previous rat animal model studies that examined brain iron, DA, and generally utilized a post-natal model of iron deficiency [4], [11], [12], [30], [50], [51]. Some studies commenced an iron deficient diet at P4 [11], [12], others at P10 [34], [35], others at P21 [4], [6], [50], [51] and all used a severe dietary restriction to produce animals that generally had brain iron losses >50% in many brain regions. Other rodent studies utilized designs of pre-natal iron deficiency to examine the influences of intrauterine iron deficiency on brain development and subsequent functioning [9], [13], [22], [25], [42].
Many of the cited rodent studies utilized designs in which the brain iron deficiency was quite severe and concentrations were reduced by more than 50% in many brain regions. In some studies, the severity was chosen to match the degree of iron deficiency that occurs in human conditions such as intrauterine growth retardation and diabetes mellitus during pregnancy where fetal (but not post-natal) iron balance is compromised [17], [32], [33], [41]. For instance, some infants of diabetic mothers may have a greater than 40% reduction in brain iron concentration and a 60% reduction in liver iron. Studying severe iron deficiency in rodent models has been very useful in defining changes in biology in the extreme. However, such situations fail to answer questions regarding less severe degrees of iron deficiency anemia like that commonly occurring throughout the period of human pregnancy and infancy that result in biologically meaningful alterations in CNS functioning.
The objective of this study was to define the effects of a modest degree of brain iron deficiency during intrauterine life and lactation on regional iron concentrations, monoamine metabolism, and developmental milestones in a rat model. In order to avoid the teratology and profound growth failures of some earlier studies of iron deficiency during gestation in rodents, we utilized a dietary protocol designed to reduce brain iron by 10–20%. The hypothesis was that moderate iron deficiency that persisted through gestation and lactation would alter developmental progress and monoamine metabolism The model was chosen to be relevant to common conditions in the developing world where maternal ID is widespread, infants are likely born with proportionately reduced iron stores, and the iron deficiency continues for the maternal-infant dyadic through the period of lactation.
To test this hypothesis, we used a developmental model of iron deficiency in rodents designed (by dietary means) to maintain a moderate level of anemia in the pups during lactation.
Section snippets
Design
Young Sprague–Dawley (Harlan, Sprague–Dawley) females, approximately 125 g, were obtained and fed an iron sufficient diet (40 ppm iron, Harlan Teklad Nutritionals) for 2 weeks prior to mating. Pregnant dams were then randomly assigned to either a 4 ppm iron deficient diet, or continued the 40 ppm iron diet (the control group, CN) from gestation day (G5) to post-natal day (P7). All litters were culled to 10 pups per litter by P2 retaining equal numbers of males and females as able. At this time, the
Growth and physical development
Maternal body weight did not differ significantly by diet group during gestation or lactation. The mothers consuming the ID diets had significantly lower hemoglobin concentrations than controls at G20 (13.6 ± 3.1 g/dl versus 15.9 ± 3.0 g/dl), P1 (12.5 ± 1.6 g/dl versus 15.2 ± 2.1 g/dl), P10 (12.3 ± 2.8 g/dl versus 15.6 ± 3.9 g/dl) and a trend at P20 (14.6 ± 3.2 g/dl versus 17.2 ± 3.9 g/dl). This indicates that pups from these dams experienced a modest iron deficiency in utero and during lactation. The ID group pup
Discussion
The current study extends our knowledge regarding the consequences of iron deficiency during both pregnancy and lactation on the developing brain and on behavior in several ways. The rat model developed in this study demonstrates that iron deficiency anemia from gestation through mid-lactation at P10, does not necessarily lead to early deficits in regional brain iron concentration. But prolonging iron deficiency to the end of weaning does change the brain iron concentration demonstrated that
Acknowledgements
The entire group of investigators participating in the Brain and Behavior in Early Iron Deficiency Program Project contributed to our thinking about the issues in this study. The work in this study and contributions of the authors are as follows. John Beard assisted in design, directed the analysis of all biologic variables, and was primary author of the manuscript. Barbara Felt designed the model, trained and supervised staff performing behavioral testing, conducted the behavioral data
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Supported by PO1 HD39386 (Brain and Behavior in Early Iron Deficiency, Betsy Lozoff, Principal Investigator), and RO1 NS35088 (JB).