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3 Department of Nutritional Sciences and 4 Department of Biobehavioral Health, Pennsylvania State University, University Park, PA 16802
* To whom correspondence should be addressed. E-mail: jbeard{at}psu.edu.
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ABSTRACT |
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 TOP ABSTRACT IntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Introduction |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Investigators have explored central nervous system effects of iron deficiency anemia in rodents for several decades (6,7) using research designs that incorporate both preweaning and postweaning iron-deficiency treatment protocols (8,9). 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 progress throughout the lifespan (10). Moreover, 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 many important consequences of iron restriction to the brain are likely to be related directly to critical periods in neurobiological development.
The direct and indirect effects of iron deficiency are not clear, but possibly include effects on cell growth and differentiation (11), cellular bioenergetics (12), and biochemistry (5,8). We and others have identified manifestations of iron deficiency in neurotransmitter systems (13–17), myelin biology (18–20), and behavior (13,14,20,21). New observations regarding metabolism and dendritic arborization in the hippocampus document lasting effects of pre- and postnatal iron deficiency on brain morphology (8,11). Changes in monoamine function can be used as a marker of developmental brain pathology or compensatory reorganization in the forebrain involving other neurotransmitters and cellular and molecular events (22–24). Recently published studies indicate that relatively mild early iron deficiency in human infants results in delays in the achievement of both short-term and long-term developmental milestones (25,26). The observations of decreased spontaneous activity in iron-deficient infants and poorer executive functioning as they reach adolescence may be explained in part, by alterations in the monoamergic systems.
Most investigators who examined brain iron and dopamine in rats applied iron-deficient treatments postnatally (7,13–15,27). Some studies initiated an iron-deficient diet at postnatal d 4 (P4)5 (13,14), others at P10 (10,21) and P21 (20,27,28), and all used a severe dietary restriction to produce rats that showed brain iron losses as much as or >50% in many brain regions. In 2 studies, rats made iron deficient at P4 or P10 were fed iron-adequate diets at P21 (10,14). In these rats, iron repletion brought blood and peripheral iron measures into line with control values in adulthood; however, iron deficiency-induced behavioral deficits in spontaneous activity and exploration were not reversed by iron repletion (10,21). Taken together, the data demonstrate that iron treatment at the end of weaning is too late to correct the effects of iron deprivation during either the entire lactation period or even for just the latter half of lactation.
Timing, severity, and duration of iron deficiency during early development are recognized as 3 important issues regarding its ultimate impact. Some of the studies cited used dietary treatments that reduced brain iron by >50% in rodents, which is similar to the degree of iron deficiency and its sequelae that occur in humans such as intrauterine growth retardation and diabetes mellitus during pregnancy where fetal iron balance is compromised (22,29–31). A recent study (32,33) used a more modest dietary restriction throughout gestation and lactation and resulted in reductions in brain iron of <30%, but there were still persistent biochemical and behavioral effects in adulthood. Thus, a modest iron deprivation of long duration during a period of very active neurogenesis results in irreversible changes even if a control-diet intervention occurs after weaning.
The goal of this study was to determine the extent to which the effects of prenatal iron deficiency, i.e., decreased regional brain iron concentrations and altered monoamine function, can be reversed with dietary iron repletion in early postnatal life. Our hypothesis was that early iron deficiency alters developmental progress and that intervention soon after birth may be early enough to reverse the alterations in functioning and development caused by in utero iron deficiency. The experimental regimen chosen simulated the human condition of iron deficiency in the 2nd to 3rd trimester, whereas the intervention would correspond to iron supplementation in the middle 3rd trimester through lactation.
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Materials and Methods |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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80 µg/g iron) diet at least 2 wk prior to mating. These diets were nutritionally adequate and followed AIN 93G guidelines with the exception of the amount of iron in the powdered diets, as described below (34). Female rats >10 wk of age were placed with male rats for 5 d or until a vaginal plug was observed. Pregnant dams were fed the iron adequate diet until gestational d 15 (G15), at which time they were divided into 2 groups; 1 was fed an iron-adequate diet (80 µg/g iron), and the other was fed an iron-deficient diet (<3 µg/g iron) until 4 d after parturition. When the pups were 4 d of age (P4), the litters were culled to 12 pups each. Pups from iron-deficient dams were divided into 2 groups, 1 group was out-fostered to iron-deficient dams (ID group) and the others out-fostered to dams maintained on the iron-adequate diet (IDCN group). Similarly, on P4, pups from dams fed an iron-adequate diet were out-fostered to control diet dams (CN group) and fed the control diet until weaning. All pups were weaned to their respective dietary iron group until the experiment was terminated at P65. Thus, the following groups of rats were generated. CN, rat pups that were iron adequate in gestation, lactation, and postweaning (G15 to P65); ID, rat pups that were iron deficient in gestation, lactation, and postweaning (G15 to P65); and IDCN, rat pups that were iron deficient from G15 to P4 followed by iron adequacy to P65. All rats were fed food and water ad libitum. Control and iron-deficient diets were prepared in our laboratory following the recipe of the American Institute of Nutrition (AIN)-93G diet with cornstarch as the sole source of carbohydrate (21,34). Pregnant dams were housed singly in shoebox cages measuring 45 x 24 x 20 cm in a temperature- (23 ± 2°C) and humidity- (40%) controlled room, and maintained on a 12:12 h light:dark cycle (lights on at 0600). All experimental protocols were performed in accordance with NIH Animal Care guidelines and were approved by the Pennsylvania State University Institutional Animal Care and Use Committee.
Behavioral testing. From P60-P63, open-field behavioral studies were conducted using automated activity monitors (Digiscan Activity Monitors, Omnitech Electronics) to assess ambulation and exploratory behavior, as reported previously (13,21). The parameters assessed in the current study include total distance traveled, number of stereotypic movements, and center time, which were measured over a 20-min period and presented as summed activities in 5-min intervals. All behavioral testing was performed between 0900 and 1200 h.
Hematology and iron status. Toward the end of pregnancy, blood was collected from the dams by tail bleed to evaluate hemoglobin and hematocrit (10). Milk from lactating dams was obtained and analyzed for iron content, as described by O'Connor, et al. (35). At P4, blood and livers from 6–8 pups per dietary group were collected for hemoglobin measurement and liver iron analysis. Termination of the experiment was at P65 with the decapitation of all rats after CO2 suffocation. At this time, trunk blood was collected and livers were rapidly removed and immediately frozen at –80°C. Hemoglobin, hematocrit, plasma iron, transferrin saturation, total iron binding capacity, and liver nonheme iron were measured, as previously reported (10). The brain was hemi-sectioned and the right hemisphere was quickly dissected on ice for prefrontal cortex, caudate putamen, ventral midbrain (ventral tegmentum-substantia nigra), pons, cerebellum, and cortex. The tissues were placed immediately in storage tubes and frozen at –80°C. The left brain hemisphere was prepared for autoradiographic determination of monoamine transporters receptors by being frozen slowly in a dry ice:isopentane slurry and then stored at –80°C.
Regional brain iron and monoamines. Brain regions were prepared and analyzed by atomic absorption spectrophotometry (10), as described previously. Catecholamine analysis was conducted by HPLC with coulometric detection, as recently described by our laboratory (32).
ELISA analysis of brain homogenate proteins. Brain region homogenates were prepared and analyzed by ELISA, as previously described (10) with the exception of antibodies utilized for various proteins. All antibodies were available from commercial sources and, in this study, we examined tyrosine hydroxylase (TH; Sigma-Aldrich), phosphorylated tyrosine hydroxylase (pTH; Ser 40; Zymed), ferritin (Sigma-Aldrich), transferrin (Chemicon), vesicular monoamine transporter type 2 (Chemicon), and thymus cell antigen-1 (Thy-1; Sigma-Aldrich). Between 1 and 2 µg of protein homogenate was utilized in each well of the microtiter plate and all samples were analyzed in triplicate. Dilution of primary antibody was 1:1000, whereas the dilution of the secondary antibody varied from 1:2000 to 1:8000.
Ligand binding protocol. Radioligand binding for the dopamine and serotonin transporters and the dopamine D2 receptor was performed, as reported earlier (32).
Statistical analysis. All biological and behavioral data were examined for normal distributions and log transformed when necessary prior to 1-way ANOVA for diet as the between-subjects variable for behavioral and biochemical variables (Systat 10.2). Pair-wise comparisons between control and the other treatments were made using the Dunnett's t test. For iron and monoamine measures, brain region was included as a within-subjects variable. Covariance analysis for effect of dam was examined and considered within a General Linear Models analysis. Alpha for main effects and interactions was set at P < 0.05.
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Results |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Discussion |
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30 wk of gestation, or early in the 3rd trimester. Prolonged and persistent iron deficiency extending into young adulthood resulted in changes in behavior and biology in a manner consistent with findings from previous studies in rodents (13,14,36). The identification of timing for the successful correction of effects of early iron deficiency has been the focus of a number of human studies (37–40). In rodents, when dietary iron deprivation was started at G5, dietary iron intervention at P25 did not successfully reverse the effects of iron deficiency on brain and behavior (33). This failure suggests that an earlier intervention window of opportunity may exist for brain-behavioral endpoints as it does for other outcome variables such as growth (38). Iron deficiency in rodents from G5-P25 was associated with adaptive changes in the striatal monoamine system preceding the decline in brain iron content (34). Thus, the rodent brain appears to have a vulnerable period that extends to a younger age than our previous identification of a P4-P21 window (41). Vulnerable periods with respect to iron deficiency are also believed to exist in human infants (42). The current study demonstrates however, that effects of iron deficiency from mid-gestation through early lactation can be reversed with dietary iron therapy, suggesting that an earlier timing of intervention needs to be considered.
The protocol in the current study is a significant deviation from previous rodent studies on the timing, severity, and duration of iron deficiency early in life. The 1st studies in rats focused on postweaning, as this period is developmentally similar to when most human infants are experiencing an iron deficit (7,42,43). Moreover, the effects of postweaning iron deficiency in rodents were largely reversible with later iron therapy; a finding not supported by early infant literature on humans. Because rodent and human infants differ dramatically in the timing of neurological development (44), it seemed prudent for investigators to adjust timing of treatments to earlier developmental time points. When iron deficiency was started in rodents at mid-lactation, P10 or P14, and extended to P21 (10,21), there was a severe reduction in brain iron and changes in behaviors that were not corrected with several weeks of iron therapy begun at weaning (36,41). The findings from these studies point to at least 1 critical period in the 2nd half of lactation when iron deficiency permanently altered the course of neurological development. Moving the window of iron deficiency even further forward to P4, followed by iron repletion at P21, produced essentially the same result (13,32). These studies helped to redirect our intervention timing to an earlier age. In the current design, the iron deprivation started in mid-gestation but stopped early in lactation and prior to the period of rapid striatal dopamine receptor differentiation and development. Dams became mildly anemic by parturition; thus the pups were only mildly iron deficient. The nearly complete normalization of brain monoamines, iron, and behavioral measures in these rats shows that a period of iron deficiency before the period of maximal neurogenesis and differentiation in the rodent had no lasting effects.
The good news conveyed in our results may, however, also reveal a down side. The iron-repleted rats had more brain iron in several regions than CN rats. This excessive accumulation of iron may have long-term deleterious consequences (40). In our study, 2 brain regions, the ventral midbrain and frontal cortex, showed an over-compensation in brain iron concentration in adults that had been iron deficient from G15-P4 but then iron sufficient into adulthood. We previously observed an upregulation of the transferrin receptor and the iron transporter, DMT-1, in ID rat pup brains (10) and showed that aggressive dietary iron therapy resulted in much higher ventral midbrain iron concentrations in adults than in cohort CN rats. Aggressive iron therapy following fetal iron deficiency in C57BL/6 mice was recently claimed to be related to the development of Parkinson-like neurodegeneration (45). The fetal programming of the set-point for brain iron concentrations has not been carefully explored, but the previous work and the current observations suggest that resetting the set-point for iron homeostasis may occur when iron deficiency commences in early life. Iron deficiency may involve prioritization and even redistribution of iron across tissues, an effect that may be related to the stage of particular organ differentiation (29,40,46–48).
The earlier age of onset of iron deficiency in the current results demonstrates a quantitatively smaller reduction in regional brain iron concentrations and changes in dopamine variables than did studies in which iron deficiency was started at lactation (10,36) or at weaning (13,34). In these latter studies, it was not uncommon to see a 30–50% decline in regional brain iron and 30% decreases in dopamine transporter or receptor density. Whereas behavioral outcomes such as open-field exploration or stereotypy appeared to be affected in all these developmental models equally, the recent study involving G5 age of onset of iron deficiency provided strong evidence for the existence of an adaptive neural-developmental change that may protect the brain (32). Perhaps neural differentiation and growth in an early iron-deficit diet provides some protection compared with iron deficiency imposed during and immediately after the period of most rapid brain growth.
There are a number of genes in the brain that change their expression in response to early iron deficiency. These fall into 3 categories of genes, those that are involved in structure, iron transport, and apoptosis (49). Those gene expression studies did not examine effects of iron deficiency during gestation apart from iron deficiency effects during or after lactation, so the question of temporal effects on persistent gene expression profiles cannot be answered at this time. A subsequent report will describe the results of instituting iron deficiency at P4 compared with G15 on the relation of timing and duration of iron deficiency on brain monoamine metabolism and behaviors.
In conclusion, this study was designed to model a period of transient iron deficiency in humans where preconception maternal iron status is adequate, iron deficiency starts at mid-2nd trimester, and aggressive iron intervention is initiated in the 3rd trimester. Our rodent model suggests that the impact of this period of iron deficiency is reversible when the intervention is started early. Importantly, the consequences of iron deficiency with no intervention do not differ much from what is observed when iron deficiency occurs early postnatally. Subtle differences (less-severe depletion of regional brain iron and monoamines), however, suggest that there are protective mechanisms responsive to iron deficiency at this stage of development. Alternatively, this lesser response occurred simply because the early iron deficiency occurred prior to the critical period for dopamine differentiation. The question of whether this is a heuristic model for he human condition is complicated from the perspective that the rat fetus and preweanling pup have a rapid period of neurogenesis and higher iron demands than the developing human infant (25,26,50).
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FOOTNOTES |
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2 Author disclosures: J. L. Beard, no conflicts of interest; E. L. Unger, no conflicts of interest; L. E. Bianco, no conflicts of interest; T. Paul, no conflicts of interest; S. E. Rundle, no conflicts of interest; and B. C. Jones, no conflicts of interest.
5 Abbreviations used: CN, rat pups fed an iron adequate diet from G15 to P65; G, gestational day; G15, gestational d 15; ID, rat pups fed an iron deficient diet from G15 to P65; IDCN, Rat pups fed an iron-deficient diet from G15 to P4 followed by an iron-adequate diet from P4 to P65; OD, optical density; P, postnatal day; P4, postnatal d 4; P65, postnatal d 65; SERT, serotonin transporter; Tf, transferrin; TH, tyrosine hydroxylase.
Manuscript received 6 January 2007. Initial review completed 2 February 2007. Revision accepted 5 March 2007.
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