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Ingestive Behavior and Neurosciences

Early Iron Deficiency Alters Sensorimotor Development and Brain Monoamines in Rats¹

² Department of Nutrition Sciences and ³ Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA 16802; and ⁴ Center for Human Growth and Development, University of Michigan, Ann Arbor, MI 48109

^* To whom correspondence should be addressed. E-mail: jbeard{at}psu.edu.

	ABSTRACT

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
Iron deficiency in human infancy reportedly leads to developmental delays and changes in neurobiology that may be irreversible. Using a rodent model, the present study examined whether dietary iron deficiency late in pregnancy and during lactation alters sensorimotor development and brain monoaminergic systems. Rats were assigned to 1 of 4 dietary treatments during gestation and lactation: 1) iron sufficient control; 2) prenatal iron deficiency beginning on gestational d 15 (G15); 3) postnatal iron deficiency beginning on postnatal d 4 (P4); 4) iron deficiency beginning on G15 followed by an iron sufficient diet on P4. Developmental milestones, open field behavior, brain iron and proteins, monoamines, and their transporters were evaluated between P6 and P21. Only G15 iron deficient rats had greater dopaminergic activity than controls as indicated by increased tyrosine hydroxylase levels, phosphorylated tyrosine hydroxylase levels, and cellular dopamine in prefrontal cortex and striatum at P15. These rats also showed delayed eye opening, ear development, and reduced locomotor activity. Iron repletion at P4 returned most measures to control levels by the time of weaning. Postnatal iron deficiency reduced striatal and ventral midbrain iron as well as cellular dopamine levels in prefrontal cortex and striatum at P21. Developmental delays in ear development and achievement in bar holding and surface righting also resulted from postnatal iron deficiency. These results indicate that iron deficiency begun at G15 affects early dopamine neurobiology, the development of specific developmental milestones, and behavior in preweaned rats.

	Introduction

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

Preweaning iron deficiency produces decreases in the dopamine transporter and in D1 receptor densities, but increases in the D2 receptor when the iron deficiency is started at postnatal d 4 (P4)⁵ (7). Although some phenotypic characteristics were restored to levels similar to controls with iron therapy at weaning (P21), other brain regions and behaviors remained significantly different from rats that had never been iron deficient (7). The most recent study moved the onset of iron deficiency back to gestational d 0 (G0) and found that iron therapy at weaning did not normalize behavior and brain biology in adulthood (14). These 2 studies, taken together, clearly indicate that waiting until weaning to "rescue" perinatal or early postnatal iron deficiency is too late to restore these measures.

Delaying the onset of iron deficiency to weaning (P21) and subsequent repletion at P49 was found to restore neurobehavioral measures (15) and pharmacology (8) to normal as iron status was returned to normal. This effect of iron deficiency was first investigated by Youdim and Green (16,17). Combined, these studies indicate that the most common behavioral effects in iron deficient rats include decreased activity and exploratory behaviors and increased fear-like behaviors (6,18).

A battery of sensory-motor developmental endpoints was applied in one previous study of gestational ID (19). An iron deficient diet was instituted at gestational d G5 resulting in pups that had been iron deficient through most of pregnancy and lactation. Those pups had significant developmental delays in a number of striatal based behaviors. In the present study, we sought to extend those observations by delaying the onset of dietary iron deficiency to later in pregnancy, gestational d 15 (G15), to determine whether iron deficiency begun at this time point had the same effects. In addition, we explored the effects of early postnatal iron deficiency on these developmental milestones and monoamine regulation. The final objective was to determine whether early postnatal iron repletion would result in a rapid correction of effects of intrauterine iron deficiency. We contend that changes in these developmental indices may serve as links to later developmental difficulties associated with infantile iron deficiency.

	Materials and Methods

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
    Rats and dietary treatment. Male and female Sprague-Dawley rats for breeding stocks were purchased from Harlan Sprague Dawley. Male breeders were fed a pelleted diet (Purina Mills Lab Diet 5001), and female breeders were fed a powdered iron adequate diet (80 µg/g iron) at least 2 wk prior to mating. Females >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; one was fed an iron adequate diet (80 µg/g iron; see below) and the other fed an iron deficient diet (<3 µg/g iron) through P4. At this time, pups of dams fed the iron adequate diet were cross fostered into 2 groups, one set of pups was fostered to dams maintained on the iron adequate diet (CN) and the other pups fostered to dams consuming the iron deficient diet (<3 µg/g; CNID). Similarly on P4, pups from dams fed the ID diet in utero were maintained on the ID diet (ID) or were switched to dams fed the iron adequate diet (IDCN). After cross-fostering, pups remained with their respective dams until the end of the study. Thus, the 4 groups of pups were CN, ID, CNID, and IDCN. Litters were culled to 12 pups/litter on P4.

All rats consumed food and deionized distilled water ad libitum. Control and iron deficient (AIN)-93G based diets were prepared in our laboratory with cornstarch as the sole source of carbohydrate (15,20). The iron deficient diet contained all components of the control diet with the exception of ferric citrate. All pregnant dams were housed singly in clear plastic shoebox cages measuring 45 x 24 x 20 cm in a temperature (23 ± 2°C) and humidity (40%) controlled room maintained on a 12:12 h light/dark cycle (lights on at 0600). All experimental protocols were in accordance with the NIH Animal Care guidelines and were approved by the Pennsylvania State Institutional Animal Care and Use Committee.

    Hematology and liver iron. At P9, P15, and P21, male and female rat pups were weighed and decapitated after brief exposure to CO₂ and trunk blood was collected. Whole blood was centrifuged at 3000 x g at 4°C for 15 min and then sera were frozen at –80°C. Serum iron and total iron binding capacity (TIBC) were determined by standard methods (8,15) and transferrin saturation was calculated as serum iron/TIBC x 100. Hemoglobin (Hb) concentrations were measured photometrically using cyanomethemoglobin standard solution (Sigma Aldrich), and hematocrit was calculated after centrifugation of blood samples in hepranized microcapillary tubes (5 min at RT). Livers were rapidly removed, weighed, and frozen at –80°C. Liver nonheme iron was measured using the standard technique described by Cook et al. (21). All treatment groups included 8–19 rats that represented 3–9 litters of pups. Milk was collected during lactation from CN and ID dams (n = 4/treatment group) after administration of oxytocin (ip, 5 IU) for iron analysis.

    Brain dissection. The brain was hemisectioned and the right hemisphere was quickly dissected on ice for cortex, hindbrain, frontal cortex, caudate putamen, ventral tegmentum-substantia nigra (ventral midbrain). The regions were placed immediately in storage tubes and frozen at –80°C. The left brain hemisphere reserved for autoradiography was frozen slowly in a dry ice:isopentane slurry and then stored frozen at –80°C.

    Regional brain iron, brain proteins, and monoamine concentrations. Frozen brain regions and dam milk were wet digested using published standard procedures and were analyzed for iron concentration by atomic absorption spectrophotometry (15). Brain ferritin, transferrin, tyrosine hydroxylase (THase), phosphorylated THase (p-THase), and thymus cell antigen-1 (thy-1, a cell surface protein) were evaluated by ELISA as described elsewhere (19). Catecholamine analysis was conducted by HPLC with coulometric detection as previously described (19). Each treatment group included 6–9 rats that represented 3–4 litters of pups.

    Monoamine transporter and receptor analysis. Left brain hemispheres were sectioned sagitally (20 µm) at –20°C, thaw mounted on gelatin-coated slides and stored desiccated at –80°C. Procedures for dopamine (DA) transporter and dopamine D2 receptor (D2R) ligand binding were performed as reported elsewhere (19). Each treatment group included 7–10 rats that represented 3–4 litters of pups.

    Developmental and behavioral assessment. Developmental milestones, based on the methods of LaPointe and Nosal (22), were assessed in rat pups from each group on the same days. A 6-point scale (0–5) was used to assess fur development (0 = no fur, 5 = thick, full fur), eye opening (0 = neither eye open, 5 = full bilateral eye opening), ear opening (0 = bumps only, 5 = bilateral ear canals open), bar holding (0 = no ability to grasp, 5 = ability to support body weight on the bar >10 s), surface righting (0 = >15 s to turn over on all 4 paws, 5 = immediate righting), and negative geotaxis (0 = >15 s to climb and pivot on a 45° incline, 5 = immediate climbing and pivoting). All developmental examination and behavioral testing was performed between 0800 and 1600 by a single observer who did not know the treatment group. Each treatment group included 8–16 rats that represented 3–7 litters of pups.

    Activity analysis. One day prior to killing, locomotor activity was assessed in each treatment group in dimly lit Accuscan activity monitors (Accuscan Instruments). Data were collected for 20 min after placement into the testing apparatus. Total distance traveled, center time, and number of stereotypic movements over the 20 min time period were analyzed. Activity was measured in 6–14 rats/treatment group and all measurements were recorded between 0800 and 1600.

    Statistical methods. Variables were analyzed using a mixed methods approach with diet as the fixed effect and dam as the random effect using SAS (SAS Institute). Comparisons were made only to controls at each time point. In all cases, excluding the developmental and behavioral assessments, values are expressed as means ± SEM. Developmental and behavior assessments data are presented as the percentage of rats achieving a score of 5. All data were previously examined for normality of distribution. Differences were considered significant at P < 0.05.

	Results

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
    Growth and hematology. Blood samples were obtained on P4 from a subset of pups from 4 iron deficient litters and 4 control mother litters. Pups from dams fed the ID diet from G15 had lower Hb concentrations compared with pups from those fed the CN diet (79 ± 3 vs. 89 ± 2 g/L, P < 0.05). When pups persisted on these 2 dietary protocols for an additional 2 d, the Hb concentration of CN pups remained nearly the same (82 ± 2 g/L), whereas that of the pups suckling with ID dams fell quickly to 71 ± 2 g/L. Milk iron analysis supported this evidence of low iron intakes during suckling with a mean milk Fe concentration of 25.1 ± 1.4 mmol/L in ID dams and 106.0 ± 1.8 mmol/L in milk of CN dams. Despite these differences in iron status, ID dams still delivered between 9–11 pups/litter, which was not different from the litter sizes of dams fed the control iron diet.

By P9, G15 ID rats developed severe anemia as indicated by lower hemoglobin (P < 0.05) and serum iron concentrations (P < 0.05) than CN rats, which continued through P15 and P21 (Table 1). These indices of iron status did not differ in IDCN rats compared with CN rats on P4. Postnatal ID begun on P4 (CNID) tended to lower hemoglobin (P = 0.09) and serum iron concentrations (P = 0.09) by P15 compared with CN rats. Body weight was reduced relative to the CN group only in the ID group at P15 (P < 0.05).

Brain iron–requiring protein concentrations were measured in striatum of rats as indices of functional iron deficit (Table 2). Striatum transferrin was greater in ID rats than in CN rats by >35% at P15 (P < 0.05) and 21 (P < 0.05), whereas ferritin concentrations did not differ (data not shown). Proteins related to monoamine synthesis and release were also measured. THase and the active form of THase, p-THase, were both elevated in ID rats at P15 but were not different from CN levels at P21 (P < 0.05). Vesicular monoamine transporter type 2, part of the vesicular secretory complex, was elevated in striatum of ID rats at P9, but by P21, when the region was deficient in iron, it had fallen to 50% of CN levels (data not shown). Thy-1, a cell surface protein involved in synaptic efficacy, did not differ between CN and ID rats. IDCN pups had more THase at P9, 15, and 21 compared with CN rats (P < 0.05), as well as increased levels of Thy-1 at P9 and P15. CNID pups had more THase and p-THase at P9 and P15 compared with CN pups (P < 0.05).

Two terminal DAergic fields were also examined, the PFC and the striatum (caudate putamen). PFC DA was elevated in ID pups at P9 (P < 0.05) and at P15 (P < 0.05) compared with CN pups (Table 3).The increased PFC DA in ID pups in early postnatal life was similar to that of VMB DA in ID pups at P15. IDCN pups also had greater PFC dopamine concentrations at P9 (P < 0.05) and P15 (P < 0.05) than CN pups. In striatum, ID pups also had elevated DA at P15 (P < 0.05) and greater HVA concentrations (P < 0.05) relative to same-age CN pups (Table 4). In contrast, CNID rats had lower striatal DA, HVA, dihydroxyphenylacetic acid, NE, and epinephrine concentrations than CN pups at P21 (P < 0.05). The iron therapy group (IDCN) did not differ from CN pups in striatal dopamine concentrations (P > 0.44 at all ages).

View larger version (18K): [in this window] [in a new window]   Figure 1  Developmental achievement of fur development (A), eye opening (B), and ear development (C) in CN, ID, CNID, and IDCN rat pups. Rats were scored on a scale of 0–5 on P6, 9, 12, 15, 18, and 21. Data are shown as percentage of rats achieving a score of 5 at each time point.

    Negative geotaxis, bar holding, and surface righting. Only CNID pups showed delayed achievement in bar holding ability at P12 (P < 0.05) and surfacing righting ability at P6 (P < 0.05) relative to CN pups. In these measures, 27.3% of CNID rats reached a score of 5 for bar holding at P12 compared with 66.0% of CN rats, and only 2.4% reached a score of 5 for surface righting at P6 compared with 12.3% of CN rats (Fig. 2A, 2B).Negative geotaxis was not affected by dietary treatment (Fig. 2C).

View larger version (18K): [in this window] [in a new window]   Figure 2  Developmental achievement of bar holding (A), surface righting (B), and negative geotaxis (C) in CN, ID, CNID, and IDCN rat pups. Rats were scored on a scale of 0–5 on P6, 9, 12, 15, 18, and 21. Data are shown as percentage of rats achieving a score of 5 at each time point.

View larger version (12K): [in this window] [in a new window]   Figure 3  Locomotor activity as total distance traveled was measured over 20 min in CN, ID, CNID, and IDCN rat pups on P15 and P21. Data are means ± SEM, n = 6–14. *Different from CN at that age, P < 0.05.

	Discussion

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

There is an extant literature on the effects of iron depletion and repletion on physiological markers, protein expression, and behavior; however, the consequences of both prenatal and postnatal iron deficiencies on the developmental milestones measured here have not been addressed to any great extent. In fact, only a few studies have examined the influences of prenatal iron deficiency on behavioral measures (23–25). One (23) had few biologic measures, whereas the other 2 were studies in Swiss-Webster mice. Prenatal iron deficiency had long-lasting effects on postweaning behavior and neurochemistry. Adult mice fed a reduced iron diet (12.5 µg/g) from G0 to P60 showed a consistent reduction in forelimb and hindlimb grip strength, lowered brain iron and catecholamine levels, attenuated startle response, and impaired performance in the Morris water maze in mice of both sexes (24,25). The timing and acquisition of developmental milestones was not assessed. These authors also showed that, although iron repletion at P21 reversed the effect of iron deficiency on acoustic startle response, maze performance continued to be impaired for up to 60 d of age, which suggests that at least some behavioral impairments caused by prenatal iron deficiency are not necessarily reversible by iron supplementation in mice.

In a similar study in which iron deficiency was started on G5 and continued until P25, physiological development (eye opening and ear development) and sensorimotor skills (bar holding, surface righting, and negative geotaxis) were altered by P15 (14). The persistence of effects on behavior was evident, despite iron therapy, in adulthood where formerly iron deficient rats had significant deficits in performance in the Morris water maze and alterations in striatal dopamine metabolism. In the present study, eye opening and ear development were also delayed by gestational iron deficiency starting at G15. The impairments in development were only observed at P15. Similar to control pups, most G15 iron deficient pups reached a score of 5 by G18. Unlike the previous study, sensorimotor tasks including bar holding, surface righting, and negative geotaxis were largely unaffected in gestational iron deficient pups. In contrast, postnatal iron deficiency appears to delay bar holding and surface righting achievement in early postnatal life. These differences in achievement likely result from the timing of iron deficiency and the critical periods for the development of these physiological markers.

The fact that we observed iron deficiency–related delays in eye opening and ear development raises the question as to whether this constitutes sensory deprivation. Sensory deprivation in mammals results in afferent pathway malformation or dysfunction with attendant changes in visual (26,27), auditory (28,29), and somatosensory (30) systems. In the studies cited, deprivation lasted from days to weeks, whereas our differences in eye and ear development occurred within 2–3 d. The extent to which this delayed development for both modalities affects later function is largely unknown as it relates to iron deficiency.

Specific neurochemical pathways including dopaminergic systems also are altered in iron deficient rats as early as P15 when dietary deprivation begins at G15. The alterations in dopamine concentration are nearly identical to those previously reported at P10 when iron deficiency commenced at G5 (19), whereas DA transporter and D2 receptor levels were largely unaffected in G15 ID rats in the present study. Because DA projection fields and intersynaptic connections develop most rapidly between P8 and P15 (31,32), iron deficiency before and during this time period likely influences synaptic connections within dopaminergic systems. THase and the active phosphorylated form of the enzyme are both elevated in iron deficient rats at this early age, along with vesicular monoamine transporter type 2. This dopaminergic footprint is consistent with increased DA synthesis and release. The timing of onset of prenatal ID did not alter this apparent preweaning hyperdopaminergic state that precedes the actual fall in striatal and prefrontal cortex iron by P65 insofar as the same phenomenon was observed when prenatal iron deficiency began at G5 (19).

Negative geotaxis and surface righting are dependent upon dopamine-mediated motor control as well as connectivity within the vestibular system and muscular strength. During development, vestibular system growth begins during the gestational period and continues to mature through P25 in rodents (33). We found that only early postnatal iron deficiency modestly altered surface righting achievement at P6 and had no effect on negative geotaxis at any age. These findings are in agreement with the lack of effect of iron deficiency on negative geotaxis in mice when fed a reduced iron diet at G0 (25). Thus, in the present study, alterations in sensorimotor tasks may point toward only modest changes in connectivity within vestibular pathways.

With regard to behavioral and sensorimotor tasks, iron deficiency can also reduce muscular strength by diminishing oxygen delivery and impairing mitochondrial content and function within skeletal muscle (34–36). These factors may underlie the reduction in activity levels in G15 iron deficient rats at P21 and in bar holding and surface righting achievement in P4 iron deficient rats. Direct measurements of neuromotor function or muscle function in this model of developmental iron deficiency have not been reported.

In summary, these new experimental data demonstrate that effects of iron deficiency on the acquisition of fundamental developmental global milestones are subtle when dietary restriction begins in utero or even in very early postnatal rodent life. This tells us that the global aspects of growth and development are not altered by moderate iron deficiency. There are, however, significant changes in brain dopamine function, proteins involved in the synthesis of monoamines, and synaptic efficacy. Importantly, this phenotype can be "rescued" in postnatal life if the intervention is started early. The failure of previous studies to rescue the phenotype with postweaning intervention affirms previous conclusions that there are highly vulnerable periods in rodents during lactation. When we translate the timing to humans, an intervention in the last trimester, or 30–32 wk, would likely be successful in ameliorating many effects of iron deficiency experienced earlier in utero. This does not imply, however, that there are not other, earlier developmentally sensitive time points where nutritional intervention would be of great benefit. In fact, it is likely that there are different critical windows for different organs and tissues.

	ACKNOWLEDGMENTS

 
The authors thank Sarah Rundle for her excellent technical assistance with the brain iron analysis. We are also grateful to Laura Bianco for her expertise in measuring brain monoamines.

	FOOTNOTES

 
¹ This work was supported in part by U.S. Public Health Service grant NS 35088 (J.L.B.) and NIH Program Project funds to B. F. for development of the milestone tests (HD 39386).

⁵ Abbreviations used: CN, rat pups fed an iron adequate diet from G15 to P21; CNID, rat pups fed an iron adequate from G15 to P4 followed by an iron deficient diet from P4 to P21; DA, dopamine; G15, gestational day 15; Hb, hemoglobin; HVA, homovanillic acid; ID, rat pups fed an iron deficient diet from G15 to P21; IDCN, rat pups fed an iron deficient diet from G15 to P4 followed by an iron adequate diet from P4 to P21; NE, norepinephrine; p-THase, phosphorylated tyrosine hydroxylase; PFC, prefrontal cortex; P4, postnatal day 4; TH, tyrosine hydroxylase; VMB, ventral midbrain.

Manuscript received 21 August 2006. Initial review completed 5 September 2006. Revision accepted 19 October 2006.

	LITERATURE CITED

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