Iron status and periodic limb movements of sleep in children: a causal relationship?
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Comment↗
Biomedical subjects
John L Beard
Publications and source records attributed to John L Beard.
Iron supplementation does not affect the susceptibility of LDL to oxidative modification in women with low iron status.
Elevated iron stores may or may not promote atherogenesis by increasing free radical formation and oxidative stress, but controlled diet and supplement trials are lacking. We tested the hypothesis that iron supplementation does not increase the susceptibility of LDL to undergo oxidative modification in women with low iron status. A randomized, double-blind, 2-period crossover study design (n=26) was used to examine the effects of the following diets on measures of LDL oxidation: average American diet (AAD) [36% of energy as fat; 15% saturated fatty acids (SFA)], and a Step 2 diet (26% fat; 7% SFA). In addition, subjects received either a supplement containing 160 mg of ferrous sulfate (50 mg elemental iron) or a placebo twice daily [supplement group received a total of 320 mg ferrous sulfate (100 mg elemental iron) daily]. After supplementation, serum ferritin differed between the supplement and placebo groups (P=0.008). Measures of LDL oxidation were not affected by supplement intake; however, they were affected by diet. Lag time was shorter after the women consumed the AAD diet than after the Step 2 diet (P<0.0001). The diets did not affect the rate of oxidation or total dienes. Although iron status was improved by aggressive iron supplementation, LDL oxidative susceptibility was not affected. As expected, lag time was increased after the women consumed the low fat, low SFA diet. Therefore, the results of this study do not support a relationship between iron status and LDL oxidation.
Adult↗
Iron status and neural functioning.
Iron deficiency in early life is associated with delayed development as assessed by a number of clinical trials using similar global scales of development; this poor development during infancy persists in most cases after iron therapy has corrected iron status. If iron deficiency occurs in preschool and older children, the consequences appear reversible with treatment. The biologic understanding of this relationship between development, brain iron status, and functioning is sparse though animal studies repeatedly demonstrate alterations in dopamine metabolism and in the myelination process. Dietary iron deficiency can rapidly deplete brain iron concentrations and repletion is able to normalize them. Residual alterations in striatal dopamine metabolism and myelin production persist if neonatal animals are used. Future studies with more specific measures of neurodevelopment in iron-deficient human infants, and animal models, will allow investigators to more clearly define causal roles of brain iron in neural development and functioning.
Adolescent↗
Quantitative genetic analysis of ventral midbrain and liver iron in BXD recombinant inbred mice.
Male and female mice from 15 of the BXD/Ty recombinant inbred strain panel were examined for regional brain and liver iron content. Brain regions included medial prefrontal cortex, nucleus accumbens, caudate-putamen and ventral midbrain. Our focal tissue was the ventral midbrain, containing the ventral tegmentum and substantia nigra. This area contains the perikarya of the dopamine neurons that project to nucleus accumbens and caudate-putamen. Genetic correlations between ventral midbrain and liver iron content were not statistically significant, suggesting that peripheral and central iron regulatory systems are largely independent. Correlations between ventral midbrain iron and iron in the caudate-putamen and nucleus accumbens, but not the prefrontal cortex were moderately high and significant. Ventral midbrain and liver iron contents were subjected to quantitative trait loci analysis to identify associated chromosomal locations. This analysis revealed several suggestive loci for iron content in ventral midbrain but fewer loci for liver. Genetic correlations between ventral midbrain iron and published dopamine functional indices were significant, suggesting a link between ventral midbrain iron status and central dopamine neurobiology. This work shows the value of quantitative genetic analysis in the neurobiology of iron and in showing the close association between ventral midbrain iron and nigrostriatal/mesolimbic dopamine function.
Animals↗
Women with low iron stores absorb iron from soybeans.
BACKGROUND: Worldwide, 30% of the population, a greater proportion of whom are women and children, is iron deficient. Soybeans are a major source of nonheme iron in many human diets, but information on iron bioavailability is still conflicting. Because much of soybean iron is in ferritin [distinct from the poorly bioavailable iron in cereals resulting from interactions between calcium, Fe(III), phytate, and proteins in the meal], soybeans provide a target for manipulating seed iron composition to achieve increased iron bioavailability. OBJECTIVE: The aim was to reevaluate soybean iron bioavailability. DESIGN: Eighteen women, most with marginal iron deficiency, consumed meals with intrinsically labeled ((55)Fe) soybeans (hydroponically grown and nonnodulating) as soup (n = 11) or muffins (n = 7) and a reference dose of (59)Fe as ferrous sulfate in ascorbate solution. The radioactivity in red cells was measured 14 and 28 d later. RESULTS: The mean (55)Fe absorption from either soup or muffins was 27% and that from the reference dose was 61%. (55)Fe was distributed approximately equally between protein (49.3 +/- 3.0%) and phytate, a contrast with nodulating soybeans likely caused by a high phosphate content in the growth medium. There was an expected inverse correlation (r = -0.793, P < 0.001) between red cell radioactivity and serum ferritin concentration. CONCLUSIONS: These results show that soybeans appear to be a good source of nutritional iron in marginally iron-deficient individuals. More study is needed on the effect of plant nodulation on the form of soybean iron, aimed at enhancing bioavailability to combat iron deficiency in at-risk populations.
Adult↗
Iron status in association with cardiovascular disease risk in 3 controlled feeding studies.
BACKGROUND: The role of body iron stores in free radical-induced peroxidation and cardiovascular disease risk has been debated, but controlled feeding studies using measurements of non-transferrin-bound iron (NTBI) and LDL oxidation have not been conducted. OBJECTIVE: We tested the hypothesis that NTBI and other measures of iron status do not affect oxidative susceptibility in healthy subjects with normal iron status. DESIGN: Plasma samples were analyzed from 77 healthy men and women aged 20-65 y who participated in 3 controlled feeding studies in which the type and amount of dietary fat were controlled. Iron status and in vitro LDL oxidation were assessed at baseline and at the end of each feeding period (4-8 wk). RESULTS: No significant relations were found between any measure of iron status (ferritin: 83 +/- 8.9 micro g/L; iron: 20.9 +/- 5.4 micro mol/L; TIBC: 74.4 +/- 11.0 micro mol/L; NTBI: 0.184 +/- 0.15 micro mol/L) and the in vitro measures of LDL oxidation (total dienes: 485 +/- 55 micro mol/mg LDL protein; lag time: 51.7 +/- 15.9 min; and rate of oxidation: 25.4 +/- 6.8 micro mol dienes.min(-1).g LDL protein(-1)). Equal-iron peanut butter-based diets were associated with higher plasma iron in men (22.4 +/- 3.8 micro mol/L) than was the olive oil diet (17.7 +/- 4.5 micro mol/L) (P = 0.02), but this slight elevation did not alter LDL oxidation. CONCLUSIONS: Diet composition may affect plasma iron in men, but LDL oxidative susceptibility is unaffected by the subtle variation in iron status. Thus, the results do not support a relation between iron status and LDL oxidative susceptibility, a possible risk factor for cardiovascular disease.
Adult↗
Low hemoglobin level is a risk factor for postpartum depression.
The role of maternal anemia in the development of postpartum depression (PPD) is unclear. PPD is a serious disorder that may negatively affect the physical and emotional health of a new mother and her infant. Although psychosocial factors that increase the risk of developing PPD are known, few studies have identified physiologic factors that predispose a woman to PPD. New mothers were visited at home on d 7, 14 and 28 after an uncomplicated labor and delivery. Hemoglobin (Hb) concentration was measured via finger-prick blood at each visit, and the women completed the Center for Epidemiological Studies-Depressive Symptomatology Scale (CES-D) on d 28. There was a negative correlation between Hb concentration on d 7 postpartum and depressive symptoms on d 28 (r = -4.26; P = 0.009). CES-D scores (means +/- SEM) on d 7 of women with normal Hb levels > 120 g/L (12 g/dL) were significantly lower (6.90 +/- 1.04) than those of women with Hb levels < or = 120 g/L (12 g/dL) [16.36 +/- 3.34; t(35) = -3.632, P = 0.001]. Thus, women suffering early postpartum anemia may be at increased risk of developing PPD.
Adult↗
Iron-deficient mice fail to develop autoimmune encephalomyelitis.
Determinations of the effects of iron status on the immune system are complicated by the fact that microorganisms and immune cells both utilize iron. To determine the role of iron in immune function, we utilized a model [experimental autoimmune encephalomyelitis (EAE)] in which a strong antigen-specific CD4+ T-cell response develops in the absence of infection. EAE is an autoimmune disease frequently used as a model for the human disease multiple sclerosis (MS). EAE was induced in B10.PL mice fed low iron (1 mg/kg), normal iron (10 mg/kg) or high iron (160 mg/kg) diets that were replete in all other nutrients. Liver iron measurements verified iron status, i.e., low iron mice had 1.9 micro mol/g tissue, normal iron mice, 3.27 micro mol/g tissue and high iron mice, 5.35 micro mol/g tissue. EAE symptoms were most severe in normal iron mice, and EAE did not develop in low iron mice. The incidence of EAE was 71% in normal iron mice, 62% in iron-overloaded mice and 0% in iron-deficient mice. Two of seven mice in the normal iron group developed severe EAE and were euthanized. None of the iron-overloaded mice developed severe EAE. Other measures of EAE severity were similar in the normal and iron-overloaded mice. The data suggest that iron deficiency provides protection from the development of EAE and that iron excess with its potential contribution to free radical formation was not an important factor. The mechanism of EAE inhibition in iron-deficient mice likely involves the delivery and metabolism of iron for optimal CD4+ T-cell development.
Animals↗
Gene expression of transferrin and transferrin receptor in brains of control vs. iron-deficient rats.
The mechanism of the regulation of transferrin (Tf) and transferrin receptor (TfR) levels in rat brain by dietary iron status is not fully elucidated. We examined Tf and TfR protein and mRNA contents in various brain regions affected by dietary iron deficiency, and analyzed the relationships between protein and mRNA contents in brains of control vs. iron-deficient rats. In a region-specific fashion, iron-deficient diet decreased significantly brain iron concentration by 22-63%, and increased Tf level by 22-130% and TfR level by 74% in thalamus and 40% in cortex. Tf mRNA content decreased by 20-50% in most brain regions demonstrating inverse correlation of Tf and its mRNA in response to iron deficiency. TfR mRNA levels remained unaffected by iron status. The corpus callosum, white matter of the cerebellum and lateral ventricles expressed highest levels of Tf mRNA, whereas TfR mRNA levels was lowest in these regions, but highest in cortex, hippocampus, and the gray matter of the cerebellum. The data demonstrate that the cells in brain have the capacity to maintain minimum iron levels during iron deficiency. This capacity may be associated with increased iron-Tf uptake from plasma, stabilization of TfR mRNA, or increased Tf mRNA translation efficiency in specific cell types within the brain.
Animals↗
Neurobehavioral analysis of developmental iron deficiency in rats.
Iron deficiency (ID) in early life alters the course of behavioral and cognitive development in humans, causing decreased physical activity and responsiveness to the environment. The effects of ID on behavior are similar in rats and hypothesized to be related to ID-related impairments in central dopamine pathways. The objective of this study was to examine the association between brain iron measures of dopamine function, and behavioral measures of activity and reactivity. Male and female weanling rats were fed either an iron deficient diet or control diet for 6 weeks. The iron deficient rats showed significantly decreased activity and increased anxiety-like behaviors. Iron deficient rats also showed significant decrements in brain iron content in the corpus striatum, prefrontal cortex, and midbrain and decreases in dopamine receptors and the transporter in the same areas. Multiple regression analysis showed ventral midbrain iron concentration and dopamine D(1) receptor density to be highly associated with exploration and repeated movements, respectively. In addition, the results showed anxiety-like behaviors to be related to prefrontal cortex dopamine transporter and dopamine D(1) receptor densities. We conclude from these analyses that iron concentration in dopamine containing regions and densities of dopamine receptors and the transporter, are significant predictors of measures of activity and reactivity. These observations also strengthen the argument that the Fe-dopamine link is fundamental to understanding biobehavioral difficulties seen in children with ID anemia.
Animals↗
Genetic differences in hepatic lipid peroxidation potential and iron levels in mice.
Oxidative damage to macromolecules, including lipids, has been hypothesized as a mechanism of aging. One end product of lipid peroxidation, malondialdehyde (MDA), is often quantified as a measure of oxidative damage to lipids. We used a commercial colorimetric assay for MDA (Bioxytech LPO-586, Oxis International, Portland, OR) to measure lipid peroxidation potential in liver tissue from young (2 month) male mice from recombinant inbred (RI) mouse strains from the C57BL/6J (B6)xDBA/2J (D2) series (BXD). The LPO-586 assay (LPO) reliably detected significant differences (P<0.0001) in lipid peroxidation potential between the B6 and D2 parental strains, and yielded a more than two-fold variation across the BXD RI strains. In both B6 and D2 mice, LPO results were greater in old (23 month) mice, with a larger age-related increase in the D2 strain. As the level of iron can influence lipid peroxidation, we also measured hepatic non-heme iron levels in the same strains. Although iron level exhibited a slightly negative overall correlation (r(2)=0.119) with LPO results among the entire group of BXD RI strains, a sub-group with lower LPO values were highly correlated (r(2)=0.704). LPO results were also positively correlated with iron levels from a group of 8 other inbred mouse strains (r(2)=0.563). The BXD RI LPO data were statistically analyzed to nominate quantitaive trait loci (QTL). A single marker, Zfp4, which maps to 55.2 cM on chromosome 8, achieved a significance level of P<0.0006. At least two potentially relevant candidate genes reside close to this chromosomal position. Hepatic lipid peroxidation potential appears to be a strain related trait in mice that is amenable to QTL analysis.
Aging↗
Iron deficiency in rats decreases acquisition of and suppresses responding for cocaine.
Iron deficiency impairs nigrostriatal and mesolimbic dopamine systems by causing decreased densities of D(1) and D(2) receptors and the dopamine transporter in the terminal fields, caudate-putamen and nucleus accumbens. Iron deficiency also causes deficits in dopamine-related pharmacological indices, e.g., deficits in locomotor stimulation by cocaine and locomotor inhibition by raclopride. Based on this knowledge, we hypothesized that iron deficiency would have a major impact on cocaine self-administration. Male Sprague-Dawley rats were fed an iron-deficient diet starting at weaning (Day 21) and continuing throughout the experiment. At 57-58 days of age, all animals had catheters implanted surgically into the jugular vein. Approximately 2 weeks later, all animals were trained to lick an empty spout for intravenous cocaine, delivered by infusion pump at 0.33 mg/kg. During the course of training, all animals acquired intravenous cocaine self-administration, however, the course of acquisition was significantly slower for the iron-deficient animals. When tested for responding on a progressive ratio (PR) schedule, the control animals maintained a constant number of infusions, whereas the responding of the iron-deficient animals fell off sharply. When the dose of cocaine was decreased, control, but not iron-deficient adjusted the amount administered by increasing the number of infusions. Finally, the failure to respond by the iron-deficient animals was not simply due to a failure to lick (i.e., a motor impairment), because both the iron-deficient and the control animals emitted approximately 1000 licks/20 min session when given free access to a palatable 0.1 M sucrose solution. Taken together, the data show that severe iron deficiency early in life can diminish the capacity of cocaine, but not sucrose to reinforce behavior. The question raised by this research thus, is whether iron deficiency alters hedonic-like responses only to dopamine-related behaviors and the degree to which willingness to "work" contributes to the effect.
Animals↗
Iron deficiency and marginal vitamin A deficiency affect growth, hematological indices and the regulation of iron metabolism genes in rats.
Iron deficiency and marginal vitamin A (VA) deficiency frequently coexist and affect billions of people, mostly children and women, worldwide. The effects of these micronutrient deficiencies alone and in combination on hematologic, biochemical and molecular indices of iron and VA status were investigated in a 2 x 2 randomized blocked study conducted in growing male Sprague-Dawley rats. From 3-8 wk of age, rats were fed one of four purified diets that were either adequate or restricted in iron (Fe) and adequate or marginal in VA: (+)Fe(+)VA, 20.3 and 0.367 micro g/g, respectively, denoted control diet; (-)Fe(+)VA, 3.34 and 0.405 micro g/g; (+)FeVA(m), 22.2 and 0.051 micro g/g; or (-)FeVA(m), 3.03 and 0.055 micro g/g. Weight-matched rats fed adequate micronutrients were included to control for possible confounding effects of Fe deficiency on growth and feed efficiency. Iron restriction reduced (P < 0.05) weight gain, feed efficiency, blood hemoglobin and hematocrit. Plasma and liver iron and plasma transferrin saturation were reduced by approximately 50%, whereas liver transferrin mRNA and protein and transferrin receptor mRNA were elevated, as was liver ferritin light-chain protein and light-chain mRNA. Liver heavy-chain ferritin mRNA, hemopexin, ceruloplasmin and cellular retinol-binding protein mRNA were not affected by iron or VA restriction. Although marginal VA deficiency did not exacerbate indices of poor iron status during iron deficiency, iron deficiency was associated with lower plasma retinol and elevated liver VA concentrations. These results are consistent with an impaired mobilization of liver retinol during iron deficiency as well as multiple alterations in iron metabolism.
Anemia, Iron-Deficiency↗
Transgenic rice is a source of iron for iron-depleted rats.
Iron deficiency is one of the most prevalent nutrient deficiencies in the world. A sustainable solution to dietary iron deficiency may be achieved in part by increasing bioavailable iron in seeds used for foods such as rice. Because ferritin is used as a natural source of iron in the early development of humans, other animals and plants, the bioavailability of iron in rice seeds, provided in amounts equal to ferrous sulfate, and in transgenic rice with ferritin was tested in iron-deficient rats. A standard hemoglobin (Hb) repletion bioassay was used with rats made anemic followed by complete diets containing equivalent amounts of iron as FeSO(4) or one of three different bioengineered rice varieties (Kitaake and two transgenic derivatives with ferritin targeted to the seed, FK11 and FK22). Rice diets were as effective as the FeSO(4) diet in replenishing hematocrit, Hb concentration and liver iron concentrations. These data suggest that Mendelian and biotechnological approaches to manipulating ferritin expression of seed iron in rice may contribute to a sustainable solution to global problems of iron deficiency.
Anemia, Iron-Deficiency↗
H and L ferritin subunit mRNA expression differs in brains of control and iron-deficient rats.
The mRNA expression of ferritin subunits has not been studied thoroughly in the brain regions of iron-deficient rats. Sprague-Dawley rats (n = 26; 21 d old) were randomly assigned to an iron-deficient (3.5 mg Fe/kg diet) or a control diet (35 mg Fe/kg diet) for 6 wk. Ferritin protein and mRNA contents were quantified and the cellular expression of ferritin subunits in brain was determined. H and L ferritin had the same mRNA locations in nearly all brain regions. Both ferritin subunit mRNAs had heterogeneous distributions and there was a regional effect across brain regions. Iron deficiency did not affect the amount of ferritin mRNA in most brain regions, suggesting the post-transcriptional regulation of messengers by iron status. H ferritin protein was predominant in neurons and oligodendrocytes, whereas L ferritin protein and iron predominated in microglia cells and astrocytes as well as in oligodendrocytes and neurons. Ferritin mRNA was detectable only in neurons. Iron deficiency did not induce new types of cells containing either ferritin protein or mRNA. The fact that ferritin protein was found in four types of cells whereas mRNA was found in only one type of cell suggests that the site of ferritin synthesis is different from protein location in the brain. All of these data suggest that regulation of ferritin subunits is cellular and/or regional specific.
Animals↗
Brain iron uptake in hypotransferrinemic mice: influence of systemic iron status.
The relationship of the heterogeneity of iron concentrations in the brain with the regulation of iron uptake into specific brain regions remains unresolved. We used hypotransferrinemic mice and an iron-deficient or control diet to explore whether plasma transferrin (Tf), transferrin saturation, and plasma iron levels influence the uptake of (59)Fe and whether there was brain region specificity. Weaning wild-type (+/+) and heterozygotic mice (+/hpx), were sorted randomly to either a iron-deficient diet or a control iron diet for 8 weeks, whereas homozygous mice (hpx/hpx) ate the control diet for 8 weeks before (59)Fe uptake studies. Iron-deficient heterozygous and wild-type mice both had significantly greater plasma Tf levels (37.5 and 42.5 microM) than control mice had (heterozygous and wild-type controls were 20 and 32.5 microM) and far more than homozygous mice (<0.2 microM) had, thus providing five distinct levels of plasma Tf concentrations. After intravenous injection of (59)Fe, brains of iron-deficient wild-type mice took up significantly more (59)Fe (0.15% dose) compared to control wild-type mice (0.056%) at 2 hr, a treatment effect that persisted through 24 hr. In contrast, diet had no effect in heterozygous mice. Importantly, homozygous mice had equivalent uptake to other groups (0.089% dose) by 24 hr. Early brain radioactivity varied by regions (hypothalamus and prefrontal cortex approximately 10-18% brain uptake > cerebellum, pons, thalamus, and striatum approximately 7-12% > cortex, hippocampus, and substantia nigra approximately 6-8%). This distribution of radioactivity changed over 24 hr in the hypothalamus of heterozygous mice, homozygous mice, and iron-deficient wild-type mice. Homozygous mice also showed higher uptake (13-15%) in some regions (hypothalamus and cerebellum) than in other regions. In wild-type and heterozygous mice, (59)Fe uptake was inversely related to brain Tf and was independent of regional brain iron concentrations and plasma Tf levels or saturation. These experimental data suggest that brain iron uptake may be constitutive and independent of plasma Tf, transferrin saturation, or regional brain iron concentration. The proteins and mechanisms responsible for additional iron uptake into specific regions, or perhaps the redistribution are unclear though the data are supportive of a non-transferrin-bound iron uptake pathway.
Analysis of Variance↗
Neurobehavioral evaluation of rhesus monkey infants fed cow's milk formula, soy formula, or soy formula with added manganese.
The possible neurobehavioral effects of excess manganese in soy formula were studied. Male rhesus monkeys (n=8/group) were fed a commercial cow's milk based formula (Control), a commercial soy protein based formula (Soy), or the soy formula with added manganese (Soy+Mn) from birth to 4 months of age. Soy formulas naturally have higher manganese (Mn) content than cow's milk formulas. Monkeys received behavioral evaluations, growth measurements, and cerebrospinal fluid (CSF) sampling from birth to 18 months of age. Soy and Soy+Mn groups engaged in less play behavior and more affiliative clinging in social dyadic interactions. These groups also had shorter wake cycles and shorter periods of daytime inactivity than controls. An impulsivity test was sensitive to the Soy group diet. The Soy+Mn group also had a blunted response to the dopamine agonist apomorphine. Groups did not differ significantly in CSF dopamine and serotonin metabolite concentrations, but these concentrations were correlated with several tasks affected by experimental formula. This experiment suggests that components of soy formula, including Mn, may influence brain development as reflected in behavioral measures.
Activity Cycles↗
Quantitative genetic analysis of brain copper and zinc in BXD recombinant inbred mice.
Copper and zinc are trace nutrients essential for normal brain function, yet an excess of these elements can be toxic. It is important therefore that these metals be closely regulated. We recently conducted a quantitative trait loci (QTL) analysis to identify chromosomal regions in the mouse containing possible regulatory genes. The animals came from 15 strains of the BXD/Ty recombinant inbred (RI) strain panel and the brain regions analyzed were frontal cortex, caudate-putamen, nucleus accumbens and ventral midbrain. Several QTL were identified for copper and/or zinc, most notably on chromosomes 1, 8, 16 and 17. Genetic correlational analysis also revealed associations between these metals and dopamine, cocaine responses, saccharine preference, immune response and seizure susceptibility. Notably, the QTL on chromosome 17 is also associated with seizure susceptibility and contains the histocompatibility H2 complex. This work shows that regulation of zinc and copper is under polygenic influence and is intimately related to CNS function. Future work will reveal genes underlying the QTL and how they interact with other genes and the environment. More importantly, revelation of the genetic underpinnings of copper and zinc brain homeostasis will aid our understanding of neurological diseases that are related to copper and zinc imbalance.
Animals↗