RESUMO
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with complicated pathogenesis with variable presentation and disease progression. There is a critical need for a panel of biomarkers to provide clinicians and researchers with additional information. In this study, multiplex immunoassays were used to screen a number of cytokines, growth factors, and iron-related proteins. ALS patients had significantly higher plasma levels of L-ferritin and lower concentrations of transferrin when compared to healthy controls and together classified a test group of subjects with 82% accuracy. Duration of ALS symptoms correlated positively with levels of monocyte chemoattractant protein 1 (MCP-1) and negatively with levels of granulocyte-macrophage colony stimulating factor (GM-CSF). The biomarker profile suggests iron homeostasis is disrupted in ALS patients, and changes in ferritin and transferrin (Tf) appear to be indicators of ongoing inflammatory processes. The data demonstrate a plasma biomarker profile in ALS patients that may differ from published reports of cerebrospinal fluid biomarkers.
Assuntos
Esclerose Lateral Amiotrófica/sangue , Esclerose Lateral Amiotrófica/genética , Homeostase/fisiologia , Ferro/metabolismo , Idoso , Envelhecimento/metabolismo , Peptídeos Catiônicos Antimicrobianos/sangue , Biomarcadores , Quimiocina CCL2/sangue , Citocinas/sangue , DNA/genética , Progressão da Doença , Feminino , Ferritinas/sangue , Genótipo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/sangue , Proteína da Hemocromatose , Hepcidinas , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Imunoensaio , Ferro/sangue , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Transferrina/metabolismoRESUMO
Restless leg syndrome (RLS) is a sensorimotor disorder. Clinical studies have implicated the dopaminergic system in RLS, while others have suggested that it is associated with insufficient levels of brain iron. To date, alterations in brain iron status have been demonstrated but, despite suggestions from the clinical literature, there have been no consistent findings documenting a dopaminergic abnormality in RLS brain tissue. In this study, the substantia nigra and putamen were obtained at autopsy from individuals with primary RLS and a neurologically normal control group. A quantitative profile of the dopaminergic system was obtained. Additional assays were performed on a catecholaminergic cell line and animal models of iron deficiency. RLS tissue, compared with controls, showed a significant decrease in D2R in the putamen that correlated with severity of the RLS. RLS also showed significant increases in tyrosine hydroxylase (TH) in the substantia nigra, compared with the controls, but not in the putamen. Both TH and phosphorylated (active) TH were significantly increased in both the substantia nigra and putamen. There were no significant differences in either the putamen or nigra for dopamine receptor 1, dopamine transporters or for VMAT. Significant increases in TH and phosphorylated TH were also seen in both the animal and cell models of iron insufficiency similar to that from the RLS autopsy data. For the first time, a clear indication of dopamine pathology in RLS is revealed in this autopsy study. The results suggest cellular regulation of dopamine production that closely matches the data from cellular and animal iron insufficiency models. The results are consistent with the hypothesis that a primary iron insufficiency produces a dopaminergic abnormality characterized as an overly activated dopaminergic system as part of the RLS pathology.
Assuntos
Dopamina/fisiologia , Putamen/fisiopatologia , Síndrome das Pernas Inquietas/fisiopatologia , Substância Negra/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Anemia Ferropriva/complicações , Anemia Ferropriva/metabolismo , Animais , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Humanos , Putamen/metabolismo , Ratos , Ratos Sprague-Dawley , Síndrome das Pernas Inquietas/etiologia , Síndrome das Pernas Inquietas/metabolismo , Substância Negra/metabolismo , Células Tumorais Cultivadas , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Monoamine metabolism in the central nervous system is altered by dietary iron deficiency, with a stronger effect seen during the active than rest span of the circadian cycle. In this report, we examined changes in intracellular and extracellular monoamine levels, synthetic enzymes, transporter and receptor densities, and responses to amphetamine-induced dopamine (DA) efflux in iron-deficient and iron-sufficient mice. Extracellular striatal DA levels were 15-20% higher in all groups during the active dark phase compared to the inactive light phase, with correspondingly lower dopamine transporter (DAT) and higher tyrosine hydroxylase levels. Iron deficiency decreased DAT density by 20% and 28% in the light and dark phases, respectively, and elevated the DOPAC/DA ratio only in the dark, indicating that iron deficiency does interact with the normal diurnal cues for cyclicity. Enhanced DA efflux after amphetamine stimulation indicates no limitation on monoamine synthesis and release and is consistent with altered synaptic efficacy and perhaps recycling of DA in iron deficiency. These experimental findings provide new evidence that brain iron insufficiency does have a differential effect on the DA system at different biological times of the day and night and may be causally related to the phasic motor symptoms observed in Restless Legs Syndrome.
Assuntos
Anemia Ferropriva/fisiopatologia , Ritmo Circadiano , Dopamina/sangue , Anfetaminas/farmacologia , Anemia Ferropriva/sangue , Animais , Relógios Biológicos , Encéfalo/metabolismo , Ferro/sangue , Ligantes , Luz , Camundongos , Camundongos Endogâmicos DBA , Receptores de Dopamina D2/metabolismo , Síndrome das Pernas Inquietas/sangue , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Iron imbalances in the brain, including excess accumulation and deficiency, are associated with neurological disease and dysfunction; yet, their origins are poorly understood. Using systems genetics analysis, we have learned that large individual differences exist in brain iron concentrations, even in the absence of neurological disease. Much of the individual differences can be tied to the genetic makeup of the individual. This genetic-based differential regulation can be modeled in genetic reference populations of rodents. The work in our laboratory centers on iron regulation in the brain and our animal model consists of 25 BXD/Ty recombinant inbred mouse strains. By studying naturally occurring variation in iron phenotypes, such as tissue iron concentration, we can tie that variability to one or more genes by way of quantitative trait loci (QTL) analysis. Moreover, we can conduct genetic correlation analyses between our phenotypes and others previously measured in the BXD/Ty strains. We have observed several suggestive QTL related to ventral midbrain iron content, including one on chromosome 17 that contains btbd9, a gene that in humans has been associated with restless legs syndrome and serum ferritin. We have also observed gene expression correlations with ventral midbrain iron, including btbd9 expression and dopamine receptor expression. In addition, we have observed significant correlations between ventral midbrain iron content and dopamine-related phenotypes. The following is a discussion of iron regulation in the brain and the contributions a systems genetics approach can make toward understanding the genetic underpinnings and relation to neurological disease.
Assuntos
Encéfalo/metabolismo , Ferro/metabolismo , Animais , Humanos , Mesencéfalo/metabolismo , Camundongos , Locos de Características Quantitativas/genéticaRESUMO
BACKGROUND: A new index to determine body iron promises a simpler approach to monitoring iron deficiency (ID) prevalence. OBJECTIVE: Our objective was to compare ID defined as body iron <0 mg/kg and calculated from the log ratio of transferrin receptor to ferritin (the body iron model) to ID defined as >/=2 of 3 abnormal concentrations in ferritin, transferrin saturation, or erythrocyte protoporphyrin (the ferritin model). DESIGN: We used measures of iron status and inflammation from 486 children aged 1-2 y, 848 children aged 3-5 y, and 3742 nonpregnant females aged 12-49 y from the National Health and Nutrition Examination Survey 2003-2006. RESULTS: ID prevalences (+/-SE) based on the body iron model in children (1-2 and 3-5 y) and in females (12-19 and 20-49 y) were 14.4 +/- 1.9%, 3.7 +/- 0.8%, 9.3 +/- 1.0%, and 9.2 +/- 1.6%, respectively. ID prevalences based on the ferritin model in children (3-5 y) and females (12-19 and 20-49 y) were 4.5 +/- 0.9%, 15.6 +/- 1.2%, and 15.7 +/- 0.8%, respectively. The kappa statistics for agreement between the 2 models were 0.5-0.7. Among females (12-49 y) the positive predictive values of ID based on the body iron model and the ferritin model for identifying anemia were 43 +/- 3% and 30 +/- 2%, respectively, whereas negative predictive values did not differ. C-reactive protein was elevated in 28.8 +/- 3.1% of females with ID by the ferritin model but not by the body iron model and in 0% of persons with ID by the body iron model but not by the ferritin model. CONCLUSIONS: The agreement between the 2 indexes was fair to good. Among females, the body iron model produced lower estimates of ID prevalence, better predicted anemia, and appeared to be less affected by inflammation than the ferritin model.
Assuntos
Anemia Ferropriva/epidemiologia , Adolescente , Adulto , Proteína C-Reativa/metabolismo , Criança , Pré-Escolar , Feminino , Ferritinas/sangue , Humanos , Lactente , Inflamação/sangue , Inflamação/epidemiologia , Ferro/sangue , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Prevalência , Estados Unidos/epidemiologia , Adulto JovemRESUMO
Both during and after a period of iron deficiency (ID), iron-dependent neural processes are affected, which raises the potential concern that the anemia commonly experienced by many growing infants could have a protracted effect on the developing brain. To further investigate the effects of ID on the immature brain, 49 infant rhesus monkeys were evaluated across the first year of life. The mothers, and subsequently the infants after weaning, were maintained on a standardized diet containing 180 mg/kg of iron and were not provided other iron-rich foods as treats or supplements. As the infants grew, they were all screened with hematological tests, which documented that 16 (33.3%) became markedly ID between 4 and 8 months of age. During this anemic period and subsequently at 1 year of age, cerebrospinal fluid (CSF) specimens were collected to compare monoamine activity in the ID and iron-sufficient infants. Monoamine neurotransmitters and metabolite levels were normal at 4 and 8 months of age, but by 1 year the formerly anemic monkeys had significantly lower dopamine and significantly higher norepinephrine levels. These findings indicate that ID can affect the developmental trajectory of these two important neurotransmitter systems, which are associated with emotionality and behavioral performance, and further that the impact in the young monkey was most evident during the period of recovery.
Assuntos
Anemia Ferropriva/fisiopatologia , Encéfalo/fisiopatologia , Dopamina/líquido cefalorraquidiano , Norepinefrina/líquido cefalorraquidiano , Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , Fatores Etários , Animais , Emoções/fisiologia , Epinefrina/líquido cefalorraquidiano , Índices de Eritrócitos , Feminino , Hemoglobinometria , Ácido Homovanílico/líquido cefalorraquidiano , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Macaca mulatta , Masculino , Gravidez , Valores de Referência , Serotonina/líquido cefalorraquidiano , Fatores SexuaisRESUMO
BACKGROUND: Iron deficiency is most commonly found in women of reproductive age and infants worldwide, but the influence of maternal iron deficiency on infant development is underexplored. OBJECTIVE: The objective was to examine the relation between maternal iron status and mother-child interactions in a randomized, double-blind, intervention trial conducted in South Africa. DESIGN: Women were recruited into the study from a health clinic at 6-8 wk postpartum and were classified as either iron-deficient anemic (IDA) or iron-sufficient after blood analysis. IDA mothers received iron supplements of 125 mg FeSO(4) (IDA-Fe; n = 34) or placebo (IDA-PL; n = 30) daily from 10 wk to 9 mo postpartum. The control group (n = 31) consisted of iron-sufficient mothers. Free-play mother-child interaction sessions were videotaped in the clinic at 10 wk (n = 80) and 9 mo (n = 66) postpartum and coded per the Emotional Availability Scales (4 maternal scales: sensitivity, structuring, nonintrusiveness, and nonhostility; 2 infant scales: responsiveness and involvement). RESULTS: At 10 wk, scores for maternal sensitivity and child responsiveness were significantly greater in the control group than in the IDA groups (P = 0.028 and 0.009, respectively). At 9 mo, the control and IDA-Fe groups no longer differed. These 2 groups scored significantly better on the maternal sensitivity, structuring, and nonhostility scales and on the child responsiveness scale than did the IDA-PL group (P = 0.007-0.032), whose iron status remained low. CONCLUSION: These data indicate that maternal iron deficiency negatively affects mother-child interactions and that iron supplementation protects against these negative effects.
Assuntos
Anemia Ferropriva/tratamento farmacológico , Anemia Ferropriva/psicologia , Compostos Ferrosos/uso terapêutico , Relações Mãe-Filho , Adolescente , Adulto , Método Duplo-Cego , Feminino , Humanos , Lactente , Ferro/sangue , Período Pós-Parto , África do Sul , Gravação de Videoteipe , Adulto JovemRESUMO
OBJECTIVE: The aim of this study was to ascertain whether high-dose intravenous (IV) iron sucrose could improve symptoms and change brain iron concentrations in idiopathic RLS. METHODS: The study was a randomized, parallel-group double-blind study of 1000mg iron sucrose given IV versus placebo. Primary measures of the clinical status were global rating scale (GRS) and periodic leg movements of sleep (PLMS). Primary measures of brain iron status were CSF ferritin and MRI-determined iron in the substantia nigra. RESULTS: At the time of the interim analysis there were 7 placebo and 11 iron-treated subjects. At 2-weeks post-treatment, iron treatment resulted in a small but significant increase in CSF ferritin and a decrease in RLS severity (GRS) but did not change PLMS or MRI iron index. None of the secondary outcomes changed with treatment. There was no single case of clear treatment benefit in any of the patients. This interim analysis revealed an effect size that was too small to allow for adequate power to find significant differences with the planed 36-subject enrollment for either the primary objective outcome of PLMS or any of the secondary outcomes. The study was stopped at this planned break-point given the lack of both adequate power and any indication for clinically significant benefit. CONCLUSIONS: High-dose IV iron failed to demonstrate the robust changes reported in three prior open-label studies. Differences in iron formulation, dosing regiment, and peripheral iron status may explain some of the discrepancies between this and previous IV iron treatment studies.
Assuntos
Compostos Férricos/uso terapêutico , Hematínicos/uso terapêutico , Síndrome das Pernas Inquietas/tratamento farmacológico , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Óxido de Ferro Sacarado , Ferritinas/líquido cefalorraquidiano , Ácido Glucárico , Humanos , Infusões Intravenosas , Ferro/metabolismo , Masculino , Pessoa de Meia-Idade , Síndrome das Pernas Inquietas/metabolismo , Substância Negra/metabolismo , Falha de TratamentoRESUMO
Iron movement between organ pools involves a dynamic equilibrium of iron efflux and uptake, and homeostatic mechanisms are likely involved in providing iron to cells and organs when required. Daily iron levels in the plasma pool fluctuate with the diurnal cycle, but clear explanations regarding the objectives and regulation of the flux are lacking. The association between diurnal cycle and iron flux is relevant in the disease of restless legs syndrome (RLS), where individuals display diurnal deficits in motor control, have impaired brain iron metabolism, and perhaps altered iron uptake from the plasma pool. The goal of the present study was to examine diurnal variations in peripheral and regional brain iron to evaluate iron flux between organs in iron-sufficient and iron-deficient mice. In mice fed control diet, liver iron was elevated 30-40%, and plasma iron was reduced 20-30% in the active dark period compared with the inactive light phase. Dietary iron deficiency eliminated this variation in liver iron in male and female mice and in plasma iron in male mice. Reductions in ventral midbrain and nucleus accumbens iron and ferritin were apparent in iron-deficient mice during both diurnal phases, but only during the light phase was an approximately 25% reduction in whole brain iron observed, suggesting different brain iron requirements between phases. These data demonstrate that iron flux between organs is sensitive to diurnal regulatory biology. Importantly, variations in brain iron may have temporal implications regarding neural functioning and may contribute to the diurnal cycle-dependent symptoms of RLS.
Assuntos
Encéfalo/metabolismo , Ritmo Circadiano , Deficiências Nutricionais/metabolismo , Ferro/metabolismo , Fígado/metabolismo , Baço/metabolismo , Animais , Peso Corporal , Deficiências Nutricionais/sangue , Modelos Animais de Doenças , Feminino , Ferritinas/metabolismo , Hematócrito , Hemoglobinas/metabolismo , Homeostase , Ferro/sangue , Deficiências de Ferro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Síndrome das Pernas Inquietas/sangue , Síndrome das Pernas Inquietas/metabolismo , Fatores SexuaisRESUMO
Iron deficiency anemia in early life alters the development and functioning of the dopamine neurotransmitter system, but data regarding the specific effects of brain iron loss on dopamine D(2) receptor regulation are lacking. Cell culture and animal models were employed in this study to determine whether D(2) receptor expression is altered when cellular iron levels are depleted. Endogenous D(2) receptor-expressing PC12 cells exposed to increasing concentrations of the iron chelator desferrioxamine (25-100 micromol/L) exhibited dose-dependent decreases in total D(2) receptor protein concentrations (20-65%), but there were minimal effects on D(2) receptor mRNA levels. When iron-deficient cells were repleted with ferric ammonium citrate for 24 h, D(2) receptor protein densities were similar to control. Dietary iron deficiency for 6 wk in weanling rats also reduced regional iron concentrations by nearly 50% in the ventral midbrain and caudate but did not affect D(2) receptor mRNA levels in the ventral midbrain. Iron deficiency significantly reduced membrane D(2) receptor protein levels by >70% in caudate, whereas cytosolic concentrations showed only 25% losses. D(2) receptor protein densities and regional iron concentrations were restored within 2 wk of dietary iron repletion. These results support the concept that D(2) receptor gene expression is not significantly changed by iron deficiency, whereas dopamine receptor trafficking is affected and is likely related to known dopamine system alterations in iron deficiency.
Assuntos
Encéfalo/metabolismo , Ferro/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Animais , Sequência de Bases , Primers do DNA/genética , Desferroxamina/farmacologia , Expressão Gênica/efeitos dos fármacos , Quelantes de Ferro/farmacologia , Deficiências de Ferro , Ferro da Dieta/administração & dosagem , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Células PC12 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Infants who experience iron deficiency during the first 6-12 mo of life are likely to experience persistent effects of the deficiency that alter functioning in adulthood. A lack of sufficient iron intake may significantly delay the development of the central nervous system as a result of alterations in morphology, neurochemistry, and bioenergetics. Depending on the stage of development at the time of iron deficiency, there may be an opportunity to reverse adverse effects, but the success of repletion efforts appear to be time dependent. Publications in the past several years describe the emerging picture of the consequences of iron deficiency in both human and animal studies. The mechanisms for iron accumulation in the brain and perhaps redistribution are being understood. The data in human infants are consistent with altered myelination of white matter, changes in monoamine metabolism in striatum, and functioning of the hippocampus. Rodent studies also show effects of iron deficiency during gestation and lactation that persist into adulthood despite restoration of iron status at weaning. These studies indicate that gestation and early lactation are likely critical periods when iron deficiency will result in long-lasting damage.
Assuntos
Desenvolvimento Infantil/fisiologia , Deficiências de Ferro , Anemia Ferropriva/dietoterapia , Anemia Ferropriva/fisiopatologia , Anemia Ferropriva/psicologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiologia , Potenciais Evocados Auditivos do Tronco Encefálico , Feminino , Humanos , Lactente , Recém-Nascido , Ferro da Dieta/administração & dosagem , GravidezRESUMO
OBJECTIVE: Studies using cerebrospinal fluid, magnetic resonance imaging, and autopsy tissue have implicated a primary role for brain iron insufficiency in restless legs syndrome (RLS). If the abnormalities of brain iron regulation reflect a basic disturbance of iron metabolism, then this might be expressed at least partially in some peripheral systems. Thus the study aim was to determine whether patients with RLS and control subjects show differences in lymphocyte iron regulator proteins. METHODS: Fasting morning blood samples were used to obtain common serum measures of iron status and to determine lymphocyte iron management proteins. Twenty-four women with early-onset RLS and 25 control women without RLS symptoms were studied. RESULTS: RLS and control subjects were matched for age, hemoglobin, and serum iron profile. However, transferrin receptor (TfR) and DMT1 (divalent metal transporter 1 protein) levels in lymphocytes were significantly higher for RLS patients than for controls. No significant differences in ferritin subtypes or transferrin levels were found. No significant correlations were found between lymphocyte and serum indices of iron status. INTERPRETATION: RLS lymphocytes showed an increase in ferroportin, implying increased cellular iron excretion, in the face of increased iron need (increased TfR and DMT1). In the absence of changes in H-ferritin, the findings indicate a balance between input and output with no net iron change but probable overall increase in iron turnover. The lack of any significant correlation between serum and lymphocyte iron indices indicates that iron management proteins from lymphocytes are at a minimum an alternative and independent marker of cellular iron metabolism.
Assuntos
Proteínas de Transporte de Cátions/sangue , Hemoglobinas/metabolismo , Ferro/metabolismo , Linfócitos/metabolismo , Receptores da Transferrina/metabolismo , Síndrome das Pernas Inquietas/metabolismo , Síndrome das Pernas Inquietas/fisiopatologia , Adulto , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Iron deficiency (ID) disrupts brain dopamine (DA) and norepinephrine (NE) metabolism including functioning of monoamine transporters and receptors. We employed caudate microdialysis and no net flux (NNF) in post-weaning rats to determine if ID decreased the extraction fraction (E(d)). Five micromolar quinpirole, a dopamine D(2) receptor agonist, resulted in 80% decrease in extracellular DA and 45% higher E(d) in control animals. The D(2) agonist had no effect on E(d) in ID animals despite a reduction in basal DA. DAT mRNA levels were reduced by 58% with ID, while DAT protein in ventral midbrain and caudate and membrane associated DAT were also reduced by ID. Carbidopa/l-DOPA was administered to determine if elevated extracellular DA in ID was due to increased release. The DA response to l-DOPA in ID rats was 50% smaller and delayed, whereas the NE response was threefold higher. The caudate concentration of NE was also elevated in ID. Elevated dopamine-beta-hydroxylase activity in ID provides a tentative explanation for the increased NE response to l-DOPA. These experiments provide new evidence that ID results in altered synthesis and functioning of DAT and perhaps suggests some compensatory changes in NE metabolism.
Assuntos
Encefalopatias Metabólicas/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Dopamina/metabolismo , Deficiências de Ferro , Levodopa/farmacologia , Animais , Encéfalo/fisiopatologia , Encefalopatias Metabólicas/fisiopatologia , Núcleo Caudado/efeitos dos fármacos , Núcleo Caudado/metabolismo , Núcleo Caudado/fisiopatologia , Dopaminérgicos/farmacologia , Agonistas de Dopamina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Líquido Extracelular/efeitos dos fármacos , Líquido Extracelular/metabolismo , Masculino , Microdiálise , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Norepinefrina/biossíntese , Quimpirol/farmacologia , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Síndrome das Pernas Inquietas/tratamento farmacológico , Síndrome das Pernas Inquietas/metabolismo , Síndrome das Pernas Inquietas/fisiopatologia , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/fisiopatologia , Regulação para Cima/efeitos dos fármacosRESUMO
Fe, Cu, and Zn are of widespread neurobiological importance, but must be regulated closely as too much or too little of these metals can have adverse effects on brain function. Recent evidence from nutritional models notes that the hippocampus is particularly vulnerable to Fe and Zn deficiencies. We recently performed a quantitative trait loci (QTL) analysis as a preliminary step in identifying genes that contribute to natural variation in hippocampal Fe, Cu, and Zn content. We used ICP-MS to measure the concentrations of these metals in 120-day-old mice from 30 strains of the BXD/TY panel. The BXD/Ty recombinant inbred strain panel is well-suited for complex trait analysis, as all strains are genotyped with a dense marker set and have been phenotyped extensively for neurobehavioral traits and hippocampal gene expression. We observed a wide-range of hippocampal Fe, Cu, and Zn concentrations across the BXD strains. These concentrations were related to systemic Fe status, but not to Fe, Cu, and Zn elsewhere in the brain. The three metals also showed strong covariance, suggestive of overlap in their regulatory pathways. We identified two QTL, on chromosomes 14 and 9, most strongly associated with Cu but also suggestively associated with Fe (chr. 14) and Zn (chr. 9). We also performed genetic correlational analyses with existing data on these strains and revealed associations with cognitive, anxiety-related, and alcohol-related phenotypes. Covariance of these metals with gene expression is also discussed. This work shows that hippocampal Fe, Cu, and Zn are under polygenic influence and that trace metal regulation is associated with hippocampus-related behaviors. Future work will elucidate the genes underlying the two QTL identified, to aid in identifying homologous genetic variants in human populations, which may underlie altered trace metal homeostasis and related neurological disease.
Assuntos
Cobre/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Hipocampo/metabolismo , Ferro/metabolismo , Zinco/metabolismo , Animais , Mapeamento Cromossômico , Feminino , Marcadores Genéticos/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Genótipo , Hipocampo/crescimento & desenvolvimento , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Transtornos Neurocognitivos/genética , Neurônios/metabolismo , Fenótipo , Locos de Características Quantitativas/genéticaRESUMO
Iron deficiency (ID) anemia during infancy results in long-term neurological consequences, yet the mediating mechanisms remain unclear. Infant monkeys often become naturally anemic during the first 6 months of life, presenting an opportunity to determine the effect of developmental iron deficiency. After weaning, animals were chosen randomly for supplementation with oral iron or, fed a standard commercial chow diet. The control group was never iron deficient. ID anemia was corrected by 12 months in both groups, as indicated by hematological parameters. CSF was collected for proteomic analysis at 12 months of age to assess the impact of developmental ID on the brain. The CSF proteome for both formerly iron deficient groups was similar and revealed 12 proteins with expression levels altered at least twofold. These proteins were identified by matrix assisted laser desorption ionization time-of-flight spectrometry and included prostaglandin D synthase, olfactory receptors and glial fibrillary acidic protein. Thus the proteomic analysis reveals a persistent effect of ID and provides insights into reports of disturbed sleep, hypomyelination and other behavioral alterations associated with ID. Furthermore, alterations in the CSF proteome despite normal hematologic parameters indicate that there is a hierarchical system that prioritizes repletion of red cell mass at the expense of the brain.
Assuntos
Anemia Ferropriva/líquido cefalorraquidiano , Líquido Cefalorraquidiano/metabolismo , Proteômica/métodos , Fatores Etários , Anemia Ferropriva/metabolismo , Animais , Animais Recém-Nascidos , Peso Corporal/fisiologia , Modelos Animais de Doenças , Eletroforese em Gel Bidimensional , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Oxirredutases Intramoleculares/líquido cefalorraquidiano , Lipocalinas/líquido cefalorraquidiano , Macaca mulatta , Análise Serial de Proteínas , Distribuição Aleatória , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
A number of algorithms have been developed to predict the bioavailability of iron from mixed meals and diets, but their direct validity in predicting change in iron status remains questionable. Throughout the course of conducting a large feeding trial in 10 convents in Manila, we collected weighed food intake data (n = 317) and directly compared the performance of these prediction equations to each other and to the change in serum ferritin (SF). Dietary weighed food intakes were measured on d 3 every 2 wk for each woman and iron status determined at baseline, 4.5 mo, and 9 mo. The Monsen and Balintfy equation predicted higher median absorption efficiency (7.3%) than did the equations of Hallberg and Hulthen (6.1%) and Reddy et al. (5.8%). In contrast, the predictions that used the equations of Bhargava et al. (3.8%), Tseng et al. (2.9%), and Du et al. (2.6%) were significantly lower. The iron absorption efficiencies calculated using the Monsen and Balintfy equation correlated with those using the Hallberg and Hulthen equation (r = 0.91, P < 0.001). This slope did not differ from unity, whereas all other equations underestimated iron absorption efficiency relative to Monsen and Balintfy's equation. The median efficiency of absorption, based on change in SF in 114 subjects, was 17.2%, suggesting that these equations underestimate iron absorption. The inhibitory and enhancing factors in the published prediction equations were quantitatively either too large or perhaps too small to correctly predict apparent iron bioavailability over a 9-mo period. The causes of the lack of agreement between change in iron status estimated by SF change and absorption predicted by algorithms are open to discussion and will need to be resolved.
Assuntos
Algoritmos , Ferro da Dieta/metabolismo , Ferro/metabolismo , Absorção , Disponibilidade Biológica , Dieta , Inquéritos sobre Dietas , Feminino , Alimentos , Humanos , Ferro da Dieta/administração & dosagem , FilipinasRESUMO
Many genes are likely involved in the control of iron metabolism in brain and in peripheral tissues, and genetically-defined murine strains present the opportunity to investigate genetic variations in iron metabolism. Weanling C57BL/6 (B6) and DBA/2 (D2) mice were divided into two treatment groups receiving distilled water with or without 5000 ppm ferric chloride ad libitum as their sole fluid source for 100 days. Iron overload increased liver, spleen and plasma iron levels in male and female B6 and female D2 mice. In D2 males, liver iron was increased relative to control, but spleen and plasma iron remained unaffected. Brain iron content was not different between control and iron-treated mice in ventral midbrain, caudate, pons or hippocampus, but D2 iron overloaded mice displayed lower iron levels in nucleus accumbens and prefrontal cortex. We conclude that genetic background influences the accumulation of excess iron in the periphery and iron regulation in the central nervous system.
Assuntos
Homeostase/fisiologia , Sobrecarga de Ferro/metabolismo , Ferro/metabolismo , Animais , Peso Corporal , Encéfalo/metabolismo , Feminino , Ferro/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Caracteres Sexuais , Baço/metabolismoRESUMO
Iron homeostasis is one of the most critical functions in living systems. Too little iron can lead to anemia and tissue-specific disorders, such as splenomegaly. Excessive systemic iron is characteristic of hemochromatosis and is implicated in the brain in Parkinson's disease. With the exception of some single gene diseases like hemochromatosis, we know little about genetic-based, individual differences in iron-related parameters and their impact on biology. To model genetic control of iron homeostasis, we measured liver, spleen, and plasma iron concentrations, hematocrit and hemoglobin, transferrin saturation, and total iron-binding capacity in several BXD/Ty recombinant inbred mouse strains derived from C57BL/6 and DBA/2 progenitors. At 120 days of age, the animals were killed for iron analysis. All measures showed genetic-based variability consistent with polygenic influence. Analysis of principal components of the seven measures revealed three factors that we named availability, transport, and storage. Quantitative trait loci (QTL) analysis revealed one suggestive QTL on chromosome 5 for availability, two suggestive QTL (one on chromosome 1 and the other on chromosome 7) for transport, and one weak QTL on chromosome 2 for storage. The results show that iron homeostasis is a complex trait and is influenced by multiple genes.
Assuntos
Ferro/metabolismo , Animais , Feminino , Expressão Gênica/fisiologia , Hematócrito , Hemoglobinas/metabolismo , Ferro/sangue , Proteínas de Ligação ao Ferro/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Estado Nutricional , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo Genético , Análise de Componente Principal , Especificidade da Espécie , Baço/metabolismo , Transferrina/metabolismoRESUMO
Iron deficiency anemia in early childhood causes developmental delays and, very likely, irreversible alterations in neurological functioning. One primary goal for the present study was to determine whether the effects of late gestational iron deficiency on brain monoamine metabolism, iron content, and behavioral phenotypes could be repaired with iron intervention in early lactation. Young pregnant rats were provided iron-deficient or control diets from mid-gestation (G15). At postnatal d 4 (P4), pups from iron-deficient dams were out-fostered either to other ID dams or control dams while pups of control dams were similarly fostered to other control dams. Dietary treatments continued to adulthood (P65) when brain iron and regional monoamines were evaluated. P4 iron repletion normalized body iron status, brain iron concentrations, monoamine concentrations, and monoamine transporter and receptor densities in most brain regions. Dopamine transporter densities in caudate and substantia nigra were lower in ID rats but were normalized with iron repletion. Serotonin transporter levels in most brain regions and open-field exploration were also normalized with iron repletion. The success of this approach of early postnatal iron intervention following iron deficiency in utero contrasts to a relative lack of success when the intervention is performed at weaning. These data suggest that a window of opportunity exists for reversing the detrimental effects of iron deficiency in utero in rats and provides strong support of intervention approaches in humans with iron deficiency during pregnancy.
Assuntos
Deficiências Nutricionais/dietoterapia , Deficiências Nutricionais/embriologia , Deficiências de Ferro , Ferro/administração & dosagem , Envelhecimento/metabolismo , Anemia Ferropriva/sangue , Anemia Ferropriva/metabolismo , Animais , Animais Recém-Nascidos , Comportamento Animal , Monoaminas Biogênicas/metabolismo , Encéfalo/metabolismo , Deficiências Nutricionais/metabolismo , Deficiências Nutricionais/psicologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Comportamento Exploratório , Feminino , Ferritinas/metabolismo , Ferro/metabolismo , Atividade Motora , Gravidez , Ratos , Ratos Sprague-Dawley , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Distribuição Tecidual , Transferrina/metabolismoRESUMO
BACKGROUND: Evidence suggests that brain iron deficiency at any time in life may disrupt metabolic processes and subsequently change cognitive and behavioral functioning. Women of reproductive age are among those most vulnerable to iron deficiency and may be at high risk for cognitive alterations due to iron deficiency. OBJECTIVE: We aimed to examine the relation between iron status and cognitive abilities in young women. DESIGN: A blinded, placebo-controlled, stratified intervention study was conducted in women aged 18-35 y of varied iron status who were randomly assigned to receive iron supplements or a placebo. Cognition was assessed by using 8 cognitive performance tasks (from Detterman's Cognitive Abilities Test) at baseline (n = 149) and after 16 wk of treatment (n = 113). RESULTS: At baseline, the iron-sufficient women (n = 42) performed better on cognitive tasks (P = 0.011) and completed them faster (P = 0.038) than did the women with iron deficiency anemia (n = 34). Factors representing performance accuracy and the time needed to complete the tasks by the iron-deficient but nonanemic women (n = 73) were intermediate between the 2 extremes of iron status. After treatment, a significant improvement in serum ferritin was associated with a 5-7-fold improvement in cognitive performance, whereas a significant improvement in hemoglobin was related to improved speed in completing the cognitive tasks. CONCLUSIONS: Iron status is a significant factor in cognitive performance in women of reproductive age. Severity of anemia primarily affects processing speed, and severity of iron deficiency affects accuracy of cognitive function over a broad range of tasks. Thus, the effects of iron deficiency on cognition are not limited to the developing brain.