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Nutrition Department, College of Human Development, The Pennsylvania State State University, University Park, PA 16802
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONCHEMISTRYMODEL OF INTERORGAN IRON...GENERAL CLINICAL MANIFESTATIONSIMPAIRED IMMUNE FUNCTIONMENTAL FUNCTION DURING IRON...IRON AND NEUROTRANSMITTER...IMPAIRED PHYSICAL PERFORMANCESUMMARY AND CONCLUSIONSDISCUSSIONREFERENCES |
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KEY WORDS: • iron deficiency • anemia • immune system • central nervous system exercise
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCHEMISTRYMODEL OF INTERORGAN IRON...GENERAL CLINICAL MANIFESTATIONSIMPAIRED IMMUNE FUNCTIONMENTAL FUNCTION DURING IRON...IRON AND NEUROTRANSMITTER...IMPAIRED PHYSICAL PERFORMANCESUMMARY AND CONCLUSIONSDISCUSSIONREFERENCES |
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) and review the known biological aspects of
the role of iron in immune system function (Hershko 1996
), the biology of iron in neural functioning (Beard et al. 1993
) and the role of iron in muscle function and energy
metabolism (Beard and Dawson 1996
). This review will not
be comprehensive or exhaustive but will identify the key biological
processes in each of the outcome domains identified as the focus of
this conference (Fig. 1
).
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CHEMISTRY |
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TOPABSTRACTINTRODUCTIONCHEMISTRYMODEL OF INTERORGAN IRON...GENERAL CLINICAL MANIFESTATIONSIMPAIRED IMMUNE FUNCTIONMENTAL FUNCTION DURING IRON...IRON AND NEUROTRANSMITTER...IMPAIRED PHYSICAL PERFORMANCESUMMARY AND CONCLUSIONSDISCUSSIONREFERENCES |
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). The
general classification of these reactions is oxygen transport and
storage, electron transfer and substrate oxidation-reduction. It is
important to note that the activity of many of these enzymes decreases
during tissue iron deficiency. Only rarely, however, have direct
connections between biochemical events and clinical manifestations been
firmly established.
Four major classes of iron-containing proteins carry out these
reactions in the mammalian system: 1) iron-containing
nonenzymatic proteins (hemoglobin and myoglobin), 2)
iron-sulfur enzymes, 3) heme-containing enzymes and
4) iron-containing enzymes that are noniron-sulfur,
nonheme enzymes (Fig. 2
). In the principal oxygen transport nonenzymatic proteins, hemoglobin
and myoglobin, iron functions as a critical ligand for the binding of
dioxygen. In iron-sulfur enzymes, iron participates in
single-electron transfer reactions primarily in energy metabolism.
In the third category, iron is bound to various forms of heme and
participates again in electron transfer reactions when associated with
various cofactors (e.g., cytochrome P450 complexes). The final group of
iron-containing enzymes is a catch-all grouping in which iron
is not bound to a porphyrin ring structure or in iron-sulfur
complexes.
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The movement of oxygen from the environment to terminal oxidases is one of the key functions of iron in which oxygen is bound to porphyrin ring iron-containing molecules either as part of the prosthetic group of hemoglobin within red blood cells or as the facilitator of oxygen diffusion in tissue, myoglobin.
Hemoglobin is a tetrameric protein with two pairs of identical subunits
(
2, ß2; MW 64,000). Each subunit has one prosthetic group,
Fe-PP-IX, whose ferrous iron reversibly binds dioxygen. The synthesis
of erythroid heme is controlled in part by the availability of iron to
these maturing erythroblasts because iron regulates the initial
rate-limiting step in heme biosynthesis by altering the stability
of the specific [
-amino-levulinic acid synthetase] mRNA. The four
subunits are not covalently attached to each other but do react
cooperatively with dioxygen with specific modulation by pH,
pCO2, organic phosphates and temperature. These
modulators of the affinity of hemoglobin for iron determine the
efficiency of transport of oxygen from the alveoli capillary interface
in the lung to the red cell–capillary-tissue interface in peripheral
tissues. The allosteric effect of decreasing pH, the well-known
Bohr effect, decreases the binding affinity of heme-Fe for dioxygen
via protonation of His-146 on ß chains and Val-1 on chains in the
presence of Cl-1 and
CO2. CO2 forms a Schiff
base with the terminal amino acids of each chain and decreases dioxygen
affinity. This favors the unloading of oxygen in tissues in which the
pH is lower and pCO2 is higher than in arterial
blood. 2,3-Diphosphoglycerate is a product of a side pathway within
erythrocytes and binds to a specific region of the ß chain to
decrease Hb-O2 binding affinity. Homeostasis with
respect to oxygen transport is evident in iron-deficient anemic
individuals. There is usually a right shift of the dissociation curve
with anemia, in which the blood content of hemoglobin is significantly
reduced, and an increased cardiac output that is only partially
compensatory. The increase in cardiac output is the result of an
increase in both stroke volume and heart rate, with a resulting
hypertrophy of the ventricular muscle wall that is concentric in nature
(Mederios and Beard 1998
). Physiological conditions that
increase the demand for oxygen transport such as high physical exertion
rates (discussed later in this review and by others at this meeting)
may exist, with a resulting decreased maximal aerobic capacity because
of limitations in oxygen transport ability. It is uncommon, however, to
find significant arterial desaturation unless very high rates of oxygen
transport are required.
Myoglobin is the single-chain hemoprotein in cytoplasm (MW 17,000)
that increases the rate of diffusion of dioxygen from capillary red
cells to cytoplasm and mitochondria. The concentration of myoglobin in
skeletal muscle is drastically reduced (40–60%) in tissue iron
deficiency, thus limiting the rate of diffusion of dioxygen from
erythrocytes to mitochondria (Beaton et al. 1989
). The
sensitivity of myoglobin concentration in other tissues to iron status
has not been established.
Electron transport.
The second group of iron-containing proteins comprises heme enzymes
that use Fe within the porphyrin ring structure and are usually coupled
with other enzymes in integrated electron transport processes. The
overall scheme of the electron transport chain and the forms of iron
that participate in electron transport are summarized elsewhere
(Beard and Dawson 1996
). The family of cytochromes
contains heme as the active site, with the Fe-porphyrin ring
functioning to reduce ferrous iron to ferric iron with the acceptance
of electrons.
The third group of iron-containing proteins, the iron sulfur
enzymes, also acts as electron carriers via the action of iron bound to
either 2 or 4 sulfur atoms and cysteine side chains. The 40 different
proteins that constitute the respiratory chain contain 6 different heme
proteins, 6 iron sulfur centers, 2 copper centers, as well as
ubiquinone to connect NADH to oxygen. There are numerous examples of
these proteins and enzymes, which are summarized in Table 1
. Although the sensitivity of many of these enzymes to iron depletion
has been observed in one study or another, the systematic evaluation of
tissue sensitivity for this modest list is lacking.
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MODEL OF INTERORGAN IRON EXCHANGE |
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TOPABSTRACTINTRODUCTIONCHEMISTRYMODEL OF INTERORGAN IRON...GENERAL CLINICAL MANIFESTATIONSIMPAIRED IMMUNE FUNCTIONMENTAL FUNCTION DURING IRON...IRON AND NEUROTRANSMITTER...IMPAIRED PHYSICAL PERFORMANCESUMMARY AND CONCLUSIONSDISCUSSIONREFERENCES |
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, Dallman 1982 and 1986
, Finch and Heubers 1982
). The regulation of iron movement across the
enterocyte optimizes iron assimilation into the body when an individual
is iron depleted and limits iron absorption when iron stores are
replete. The exact nature of the feedback signal from body iron status
to the enterocyte remains unknown. A prolonged negative iron balance or
an acute rapid blood loss both ultimately lead to a depletion of the
storage iron pool, which can contain as much as 2–3 g iron (Fig. 3
). The storage iron bound to tissue ferritin is used to meet the daily
requirements not provided by the diet. Nearly all cells contain
ferritin, although the bulk of the body’s storage iron pool is in
liver and spleen (Bothwell et al. 1979
). Iron mobilized
from tissue iron is transported by the iron transporter, transferrin.
This plasma protein is normally only 25–50% saturated with iron bound
to its two identical binding sites (Princiotto and Zapolski 1976
). A negative iron balance will eventually lead to the
depletion of the storage iron pools, with a resulting decline in the
transferrin saturation to <15%, and less than adequate iron is
available for delivery to essential body iron proteins (Bothwell et al. 1979
).
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). The regulation of this transferrin receptor population
is influenced by the cellular iron status and its interaction with iron
response elements (Casey et al. 1988
). That is, as the
cellular pool of low-molecular-weight iron decreases, there is an
up-regulation of iron intake into cells and a down-regulation
of the synthesis of the iron storage proteins. This influence is
exerted via the existence of iron regulatory proteins in the nuclear
fraction and their role in gene transcription and translation
(Casey et al. 1988
, Ponka et al. 1998
,
Rao et al. 1986
). Iron turnover and redistribution.
Iron turnover is mediated primarily by destruction of senescent
erythrocytes by the reticuloendothelial system (Finch et al. 1970
). For example, in a 70-kg individual with a normal iron
status, 
35 mg/d of iron is turned over in the plasma (Finch et al. 1970
). Erythrocytes, which contain 80% of the
body’s functional iron, have a mean functional lifetime of 120 d
in humans. About 85% of the iron derived from hemoglobin degradation
is rereleased to the body in the form of iron bound to transferrin or
ferritin. Each day, 0.66% of the body’s total iron content is
recycled in this manner (Finch et al. 1970
). Smaller
contributions are made to plasma iron turnover by the degradation of
myoglobin and iron-containing enzymes.
Storage and mobilization of iron.
The concentration of iron in the body is 30–40 mg/kg body. However,
that concentration varies as a function of the age and gender of the
individual and the specific tissues and organs being examined. About
85–90% of nonstorage iron is found in the erythroid mass
(Bothwell et al. 1979
). The storage iron concentration
in the body varies from 0 to 15 mg/kg body, depending on the gender and
the iron status of the individual. The distribution of this stored iron
is not uniform because the liver contains 60% of the ferritin in
the body. The remaining 40% is found in muscle tissues and cells of
the reticuloendothelial system. Normally, 95% of the stored iron in
liver tissue is found in hepatocytes as ferritin. Hemosiderin
constitutes the remaining 5% and is found predominately in Kupffer
cell lysosomal remnants. However, during iron overload, the mass of
hemosiderin in the liver accumulates at 10 times the rate of ferritin
(Green et al. 1968
).
The overall structure of ferritin is conserved among higher eukaryotes
and, in humans, is composed of 24 polypeptide subunits. At least two
distinct isoforms of the polypeptide subunits exist, and combinations
of these subunits allow for considerable heterogeneity in the structure
of the full protein. The isoform designated H ferritin is a 22-kDa
protein composed of 182 amino acids. The L isoform is a 20-kDa protein
containing 174 amino acids. The subunit composition of ferritin seems
to be tissue specific. Theoretically, up to 4500 ferric iron atoms can
be stored in ferritin (Fishbach and Andreregg 1965
). In
vivo, ferritin is normally 20% saturated (800 of 4500 iron sites
occupied) with a variable ratio of H to L subunits (Crichton and Ward 1992
). The structure and composition of the mineralized
core is analogous to a polymer of ferrhydrite
(5Fe2O3 · 9H2O)
with a variable amount of phosphate (Fishbach and Andreregg 1965
). The
H-chain possesses a distinct ferroxidase site, which leads to the
current hypothesis that high H-L–ratio ferritin functions primarily to
quickly move iron into and out of the core (Levi et al. 1988
). The L-chain of ferritin lacks this ferroxidase site,
and L-chain–predominant ferritin is viewed as a longer-term
storage pool of iron (Casey et al. 1988
, Levis et al. 1989
). Pertinent to this discussion of the role of ferritin
in the storage of iron is the proposed role of H-ferritin in growth
and development and perhaps a role in nuclear regulation because
H-ferritin receptors have been identified in several tissues and
characterized in the nucleus of neurons (Hulet et al. 1999
).
Iron losses.
The low solubility of iron precludes excretion as a major mechanism of
maintaining iron homeostasis. Thus, in contrast to most other trace
minerals whose homeostasis in maintained by excretion, the primary
mechanism of maintaining whole-body iron homeostasis is to regulate
the amount of iron absorbed so that it approximates iron losses
(Hallberg and Hulthen 2000
). Iron losses can vary
considerably with the gender of the individual and pathologies that
have blood loss as a significant component. In male humans, total iron
losses from the body have been calculated to be 0.8–0.9 mg/d. For
premenopausal female humans, this loss is slightly higher. The
predominant route of loss is from the gastrointestinal tract and
amounts to 0.6 mg/d in adult males (Finch et al. 1970
).
Fecal iron losses result from shed enterocytes, extravasated red blood
cells and biliary heme breakdown products that are poorly absorbed.
Urogenital and integumental iron losses have been estimated to be
> 0.1 and 0.3 mg/d, respectively, in adult males (Green et al. 1968
). Menstrual iron loss, estimated from an average blood
loss of 33 mL/mo, equals 1.5 mg/d but may be as high as 2.1 mg/d
(Cole et al. 1971
). Oral contraceptives reduce this loss
(Cole et al. 1971
, Frassinelli-Gunderson et al. 1985
), and intrauterine devices increase it (Cole et al. 1971
, Guillebaud et al. 1979
, Kivijarvi et al. 1986
).
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GENERAL CLINICAL MANIFESTATIONS |
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TOPABSTRACTINTRODUCTIONCHEMISTRYMODEL OF INTERORGAN IRON...GENERAL CLINICAL MANIFESTATIONSIMPAIRED IMMUNE FUNCTIONMENTAL FUNCTION DURING IRON...IRON AND NEUROTRANSMITTER...IMPAIRED PHYSICAL PERFORMANCESUMMARY AND CONCLUSIONSDISCUSSIONREFERENCES |
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). Clinical manifestations of iron deficiency are glossitis, angular
stomatitis, koilonchyia (spoon nails), blue sclera, esophageal webbing
(Plummer-Vinson syndrome) and microcytic hypochromic anemia. Behavioral
disturbances such as pica, which is characterized by abnormal
consumption of nonfood items such as dirt (geophagia) and ice
(pagophagia), are often present in iron deficiency but clear biological
explanations for these abnormalities are lacking. More recently,
restless legs syndrome has been described as being causally related to
iron-deficiency anemia (Earley et al. 2000b
). This
aphasic involuntary muscle contraction appears related to altered
movement of iron to and within motor-control centers in the brain
and is treatable in most cases with either iron or levodopa.
Neuromaturational delays have been described by many research groups
and will be discussed in detail in a later section and elsewhere in
this supplement. The physiological manifestations of iron deficiency
have also been noted in immune function, thermoregulatory performance,
energy metabolism, and exercise or work performance (Beard et al. 1993
, Lozoff 1988
, Pollitt 1997
). The current understanding of the iron biology underlying
deficits in the immune system, skeletal myocyte and neural system will
be discussed in the remaining three sections of this review.
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).
Thus, although it is convenient at times to categorize individuals as
iron-deficient anemic vs. iron-deficient nonanemic, this is not
biological reality. Instead, it is more accurate to consider
individuals along a continuum of iron nutriture with different
functional consequences arising at different stages of severity. |
IMPAIRED IMMUNE FUNCTION |
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TOPABSTRACTINTRODUCTIONCHEMISTRYMODEL OF INTERORGAN IRON...GENERAL CLINICAL MANIFESTATIONSIMPAIRED IMMUNE FUNCTIONMENTAL FUNCTION DURING IRON...IRON AND NEUROTRANSMITTER...IMPAIRED PHYSICAL PERFORMANCESUMMARY AND CONCLUSIONSDISCUSSIONREFERENCES |
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). There is new evidence that
unicellular organisms and larger organisms, such as humans, share a
common lineage of metal transporters (Fishbane 1999
).
These divalent metal transporters have been identified and cloned in
both bacteria and humans and are used to internalize iron from
extracellular spaces. This suggests that transport of iron is key to
the survival of many pathogens, as well as that of the host organism.
Natural resistance–associated macrophage proteins (NRAMP 1,2) are now
known to be able to transport iron, zinc, copper, manganese and other
divalent metals from endosomal vesicles into the cytoplasmic space.
NRAMP 2 was recently renamed divalent metal transporter-1 or divalent
cation transporter-1, reflecting its functionality as a
proton-divalent metal countertransport protein (Ponka et al. 1998
). Bacterial virulence is associated with the genes that
code for iron acquisition in both Escherichia coli and
Vibrio (Fishbane 1999
, Ike et al. 1992
). Thus, the acquisition of iron from biological fluids by
siderophores secreted by bacteria is one of their routes of obtaining
this essential nutrient. In vitro studies show that the provision of
iron in rodents increases the pathogenicity of a number of bacteria
(Sussman 1974
). Data showing that this is also the case
for humans are far less convincing and are reviewed in detail elsewhere
in this supplement. An often-quoted study of Murray et al. (1978)
examined Somali nomads with iron-deficiency anemia.
Oral iron therapy led to a 12-fold increase in infections compared with
no therapy. Replication of such a powerful effect of iron status has
not been seen in other studies (Damsdaran et al. 1979
). Immunity during iron deficiency.
Experimental and clinical data suggest that there is an increased risk
of infection during iron deficiency, although a small number of reports
indicate otherwise. Hershko (1996)
urges caution in the
interpretation of many studies because the confounding issues of
poverty, generalized malnutrition and multimicronutrient deficiencies
are often present in those studies. The molecular and cellular defects
responsible for immune deficiency are complex because almost every
effector of the immune response is limited in number or action by
experimental iron deficiency. As mentioned previously, iron is
essential for proper cell differentiation and cell growth. In addition,
iron is a critical component of peroxide-generating enzymes and
nitrous oxide–generating enzymes that are critical for the proper
enzymatic functioning of immune cells. Finally, iron is likely involved
in the regulation of cytokine production and mechanism of action
through its influence on second-messenger systems (Hershko 1996
). In one of few studies of role of iron nutrition in the
development of the immune system, a delay was noted in the development
of cell-mediated immunity (Kochanowski and Sherman 1985
).
In adult animals or humans with intact immune systems, nonspecific
immunity is affected by iron deficiency in several ways. Macrophage
phagocytosis is generally unaffected by iron deficiency, but
bactericidal activity of these macrophages is attenuated
(Hallquist et al. 1992
). Neutrophils have a reduced
activity of the iron-containing enzyme, myeloperoxidase, which
produces reactive oxygen intermediates responsible for intracellular
killing of pathogens (Spear and Sherman 1992
). There is
a decrease in both T-lymphocyte number and T-lymphocyte
blastogenesis and mitogenesis in iron deficiency in response to a
number of different mitogens. This alteration is largely correctable
with iron repletion (Kuvibidila et al. 1999
,
Spear and Sherman 1992
). Recent studies of T lymphocytes
in iron deficiency noted that protein kinase C activity and
translocation of both splenic and purified T cells were altered by iron
deficiency (Kuvibidila et al. 1999
). On the other hand,
others have found a normal T-lymphocyte proliferative response to
mitogens (Canonne-Hergaux et al. 1999
).
Humoral immunity appears to be less affected by iron deficiency than is
cellular immunity. In iron-deficient humans, antibody production in
response to immunization with most antigens is preserved
(Hallquist et al. 1992
, Spear and Sherman 1992
).
Mediators of immune functioning.
There are several possible mechanisms that could explain the effects of
iron deficiency on the immune system. DNA synthesis, initiated by the
iron-containing enzyme ribonucleotide reductase, is a
rate-limiting factor in cellular replication and may be limited by
iron deficiency. Control of differentiation of cells is influenced by
the available iron and iron transport into cells via the transferrin
receptor. Galan and colleagues (1992)
reported a
reduction in interleukin-2 production by activated lymphocytes in
iron-deficient subjects. The release of interleukin-2 is
fundamental to communication between lymphocyte subsets and natural
killer cells but it does not appear to be the only cytokine that is
altered by iron status (Sussman 1974
).
Acute-phase reactants.
Tumor necrosis factor, interleukin-1 and interferon- all work as
effectors of iron movement. These cytokines operate in a coordinated
fashion to reduce the size of the intracellular labile iron pool by
reducing the amount of transferrin receptor on the cell surface,
increasing the synthesis of ferritin for iron storage and activating
nitric oxide systems (Damsdaran et al. 1979
,
Fishbane 1999
, Hallquist et al. 1992
,
Ike et al. 1992
, Kochanowski and Sherman 1985
, Murray et al. 1978
, Sussman 1974
). Regulation of gene transcription is a likely mechanism.
It is less apparent that the iron status of the individual can modify
the acute-phase response system (i.e., does the ability to mount an
acute-phase response depend in part on iron nutritional status?).
Nonetheless, there is a well-known decrease in the plasma iron
concentration as well as an increase in the plasma ferritin
concentration. Careful studies of the iron content of this newly
released ferritin are not well established; thus the role of plasma
ferritin in the sequestration of plasma iron remains uncertain.
Sequestration of iron seems to be an important part of the host
response to infection. Administration of a potent iron chelator,
deferoxamine, to humans was examined to determine the potential
antimalaria effect (Byrd and Horwitz 1989
, Fahmay and Young 1993
, Konijn and Hershko 1977
,
Lane et al. 1991
).
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MENTAL FUNCTION DURING IRON DEFICIENCY |
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TOPABSTRACTINTRODUCTIONCHEMISTRYMODEL OF INTERORGAN IRON...GENERAL CLINICAL MANIFESTATIONSIMPAIRED IMMUNE FUNCTIONMENTAL FUNCTION DURING IRON...IRON AND NEUROTRANSMITTER...IMPAIRED PHYSICAL PERFORMANCESUMMARY AND CONCLUSIONSDISCUSSIONREFERENCES |
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The brain obtains iron primarily via transferrin receptors expressed on
endothelial cells on the brain microvasculature (Connor and Benkovic 1992
, Fishman et al. 1987
). The
regulation of iron movement across this barrier is not well understood,
although regulation in response to organ iron status clearly occurs.
That is, the rate of iron uptake into the brain is increased when the
iron status of the subject is low and is decreased when the iron status
is higher (Taylor et al. 1991
). In addition, the process
is highly selective and not reflective of overall blood-brain
permeability (Crowe and Morgan 1992
, Morris et al. 1992
). The uptake of iron is reported to be homogeneous and
to be followed by redistribution to the basal ganglia, although there
are other possibilities that depend on local regulation of uptake
(Dwork et al. 1988
). The choroid plexus is a rich source
of transferrin mRNA, and transferrin secreted by this organ presumably
is used for the distribution of iron to glia and neurons for use or
storage. It is important to remember that plasma transferrin can move
across the blood-brain barrier and become part of the circulating
pool of transferrin in cerebrospinal fluid. The adaptive regulation of
transferrin synthesis and action in response to iron-deficiency
anemia in the brain is unknown.
Regions of the brain rich in iron in adulthood, i.e., the substantia
nigra, globus pallidus, nucleus accumbens, are not the regions that
have a high iron content in early life. In addition, they are far less
affected by dietary iron deficiency than are other regions such as the
cortex or the striatum that have less iron content (Erikson et al. 1997
). This iron is located primarily in microglia and
oligodendrocytes and functions in numerous metabolic activities
(Beard et al. 1993
, Epstein and Connor 1999
, Hill et al. 1985
, Mash et al. 1990
). The regional heterogeneity in the deposition of iron in
the brain is remarkably similar across many species with the basal
ganglia, substantia nigra and deep cerebellar nuclei particularly rich
in iron (Aoki et al. 1989
, Benkovic and Connor 1993
). Recent studies from our laboratory and those of
associates showed that iron accumulation in different brain regions is
a function of the stage of brain development occurring at the time of
the investigation (Fig. 4A
,
B) (Pinero et al. 2000
). For example, when brain iron
distribution is studied in a rodent model of lactational iron
deficiency, the pattern of iron loss that emerges is entirely different
from that for the effects of iron deficiency instituted during the
postweaning period.
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, Pinero et al. 2000
). For example, in
studies conducted in rodents during the mid- and late-lactational
periods (equivalent to humans between 6 and 12 mo of life), there was a
very significant 25% drop in cortex, striatum and hind-brain iron
content with a short period of feeding a low iron diet. In contrast,
there was only a 5% drop in thalamus iron content. During postweaning
iron deficiency, there are comparable 20–30% declines in cortex,
striatum and cerebellum, but the thalamus also becomes sensitive to
dietary iron deficiency and has a 20% drop in iron concentration.
These studies demonstrate that the effect of iron deficiency on brain
iron content depends on the timing of the nutritional insult.
Iron and transferrin levels have been reported to be high in
cerebrospinal fluid, especially in perinatal brains (Erikson et al. 1997
). The actual levels of iron, however, are poorly
described in conditions of iron overload and iron deficiency and during
active growth and development. Atomic absorption spectrophotometry
reveals iron concentrations of 15–25 µg/L in humans
and monkeys and 5–20 µg/L in mice (Bradbury 1997
). These concentrations are 5- to 10-fold lower than the
corresponding plasma concentrations. Some unpublished data from our
laboratory indicate that chronic diseases and pathologies (hepatitis,
liver failure, diabetes) may alter these concentrations dramatically.
In patients with restless-legs syndrome, the ratio of plasma iron
to cerebrospinal fluid iron is abnormal, suggesting that the movement
of iron across the blood-brain barrier is perturbed in these
individuals (Earley et al. 2000a
). The normal
circulating level of transferrin in cerebrospinal fluid is also poorly
described, although some reviews suggest that the total
iron-binding capacity is barely even with the circulating iron
concentrations, resulting in the apparent availability of free iron
(Bradbury 1997
). The role of the cerebrospinal fluid in
the delivery of iron to various brain cells is not well understood
(Dwork 1995
, Malecki et al. 1998
).
The brain is richer in the H subunit than in the L subunit of ferritin,
and its localization is specific to cell type (Connor and Benkovic 1992
). In rats and humans, microglia and
oligodendrocytes contain ferritin, whereas in mice astrocytes contain
ferritin. Ferritin levels correlate with brain iron content; they are
highest at birth and decline thereafter in newborn rats (Miller et al. 1996
). Moreover, the concentration can be directly
affected by the body iron burden (Chen et al. 1995b
).
Ferritin isoforms are heterogeneously distributed in brain, and not all
regions of the brain seem to be equally sensitive to an alteration in
body iron status (Erikson et al. 1997
, Kivijarvi et al. 1986
). Studies in postnatal iron deficiency involving
ferritin ratios (H:L) in pig and rodent brain reveal a dramatic effect
of iron deficiency and the expression of these two subunits of the
ferritin molecule (Erikson et al. 1998
, Han et al. 2000
). The changes in the protein expression appear to be
regulated by the iron-response–element system as described previously.
The developmental roles of the two subunits relative to iron storage or
use and detoxification are unknown, although accumulation of iron in
certain brain regions is believed to play a role in a number of
neuropathologies.
Iron deficiency effects.
Dallman and co-workers (Dallman et al. 1975
,
Dallman and Spirito 1977
) demonstrated two decades ago
that young rats deprived of iron in early postnatal life have
significantly lower (27%) whole-brain iron content than do
controls 28 d postnatally and were quite resistant to restoration
of their normal complement of brain iron (still 20% lower) despite
aggressive dietary repletion for 45 d. Although these studies were
landmark investigations at the time, they were usually misinterpreted
to indicate that brain iron content was very static and not at all
sensitive to dietary iron deficiency. This concept of a protected organ
persisted for nearly two decades, until it was demonstrated by us and
others that the brain is quite sensitive to dietary iron depletion and
repletion and uses a host of mechanisms to regulate iron flux
homeostatically.
When animals are given low iron diets in postweaning life, there is a
significant decline in brain iron content and a rapid repletion with
refeeding (Chen et al. 1995b
, Erikson et al. 1997
). This is in contrast to neonatal or preweaning iron
deficiency in which the effects appear irreversible (Dallman and Spirito 1977
, Felt and Lozoff 1996
). From animal
studies across a number of species, we assume that human brain iron
content goes down with a decrease in body iron status, although there
is no published direct proof of this. Preliminary magnetic resonance
imaging data from several restless legs syndrome patients with
iron-deficiency anemia have weighted T2 relaxation times consistent
with depleted striatal and nigra iron contents (C. Earley, unpublished
data, personal communication). The areas of the brain that are quite
sensitive to iron depletion in early life often are located within
dopaminergic regions of the brain (Chen et al. 1995a
,
Erikson et al. 1997
). Hill (1988)
argues
that the areas of highest iron concentration in the adult are not
identical to those brain regions in which dopaminergic neurons either
originate or terminate, which is not in agreement with Youdim et al. (1989)
.
Iron is required for proper myelination of the spinal cord and white
matter of cerebellar folds (Larkin and Rao 1990
), and it
is a cofactor for a number of enzymes involved in neurotransmitter
synthesis, including tryptophan hydroxylase (serotonin) and tyrosine
hydroxylase (norepinephrine and dopamine). Iron is also a cofactor for
ribonucleotide reductase, the rate-limiting step in DNA synthesis.
The predominant cell type containing iron in the brains of mice, rats,
monkeys, pigs and humans is the oligodendrocyte (Hill 1988
). These cells are responsible for the production of
myelin; hence alterations in the functioning of these cells are
associated with hypomyelination. Oligodendrocytes are responsible for
the synthesis of fatty acids (Mackler et al. 1979
,
McKay et al. 1983
) and cholesterol for myelin; both of
these metabolic processes require iron. When oligodendrocyte maturation
is disrupted, as results from some gene mutations, iron accumulation is
only 50% of normal (Connor and Menzies 1990
). In
iron deficiency, oligodendrocytes appear immature (Erikson et al. 1997
). The failure to deliver iron to these cells during
particular periods of early brain development could be causally related
to delayed motor maturation and perhaps behavioral alterations in young
humans (Rocangliolo et al. 1996
). These investigators
demonstrated a slowed nerve conduction velocity during an auditory
evoked potential test. The reversibility of this finding remains under
investigation. Although there are no quantitative data showing that
iron deficiency leads to a lesser number of oligodendrocytes,
hypomyelination occurs as a result of postnatal iron deficiency
(Larkin and Rao 1990
, Wiesinger et al. 2000
). In addition, iron deficiency could block cholesterol
biosynthesis in these cells because at least three isoforms of P450 (a
protoheme monooxygenase) are found specifically in oligodendrocytes.
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TOPABSTRACTINTRODUCTIONCHEMISTRYMODEL OF INTERORGAN IRON...GENERAL CLINICAL MANIFESTATIONSIMPAIRED IMMUNE FUNCTIONMENTAL FUNCTION DURING IRON...IRON AND NEUROTRANSMITTER...IMPAIRED PHYSICAL PERFORMANCESUMMARY AND CONCLUSIONSDISCUSSIONREFERENCES |
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Oxidation-reduction.
Iron-dependent electron transport alterations in the brain resulting
from iron deficiency are sparsely documented. Mackler and
colleagues (1979)
demonstrated that cytochrome concentrations
in mitochondria from brain of iron-deficient animals were not
different from those of controls. In addition, oxidative
phosphorylation in these mitochondria using pyruvate-malate,
succinate or -glycerol phosphate was unaffected by iron deficiency.
In animals with similar severities of iron-deficiency anemia
(hemoglobin <60 g/L), skeletal muscle oxidative capacity was reduced
by 40–50% (Sourkes 1973
). At least superficially, it
does not appear that there is a massive decrease in oxidative
metabolism in the iron-deficient brain. This must be viewed with
caution, however, because the brain is one of the most oxidative organs
of the body.
Synthesis and degradation.
Iron is a cofactor for tyrosine hydroxylase, tryptophan hydroxylase,
xanthine oxidase and ribonucleoside reductase (Youdim and Green 1978
). Thus, nutritional iron deficiency would be expected to
lead to decreased activities of these enzymes; however, this has not
been observed consistently. When brain iron levels are reduced by as
much as 40% with dietary restriction in postweanling rats, there was
no change in the activity of tyrosine hydroxylase, tryptophan
hydroxylase, monoamine oxidase, succinate hydroxylase or cytochrome c
oxidase (Ashkenazi et al. 1982
). Aminobutyric acid
transaminase and glutamate decarboxylase activities decreased, but
these observations have yet to be reproduced by others. Whole-brain
concentrations of norepinephrine and dopamine were unaltered by iron
deficiency (Ashkenazi et al. 1982
) and responded equally
well to priming doses of levodopa (50 mg/kg). Serotonin and
5-hydroxyindole acetic acid concentrations were reported to be
decreased. The turnover of norepinephrine, dopamine and serotonin in
brain homogenates was also unaffected by iron deficiency, but more
sophisticated approaches have not be used in recent years (Felt and Lozoff 1996
, Youdim and Green 1977
,
Youdim et al. 1989
).
Monoamine oxidase and aldehyde dehydrogenase are critical in the
catabolism of neurotransmitters in the dopaminergic, serotoninergic and
noradrenergic systems of the brain (Youdim et al. 1975
and 1980
). However, Mackler et al. (1979)
were
unable to demonstrate any decreased activity in brain of severely
iron-deficient rats. Youdim et al. (1980)
also
showed no effect of iron deficiency in whole-brain preparations,
although heart monoamine oxidase activity was decreased by >50%.
-Aminobutyric acid.
Hill (1988)
noted great similarity in the brain iron
distribution and brain regions that receive input from -aminobutyric
acid (GABA). She argued that the regions that have the highest
concentrations of iron, the globus pallidus, substantia nigra, ventral
pallidus and the cerebellar nuclei, also are highly innervated by
GABA-mediated nerve tracts. Because GABA release will modulate the
activity of dopaminergic neurons, this is an important point to be
resolved. In an older study, Youdim and colleagues
(1980)
observed no effect of iron deficiency on the GABA
receptor population, amount of GABA or production rates. Other
investigators, however, report that iron deficiency in utero and
postweaning is associated with significant decreases in glutamate
decarboxylase, glutamate dehydrogenase and GABA transaminase activities
(Li 1998
, Taneja et al. 1986
). These
latter two enzymes are shunt enzymes responsible for the synthesis and
degradation of GABA. Thus, although concentrations of GABA may not be
changed, there are some indications that GABA metabolism is altered by
iron deficiency. Little substantive biochemical work has been done on
this interaction, but such studies would expand the range of possible
neurotransmitter systems that are altered by iron-deficiency
anemia. No distinction has been made between intrauterine effects of
iron deficiency and later effects that may occur during lactation and
after weaning.
Dopamine.
The dopaminergic system in the only neurotransmitter system in the
central nervous system that has been consistently sensitive to
experimental changes in iron status. As whole-brain iron content
drops 15% below normal, biological and behavioral alterations occur
that may result from changes in the dopaminergic system (Erikson et al. 1997
and 2000
, Morse et al. 1999a
,
Nelson et al. 1997
, Yehuda 1990
,
Youdim 1990
). Youdim and colleagues measured affinities
and densities for dopamine D1 and
D2 receptors, serotonin, GABA, benzodiazepine,
and and ß adrenergic and muscarinic-cholinergic receptors in
brain regions after postweaning dietary iron deficiency. They observed
an effect of severe postweaning iron deficiency only on the dopamine
system. The more recent experiments demonstrate that striatum dopamine
D1 and D2 receptor
densities are significantly lower (25–35%) in postweaning
iron-deficient rats and that the dopamine transporter is also
significantly lower in density in several brain regions (Erikson et al. 1997
, Pinero et al. 2000
).
Recent in vivo animal data demonstrate that extracellular dopamine is
elevated in striatum of postweaning iron-deficient rats and returns
to normal levels when brain iron content and iron status return to
normal (Chen et al. 1995a
, Nelson et al. 1997
). Pharmacologic experiments with cocaine, a dopamine
transporter inhibitor, demonstrate both in vivo and in vitro deficits
in dopamine transport from the intersynaptic space back into
presynaptic neurons (Erikson et al. 2000
). Attentional
processing of environmental information is highly dependent on
appropriate rates of dopamine clearance from the interstitial space,
which suggests that iron status may affect behavior through effects on
dopamine metabolism. Alterations in dopamine in the mesolimbic and the
nigrostriatal tracts are associated with changes in motor control as
well as altered perception, memory and motivation. However, lesions in
many other parts of the brain may also result in alterations in
perception, memory and motivation; thus the specificity of the
connection between striatal dopamine changes and impaired spatial
memory, attentional deficits and avoidance behavior remains to be
established.
Serotonin and norepinephrine.
As mentioned earlier, tryptophan and tyrosine hydroxylase are
iron-containing enzymes that are essential for the production of
serotonin from tryptophan and norepinephrine and dopamine from tyrosine
(Webb 1992
, Youdim and Green 1977
and 1978
). As part of their initial survey of neurotransmitter
systems that may be affected by iron deficiency, Youdim and colleagues
measured the concentrations of serotonin, norepinephrine and their
primary metabolites, 5-hydroxy indole acetic acid and normetanephrine
(Youdim and Green 1977
and 1978
). They observed no
significant alterations in concentrations of these neurotransmitters or
metabolites in striatum of rats. Other studies of monoamine oxidase
activity in brain of iron-deficient rats showed no effect on this
enzyme responsible for the degradation of the monoamines, although
platelet monoamine oxidase activity was affected (Youdim et al. 1975
). Our laboratory has also examined these two
neurotransmitter systems with in vivo microdialysis and failed to
observe consistent alterations in their concentrations in extracellular
fluid in the brain (Chen et al. 1995a
, Nelson et al. 1997
). However, radioligand binding studies performed in
inbred strains of mice demonstrated significantly lower densities of
the serotonin transporter in striatum of iron-deficient mice
(Morse et al. 1999a
). This observation has some
significance because the dopamine, norepinephrine and serotonin
transporters have a high degree of homology. Our observations of a
consistent decrease in dopamine transporter density in striatum of
iron-deficient rats, in combination with the one study of serotonin
transporter, suggest a more general role of iron in the removal of
neurotransmitters from the synaptic cleft.
Developmental models.
Irreversible alterations in brain iron content have been shown in
animal studies by feeding rats low iron diets early in life before the
completion of the brain organization and myelination and the
establishment of the dopaminergic tracts (Dallman and Spirito 1977
, Felt and Lozoff 1996
). Felt and colleagues
demonstrated behavioral changes that could be associated with the
irreversible changes in brain iron content that occurred, but they did
not determine distribution of brain iron. This is in contrast to the
ability of postweanling or late-lactational iron-deficient rats to
recover brain iron content and functioning (Erikson et al. 1997
, Pinero et al. 2000
). In those studies, the
investigators demonstrated a prompt recovery of brain iron in nearly
all brain regions with feeding of a high iron diet. These studies, in
combination, suggest that important biological switches for the
acquisition of brain iron in early development may be irreversibly
altered. A significant caveat to the observations from these rodent
studies is that much of the rodent brain maturation occurs postnatally.
Peak myelination of the rodent brain is occurring between postnatal d 8
and 14, whereas in the human infant, this occurs between ages 8 and 15
mo. Thus, the timing of the nutritional studies relative to
interspecies comparisons must be carefully considered. Felt and Lozoff (1996)
developed a very nice paradigm for this
comparison that has been used very successfully by our laboratory to
produce appropriate periods of iron deficiency to mimic lactational and
early postlactational nutritional stress (Erikson et al. 1997
, Pinero et al. 2000
). Thus, much of the
early disconnect between data collected in animal models and
observations in human infants has been avoided. The next several years
will see the publication of a number of articles from active research
groups using rodent and primate models of iron deficiency that will
further delineate the biological underpinnings.
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TOPABSTRACTINTRODUCTIONCHEMISTRYMODEL OF INTERORGAN IRON...GENERAL CLINICAL MANIFESTATIONSIMPAIRED IMMUNE FUNCTIONMENTAL FUNCTION DURING IRON...IRON AND NEUROTRANSMITTER...IMPAIRED PHYSICAL PERFORMANCESUMMARY AND CONCLUSIONSDISCUSSIONREFERENCES |
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Lethargy, apathy and listlessness are frequently observed symptoms of
severe iron-deficiency anemia and perhaps anemia in general.
However, for some time, iron deficiency has been known to be associated
with decreased physical activity (Baynes and Bothwell 1990
, Dallman 1982
and 1986
, Finch and Heubers 1982
). The consistency of evaluation of this effect on
exercise tolerance and work performance hinges on the definitions of
iron-deficiency anemia that have used by investigators. This has
led to some ambiguity in the results. However, the mechanisms of these
effects have been thoroughly investigated in rodent models, and clear
distinctions between the effects of diminished oxygen transport and
oxidative capacity of muscle have been established (Dallman 1986
). When rats are fed various contents of iron in purified
diets, it is straightforward to establish that muscle myoglobin and
cytochrome c are affected to a proportionally similar degree as
hemoglobin with decreased iron intakes in young growing animals. That
is, a severely anemic rat with a 50% decrease in hemoglobin
concentration also has 50% lower myoglobin and cytochrome c
concentrations. That deceased exercise capacity is related to
diminished oxygen transport, diminished oxygen diffusion within the
exercising tissue and decreased oxidative capacity of muscle
(Maguire et al. 1982
, McLane et al. 1981
). Although the efficiency of oxygen extraction is improved
by the hemoglobin-oxygen saturation curve shifts,
VO2max is still decreased 30–50% in both
animals and humans.
The manifestations of depletion of essential body iron also have
profound effects on skeletal muscle, with a significant decrease in
mitochondrial iron-sulfur content (Maguire et al. 1982
), mitochondrial cytochrome content (McKay et al. 1983
, McLane et al. 1981
, Willis et al. 1987
) and total mitochondrial oxidative capacity (Davies et al. 1982
and 1984
, McKay et al. 1983
,
Willis et al. 1987
). Pyruvate and malate oxidase were
decreased to 35% of normal in iron-deficient muscle and improved
to 85% of normal after 10 d of iron treatment. 2-Oxoglutarate
oxidase was decreased to 47% of normal and improved to 90%. In
contrast, succinate oxidase was only 10% of normal in iron deficiency
and improved to only 42% of normal after 10 d (Perkkio et al. 1985
). The cytoplasmic enzymes, hexokinase and lactate
dehydrogenase, were unaffected by iron status. The 50–90% decrease in
both the iron-sulfur enzymes and in the heme-containing
mitochondrial cytochromes is consistent with many observations over the
past two decades (Dallman 1986
, Willis et al. 1987
). What seems to determine the amount of decline in
activity with iron deprivation is the rate of turnover of that
particular iron-containing protein in the time of cellular
deprivation of iron. Although this makes sense conceptually, the direct
testing of this hypothesis occurred in a cursory fashion.
Exercise performance at the time of severe iron-deficiency anemia
was only 20% of normal in a brief, intense exercise protocol
(Willis et al. 1987
). Treatment with iron dextran
corrected this exercise tolerance within 4 d, but mitochondrial
oxidation using either malate-pyruvate or succinate as substrates
was not improved. When -glycerol phosphate was used as the
substrate, however, a very significant improvement in the rate of
oxidation was realized, suggesting that this is the rate-limited
step in iron-dependent oxidation. Longer-term repletion led to
the normalization of other enzyme activities (Willis et al. 1990
). The interpretation of these data is consistent with
rates of turnover of cellular enzymes that require iron and thus
support the premise that rates of loss of enzymatic function in muscle
are related to turnover of iron-containing enzymes within those
cells. A study using 31P nuclear magnetic
resonance spectroscopy to examine the functional state of bioenergetics
in iron-deficient and iron-replete rat gastrocnemius muscle at
rest and during 10 min of contraction at 2 Hz demonstrated an effect of
iron status (Thompson et al. 1993
). Iron-deficient
animals had a clear increase in phosphocreatine breakdown and a
decrease in pH compared with controls and a slower recover of
phosphocreatine and inorganic phosphate concentrations after exercise.
During repletion for 2–7 d with iron dextran, there was no substantial
improvement in these indicators of muscle mitochondrial energetics.
These authors concluded that "tissue factors" such as decreased
mitochondrial enzyme activity, decreased number of mitochondria and
altered morphology of the mitochondria might be responsible for these
observations.
Anemia vs. tissue iron deficiency.
Dallman and colleagues established the concept that anemia limits the
capacity of the individual to deliver oxygen to exercising muscle,
whereas tissue iron deficiency limits the capacity of the individual to
perform oxidative metabolism (Dallman 1982
and 1986
).
This was accomplished by iron-repletion and
exchange-transfusion studies and the observation of recovery of
sprint performance compared with endurance performance (Fig. 5
). There was a stronger correlation of sprint performance with anemia
than with tissue cytochrome c content, whereas there was a strong
correlation of tissue cytochrome c with recovery of endurance
performance. Exchange-transfusion experiments in which the
hemoglobin concentration of animals was manipulated by transfusion
further demonstrated that endurance performance is almost entirely
related to muscle metabolism and relatively independent of hemoglobin
concentration down to 100 g/L.
|
Iron-containing enzymes in skeletal muscle and liver are altered in
iron deficiency to promote an increased rate of lactate production in
muscle and use by liver (Davies et al. 1982
,
Finch et al. 1979
, Henderson et al. 1986
,
Ohira et al. 1986
, Thompson et al. 1993
).
These animal studies clearly demonstrated that the rates of plasma
disappearance of radioactively labeled glucose and lactate were both
increased in iron-deficiency anemia. Even at rest, there were
higher concentrations of glucose in the plasma of iron-deficient
animals than controls. Additional studies demonstrated that lactate
dehydrogenase is increased in activity in iron-deficient skeletal
muscle and that isozyme adaptations occur to maximize this capacity for
anaerobic metabolism (Ohira et al. 1986
). In contrast,
other more recent experiments suggest that a number of nonheme
iron-sulfur proteins, especially aconitase, may be very susceptible
to variations in cellular iron content (Willis et al. 1990
). Dallman’s laboratory demonstrated that this key enzyme
in gluconeogenesis could be restored to full activity with 15 h of
an iron injection in the rat model, with a rapid return of lactate and
glucose concentrations toward normal. Rates of gluconeogenesis in
iron-deficiency anemia are increased to improve the provision of
blood glucose (Klempa et al. 1989
). The endocrine basis
of the glucose cycling was examined in our laboratory. We demonstrated
a dose-response relationship among hyperglycemia, hyperinsulinemia
and severity of iron-deficiency anemia (Borel et al. 1993
, Farrell et al. 1988
). Hyperinsulinemic
euglycemic glucose clamps were used to demonstrate an increased
sensitivity to insulin in animals with hemoglobin concentration < 120 mg/L. This was also the threshold for a significant elevation in
fasting blood glucose concentration. Interestingly, similar
observations on fuel homeostasis alterations have not been reported in
humans who have a similar proportional severity of anemia. It is
important to recall that the catecholamines (epinephrine and
norepinephrine) are key regulators of glucose production and that their
concentrations in plasma are abnormal in iron-deficient anemic
humans and rodents (Beard et al. 1988b
, Dillman et al. 1980
, Martinez-Torres et al. 1984
). Taken
together, these studies illustrate that tissue iron is associated with
an increased reliance on glucose as a fuel for endurance performance at
submaximal workloads, whereas hemoglobin-associated iron plays an
important role in oxidative capacity and maximal aerobic work
performance.
Human studies.
Although it is the responsibility of others attending this workshop to
address the human literature on the effects of iron deficiency on work
performance, it is appropriate to return to one of the key research
questions that still remain unresolved (Viteri and Torun 1974
), i.e., is there a linear relationship of iron status to
work performance or is there a curvilinear relationship with a plateau?
This question is centered on the notion of a critical cut-off value
for the severity of anemia above which there is no relationship and
below which there is a strong relationship. Viteri and colleagues used
a Harvard Step Test to demonstrate in a laboratory setting that
performance was linearly and positively correlated with hemoglobin over
the entire range normally seen in humans (Fig. 6A
). In contrast, the data of Gardener and colleagues (Edgerton et al. 1981
) clearly demonstrate that time to exhaustion for
submaximal exercise has a curvilinear relationship to hemoglobin (Fig. 6B
). The apparent conflict between these two data sets may
be resolved if we are willing to accept the animal experiments of Finch
and Dallman’s research groups. That is, lower intensity endurance
exercise is tightly correlated with tissue iron deficiency where a
curvilinear relationship is expected, whereas a brief intense exercise
(Harvard Step Test) should be more tightly correlated with severity of
anemia (Davies et al. 1982
, Finch et al. 1979
). Arterial oxygen content, oxygen delivery bound to
hemoglobin and cardiac output are all key determinants of the amount of
work that exercising muscle can do. Gardner and Edgerton evaluated the
physical work capacity and metabolic stress in iron-deficient
workers on a tea farm in Sri Lanka (Edgerton et al. 1979
). In one study, men and women with hemoglobin
concentrations of 40–120 g/L were assigned to either an
iron-treatment or a placebo group. Maximal exercise tolerance was
dramatically reduced in the anemic subjects who also transported 15%
less oxygen per pulse than did nonanemic subjects. Iron treatment
restored cardiorespiratory and work performance variables.
|
, Ekblom 1997
). This is most easily interpreted as follows: the anemic
subjects had a lower aerobic threshold relative to control subjects;
thus, exercise protocols at a fixed level of high effort were more
likely to put anemic subjects above the threshold. Thus, the protocols
that are used have a large effect on the conclusions regarding the role
of iron in exercise performance. |
SUMMARY AND CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONCHEMISTRYMODEL OF INTERORGAN IRON...GENERAL CLINICAL MANIFESTATIONSIMPAIRED IMMUNE FUNCTIONMENTAL FUNCTION DURING IRON...IRON AND NEUROTRANSMITTER...IMPAIRED PHYSICAL PERFORMANCESUMMARY AND CONCLUSIONSDISCUSSIONREFERENCES |
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONCHEMISTRYMODEL OF INTERORGAN IRON...GENERAL CLINICAL MANIFESTATIONSIMPAIRED IMMUNE FUNCTIONMENTAL FUNCTION DURING IRON...IRON AND NEUROTRANSMITTER...IMPAIRED PHYSICAL PERFORMANCESUMMARY AND CONCLUSIONSDISCUSSIONREFERENCES |
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Dr. Oppenheimer: How comfortable are we comparing myelination in the newborn rat with the newborn human?
Dr. Beard: The peak time of myelination in the rodents is between 8 and 14 d of postnatal life with peak at about 11–12 d. In the human, it is going to be somewhere between 8 and 20 mo, with the peak probably around 14–18 mo. In the human it is much more prolonged. In the rat it is compressed. We used the model on purpose to allow us to define the timing of these events.
Dr. Lozoff: It is also important to know that different systems myelinate at different rates. It is not just a question of the species but the function being looked at.
Dr. Pelletier: One can see why the Corey cycle might be a functional adaptation in iron deficiency, but why would one necessarily expect the increased glucose concentration instead of simply normal glucose concentrations?
Dr. Beard: Well, there is not an easy answer to that. It probably has to do with this insulin sensitivity issue—that this was tied into rates of glucose clearance. Why the set point changes, I do not know. Nobody that I know of is doing any work on glucose and insulin homeostasis and iron.
Dr. Oppenheimer: These were all reversible changes of glucose metabolism?
Dr. Beard: Yes, they are all reversible.
Dr. Habicht: Coming back to something you talked about earlier; regarding neurology, these outcomes were reversible, such as myelination and so on. What degree of iron deficiency was there compared with what we would see in a human population?
Dr. Beard: The severity of iron deficiency is hemoglobin around 60–70 g/L and the question is one of reversibility. The animals that were always iron-deficient anemic do not do anything. They are like doorstoppers. They do not explore the environment. However, if we give those animals iron, in as little 2 wk, from d 21 to 35, they improve dramatically. So, they do have this capacity to improve, but you will notice that it is not the same as the controls. They do not reach the same level of performance as animals that were never iron deficient.
Dr. Lozoff: This is not necessarily a myelin problem.
Dr. Beard: Not necessarily myelin.
Dr. Habicht: The question I had was at what degree of deficiency do you see these effects?
Dr. Beard: One answer to your question is the study that Drs. Felt and Lozoff published a few years ago in which they had a much milder degree of iron deficiency than what we have. They showed a defect in the homing behavior of these animals. They had very mild levels of anemia—hemoglobin around 100–110 g/L. Some data in the animal literature show that even at mild degrees of iron deficiency anemia where there is no growth retardation, no other overt signs of abnormalities in behavior occur. What Barbara Felt did not have in those data are any of the fine-grained analysis that we have been able to do, but we have not yet gone back to look at the moderate anemia.
Dr. Pollitt: I have two points to make. One is that there does not have to be a one-to-one correspondence between the kinds of operations that you have described and cognitive or other types of behavioral manifestations in children. In other words, even if you are able to demonstrate that there is reduced conduction in the auditory system, that does not mean that there is actually a functional correspondence.
The second point is that it is unfortunate that the old work on activity and on muscle in animals and humans has only been related to work performance and not really to motor development as well. Those data could actually be related to other forms of development that could be extremely important for the child’s adaptation.
Dr. Beard: I agree. You are absolutely right.
Dr. Pollitt: The amount of information that we now have on the functional consequences of iron deficiency is so broad that you would expect that development is going to be affected by very different kinds of pathways.
Dr. Beard: For the first time we are starting to get a clue that different parts of neural circuitry may be more sensitive to iron at different times. For example, the cerebellum seems to be quite sensitive during an early time period as well as a little bit later, whereas the thalamus is not sensitive at all during an early time but it is quite sensitive later. So, one could by virtue of knowing that piece of biology then start to look at the kinds of data you and Dr. Lozoff and others have collected and argue that if we have iron deficiency at that time, maybe this circuit is not developing. You are right. We need to have circuit-specific outcome variables.
Dr. Oppenheimer: Can you do intellectual tests on rats, such as maze learning and long-term memory?
Dr. Beard: Yes. You can do spatial learning and long-term memory kinds of things. It is all possible to do. Not much has been published on that yet.
Dr. Brabin: Can you tell me something about nonsomatic uterine muscle? The duration of labor—would it be prolonged? I was particularly interested in nonsomatic muscle because of the problems with uterine function in labor. These could be major problems in women who have a high prevalence for iron deficiency.
Dr. Beard: Yes, you would think that muscle contractility would be severely compromised in that situation.
|
FOOTNOTES |
|---|
2 This article was commissioned by the World
Health Organization (WHO). The views expressed are those of the author
alone and do not necessarily reflect those of WHO.
|
REFERENCES |
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TOPABSTRACTINTRODUCTIONCHEMISTRYMODEL OF INTERORGAN IRON...GENERAL CLINICAL MANIFESTATIONSIMPAIRED IMMUNE FUNCTIONMENTAL FUNCTION DURING IRON...IRON AND NEUROTRANSMITTER...IMPAIRED PHYSICAL PERFORMANCESUMMARY AND CONCLUSIONSDISCUSSIONREFERENCES |
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1.
Aoki S., Okada Y., Nishimura K., Barkovich A. J., Kjos B. O., Brasch R. C., Norman D. Normal deposition of brain iron in childhood and adolescence: MR imaging at 1.5 T. Radiology 1989;172:381-385
2. Ashkenazi R., Ben-Shachar D., Youdim M.B.H. Nutritional iron deficiency and dopamine binding sites in the rat brain. Pharmacol. Biochem. Behav. 1982;17:43-47
3. Baynes R. D., Bothwell T. H. Iron deficiency. Annu. Rev. Nutr. 1990;10:133-148[Medline]
4. Beard J. L., Connor J. R., Jones B. C. Iron on the brain. Nutr. Rev. 1993;51:157-170[Medline]
5. Beard J., Dawson H. Iron. Sunde R. O’Dell B. eds. Handbook on Nutritionally Essential Elements 1996:275-334 Marcel Dekker New York, NY.
6.
Beard J. L., Haas J. A., Tufts D., Spielvogel H., Vargas E., Rodriguez C. Iron deficiency anemia and steady-state work performance at high altitude. J. Appl. Physiol. 1988a;64:1878-1884
7.
Beard J. L., Tobin B., Smith S. Norepinephrine turnover in iron deficiency at three environmental temperatures. Am. J. Physiol. 1988b;255:R90-R96
8. Beaton G. H., Corey P. N., Steele C. Conceptual and methodological issues regarding the epidemiology of iron deficiency and the implications for studies of the functional consequences of iron deficiency. Am. J. Clin. Nutr. 1989;50:575-585
9. Benkovic S., Connor J. R. Ferritin, transferrin and iron in normal and aged rat brains. J. Comp. Neurol. 1993;337:97-113
10.
Borel M. J., Beard J. L., Farrell P. A. Hepatic glucose production and insulin sensitivity and responsiveness in iron-deficient anemic rats. Am. J. Physiol. 1993;264:E662-E667
11. Bothwell T. H., Charlton R. W., Cook J. D., Finch C. A. Iron Metabolism in Man 1979 Blackwell Scientific Publications Oxford, UK.
12. Bradbury M. Transport of iron in the blood-brain-cerebrospinal fluid system. J. Neurochem. 1997;69:443-454[Medline]
13. Byrd T. F., Horwitz M. A. Interferon gamma-activated human monocytes downregulate transferrin receptors and inhibit the intracellular multiplication of Legionella pneumophila by limiting the availability of iron. J. Clin. Investig. 1989;83:1457-1465
14. Canonne-Hergaux F., Gruenheid S., Govoni G., Gros P. The NRAMP 1 protein and its role in resistance to infection and macrophage function. Proc. Assoc. Am. Physicians 1999;111:283-289[Medline]
15. Casey J. L., Hentze M. W., Koeller D. M., Caughman S. W., Rouault T. A., Klausner R. D., Harford J. B. Iron-responsive elements: regulatory RNA sequences that control mRNA levels and translation. Science (Washington, DC) 1998;240:924-928
16. Celsing F., Blomstrand E., Werner B., Pihlstedt P., Ekblom B. Effects of iron deficiency on endurance and muscle activity in man. Med. Sci. Sports Exerc. 1986;18:156-161[Medline]
17. Chen Q., Beard J. L., Jones B. Abnormal rat brain metabolism in iron deficiency anemia. J. Nutr. Biochem. 1995a;6:486-493
18. Chen Q., Connor J. R., Beard J. L. Brain iron, transferrin and ferritin concentrations are altered in developing iron-deficient rats. J. Nutr. 1995b;125:1529-1535
19. Cole S. K., Billewicz W. Z., Thomson A. M. Sources of variation in menstrual blood loss. J. Obstet. Gynaecol. Br. Commun. 1971;78:933-939[Medline]
20. Connor J. R., Benkovic S. A. Iron regulation in the brain: histochemical, biochemical, and molecular considerations. Ann. Neurol. 1992;32:S51-S61
21. Connor J. R., Menzies S. L. Altered cellular distribution of iron in the CNS of myelin deficient rats. Neuroscience 1990;34:265-271[Medline]
22. Crichton R., Ward R. J. Iron metabolism—new perspectives in view. Biochemistry 1992;31:11255-11264[Medline]
23. Crowe A., Morgan E. H. Iron and transferrin uptake by brain and cerebrospinal fluid in the rat. Brain Res 1992;592:8-16[Medline]
24. Dallman P. R. Manifestations of iron deficiency. Semin. Hematol. 1982;19:19-30[Medline]
25. Dallman P. R. Biochemical basis for the manifestations of iron deficiency. Anun. Rev. Nutr. 1986;6:13-40
26. Dallman P. R, Siimes M. N., Manies E. C. Brain iron, persistent deficiency following short term iron deprivation in the young rat. Br. J. Haematol. 1975;31:209-215[Medline]
27. Dallman P. R., Spirito R. A Brain iron in the rat: extremely slow turnover in normal rat may explain the long-lasting effects of early iron-deficiency. J. Nutr. 1977;107:1075-1081
28. Damsdaran M., Naidu A. N., Sarma K. V. R. Anemia and morbidity in rural preschool children. Indian J. Med. Res. 1979;69:448-456[Medline]
29.
Davies K. J., Donovan C. M., Refino C. A., Brooks G. A., Packer L., Dallman P. R. Distinguishing effects of anemia and muscle iron deficiency on exercise bioenergetics in the rats. Am. J. Physiol. 1984;246:E535-E543
30.
Davies K. J., Maguire J. J., Brooks G. A., Dallman P. R., Packer L. Muscle mitochondrial bioenergetics, oxygen supply, and work capacity during dietary iron deficiency and repletion. Am. J. Physiol. 1982;242:E418-E427
31. Dillman E., Gale C., Green W., Johnson D. G., Mackler B., Finch C. A. Hypothermia in iron deficiency due to altered triiodothyronine metabolism. Am. J. Physiol. 1980;239:R377-R381
32. Dwork A. J. Effects of diet and development upon the uptake and distribution of cerebral iron. J. Neurol. Sci. 1995;134(suppl.):45-51
33. Dwork A. J., Schon E. A., Herbert J. Non-identical distribution of transferrin and ferric iron in human brain. Neuroscience 1988;27:333-345[Medline]
34. Earley, C. J., Allen, R. P, Beard, J. L. & Connor, J. R (2000a) Insight into the pathophysiology of restless legs syndrome. J. Neurosci. Res. (in press).
35.
Earley C. J., Connor J. R., Beard J. L., Malecki W., Epstein D., Allen R. P. Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology 2000b;54:1698-1700
36. Edgerton V. R., Gardner G. W., Ohira Y., Gunawardena K. A., Senewiratne B. Iron-deficiency anemia and its effect on worker productivity and activity patterns. Br. Med. J. 1979;2:1546-1549
37. Edgerton V. R., O’Hira Y., Hettiarachi J., Senewiratne B., Gardner G. W., Barnard R. J. Elevation of hemoglobin and work tolerance in iron-deficient subjects. J. Nutr. Sci. Vitaminol. (Tokyo) 1981;27:77-86[Medline]
38. Ekblom B. Micronutrients: effects of variation in [Hb] and iron deficiency on physical performance. World Rev. Nutr. Diet. 1997;82:122-130[Medline]
39. Epstein D. K., Connor J. R. The role of iron in neurodegenerative disease. Bondyed S. C. eds. Chemicals & Neurodegenerative Disease. Frontiers in Bioscience 1999:28-50 Prominent Press Scottsdale, AZ.
40. Erikson K., Beard J. L., Connor J. Distribution of brain iron, ferritin and transferrin in the 28-day old piglet. J. Nutr. Biochem. 1998;9:276-284
41.
Erikson K., Jones B. C., Beard J. L Iron deficiency alters dopamine transporter functioning in rat striatum. J. Nutr. 2000;130:2831-2837
42.
Erikson K., Pinero D., Connor J., Beard J. L. Iron status and distribution of iron in the brain of developing rats. J. Nutr. 1997;127:2030-2038
43. Fahmay M., Young S. P. Modulation of iron metabolism in monocyte cell line U937 by inflammatory cytokines: changes in transferrin uptake, iron handling and ferritin mRNA. Biochem. J. 1993;296:175-181
44. Farrell P. A., Beard J. L., Druckenmiller M. Increased insulin sensitivity in iron-deficient rats. J. Nutr. 1988;118:1104-1109
45. Felt B. T., Lozoff B. Brain iron and behavior of rats are not normalized by treatment of iron deficiency anemia during early development. J. Nutr. 1996;126:693-701
46. Finch C. A., Deubelbiss K., Cook J. D., Eschbach J. W., Harker L. A., Funk D. D., Marsaglia G., Hillman R. S., Slichter S., Adamson J. W., Canzoni A., Giblett E. R. Ferrokinetics in man. Medicine 1970;49:17-53[Medline]
47. Finch C., Gollnick P. D., Hlastala M. P., Miller L. R., Dillman E., Mackler B. Lactic acidosis as a result of iron deficiency. J. Clin. Investig. 1979;64:129-137
48. Finch C. A., Heubers H. Perspectives in iron metabolism. N. Engl. J. Med. 1982;306:1520-1528[Medline]
49. Fishbach F. A., Andreregg J. W. An X-ray scattering study of ferritin and apoferritin. J. Mol. Biol. 1965;14:458-473[Medline]
50. Fishbane S. Review of issues relating to iron and infection. Am. J. Kidney Dis. 1999;34:S47-S52[Medline]
51. Fishman J. B., Rubin J. B., Handrahan J. V., Connor J. R., Fine R. E. Receptor mediated uptake of transferrin across the blood brain barrier. J. Neurosci. Res. 1987;18:299-304[Medline]
52.
Frassinelli-Gunderson E. P., Margen S., Brown J. R. Iron stores in users of oral contraceptive agents. Am. J. Clin. Nutr. 1985;41:703-712
53. Galan P., Thibault H., Preziosi P., Hercberg S. Interleukin 2 production in iron-deficient children. Biol. Trace Elem. Res. 1992;32:421-426[Medline]
54.
Gardner G. W., Edgerton V. R., Senwiratne B., Barnard R. J., Chira Y. Physical work capacity and metabolic stress in subjects with iron deficiency anemia. Am J. Clin. Nutr. 1977;30:910-917
55. Green R., Charlton R., Seftel H., Bothwell T. H., Mayet F. Body iron excretion in man. A collaborative study. Am. J. Med. 1968;45:336-353[Medline]
56. Guillebaud J., Barnett M. D., Gordon Y. B. Plasma ferritin levels as an index of iron deficiency in women using intrauterine devices. Br. J. Obset. Gynaecol. 1979;86:51-55[Medline]
57.
Hallberg L., Hulthen L. Prediction of dietary iron absorption: an algorithm for calculating absorption and bioavailability of dietary iron. Am. J. Clin. Nutr. 2000;71:1147-1160
58.
Hallquist N. A., McNeil L. K., Lockwood J. F., Sherman A. R. Maternal-iron-deficiency effects on peritoneal macrophage and peritoneal natural-killer-cell cytotoxicity in rat pups. Am. J. Clin. Nutr. 1992;55:741-746
59. Han J., Day J. R., Thompson K., Connor J. R., Beard J. L. Iron deficiency alters H and L ferritin in rat brain. Cell. Mol. Biol. 2000;46:517-528
60.
Henderson S. A., Dallman P. R., Brooks G. A. Glucose turnover and oxidation are increased in the iron-deficient anemic rat. Am. J. Physiol. 1986;250:E414-E421
61. Hershko C. Iron and infection. Iron Nutr. Health Dis. 1996;22:231-238
62. Hill J. M. The distribution of iron in the brain. Youdim M.B.H. eds. Brain Iron: Neurochemistry and Behavioural Aspects 1988:1-24 Taylor and Francis London, UK.
63.
Hill J. M., Ruff M. R., Weber R. J., Pert C. B TfR in rat brain: neuropeptide-like pattern and relationship to iron distribution. Proc. Natl. Acad. Sci. U.S.A. 1985;82:4553-4557
64. Hulet S. W., Hess H., Debinski W., Arosio P., Bruce K., Powers S., Connor J. R. Characterization and distribution of ferritin binding sites in the adult mouse brain. J. Neurochem. 1999;72:868-874[Medline]
65. Ike K., Kawahara K., Danbara H., Kume K. Serum resistance and aerobactin iron uptake in avian Escherichia coli mediated by conjugative 100-megadalton plasmid. J. Vet. Med. Sci. 1992;54:1091-1098[Medline]
66. Kivijarvi A., Timonen H., Rajamaki A., Gronroos M. Iron deficiency in women using modern copper intrauterine devices. Obstet. Gynecol. 1986;67:95-98[Medline]
67.
Klempa K. L., Willis W. T., Chengson R., Dallman P. R., Brooks G. A. Iron deficiency decreases gluconeogenesis in isolated rat hepatocytes. J. Appl. Physiol. 1989;67:1868-1872
68. Kochanowski B. A., Sherman A. R. Cellular growth in iron-deficient rats: effect of pre- and post-weanling iron repletion. J. Nutr. 1985;115:279-287
69. Konijn A. M., Hershko C. Ferritin synthesis in inflammation: I. Pathogenesis of impaired iron release. Br. J. Haematol. 1977;37:7-16[Medline]
70. Kuvibidila S. R., Kitchens D., Baliga B. S. In vivo and in vitro iron deficiency reduces protein kinase C activity and translocation in murine splenic and purified T cells. J. Cell. Biochem. 1999;74:468-478[Medline]
71.
Lane T. E., Wu-Hsieh B. A., Howard D. H. Iron limitation and the gamma interferon-mediated anthihistoplasma state of murine macrophages. Infect. Immun. 1991;59:2274-2278
72. Larkin E. C., Rao G. A. Importance of fetal and neonatal iron: adequacy for normal development of central nervous system. Dobbing J. eds. Brain, Behavior and Iron in the Infant Diet 1990:43-63 Springer-Verlag London, UK.
73.
Levi S., Luzzago A., Cesareni G., Lozzi A., Franceschinelli F., Albertini A., Arosio P. Mechanism of ferritin iron uptake: activity of the H-chain and deletion mapping of the ferro-oxidase site. J. Biol. Chem. 1988;263:18086-18092
74. Levis A., Franceschinelli F., Cozzi A., Doerner M. H., Arosio P. Expression and structure and functional properties of human ferritin L-chain from Escherichia coli. Biochemistry 1989;28:5179-5185[Medline]
75. Li D. Effects of iron deficiency on iron distribution and gamma-aminobutyric acid metabolism in young rat brain tissue. Hakkaido Igaku Zasshi 1998;73:215-225
76. Lozoff B. Behavioral alterations in iron deficiency. Adv. Pediatr. 1988;35:331-359[Medline]
77. Mackler B., Person R., Miller L., R & Finch C. A. Iron deficiency in the rat: effects on phenylalanine metabolism. Pediatr. Res. 1979;13:1010-1011[Medline]
78. Maguire J. J., Davies J.K.A., Dallman P. R., Packer L. Effects of dietary deficiency on iron-sulfur proteins and bioenergetic functions of skeletal muscle mitochondria. Biochim. Biophys. Acta 1982;679:210-220[Medline]
79. Malecki E. A., Devenyl A. G., Beard J. L., Connor J. R. Transferrin response and Mn uptake in normal and iron-deficient mice heterozygotic for hypotransferrinemia. Biometals 1998;11:265-276[Medline]
80. Martinez-Torres C., Cubeddu L., Dillman E., Brengleman G. L., Leets I, Layrisse M., Johnson D. G., Finch C. A. Effect of exposure to low temperature on normal and iron-deficient subjects. Am. J. Physiol. 1984;246:R380-R383
81. Mash D. C., Pablo J., Flynn D. D., Efange S.M.N., Weiner W. J. Characterization and distribution of transferrin receptors in the rat brain. J. Neurochem. 1990;55:1972-1979[Medline]
82. McKay R. H., Higuchi D. A., Winder W. W., Fell R. D., Brown E. B. Tissue effects of iron deficiency in the rat. Biochim. Biophys. Acta 1983;757:352-358[Medline]
83.
McLane J. A., Fell R. D., McKay R. H., Winder W. W., Brown E. B., Holloszy J. O. Physiological and biochemical effects of iron deficiency on rat skeletal muscle function. Am. J. Physiol. 1981;241:C47-C54
84. Mederios D., Beard J. L. Dietary iron-deficiency results in cardiac eccentric hypertrophy in rats. Proc. Soc. Exp. Biol. Med. 1998;218:370-375[Medline]
85. Miller M. W., Roskams J. I., Connor J. R. Iron regulation in the developing rat brain: effect of in utero ethanol exposure. J. Neurochem. 1996;65:371-380
86. Morris C. M., Keith A. B., Edwardson J. A., Pullen R. G. Uptake and distribution of iron and transferrin in the adult rat brain. J. Neurochem. 1992;59:300-306[Medline]
87. Morse A., Beard J. L., Jones B. Behavioral and neurochemical alterations in iron deficient mice. Proc. Soc. Exp. Biol. Med. 1999a;220:147-152[Medline]
88. Morse A., Beard J. L., Jones B. Sex and genetics are important cofactors in assessing the impact of iron deficiency on the developing mouse brain. Nutr. Neurosci. 1999b;2:323-335
89. Murray M. J., Murray A. B., Murray M. B., Murry C. J. The adverse effect of iron repletion on the course of certain infections. Br. Med. J. 1978;2:1113-1115
90.
Nelson C., Erikson K. M., Pinero D. J., Beard J. L In vivo dopamine metabolism is altered in iron-deficient rats. J. Nutr. 1997;127:2282-2288
91. Ohira Y., Chen C. S., Hegenauer J., Saltman P. Adaptations of lactate metabolism in iron-deficient rats. Proc. Soc. Exp. Biol. Med. 1986;173:213-216[Medline]
92.
Perkkio M. V., Jansson L. T., Brooks G. A., Refino C. J., Dallman P. R Work performance in iron deficiency of increasing severity. J. Appl. Physiol. 1985;58:1477-1480
93.
Pinero D. J., Nan-Qi L., Connor J. R., Beard J. L. Alterations in brain iron metabolism in response to dietary iron changes. J. Nutr. 2000;130:254-263
94. Pollitt E. Iron deficiency and educational deficiency. Nutr. Rev. 1997;55:133-140[Medline]
95. Ponka P., Beaumont C., Richardson D. R. Function and regulation of transferrin and ferritin. Semin. Hematol 1998;35:35-54[Medline]
96. Princiotto J. V., Zapolski F. J. Functional heterogeneity and pH dependent dissociation properties of human transferrin. Biochim. Biophys. Acta 1976;428:766-771[Medline]
97.
Rao K., Harford J. B., Rouault T., McClelland A., Ruddle F. H., Klausner R. D. Transcriptional regulation by iron of the gene for transferrin receptor. Mol. Cell. Biol. 1986;6:236-240
98. Rocangliolo M., Garrido M., Williamson A., Lozoff B., Peirano P. Delayed maturation of auditory brainstem responses in iron-deficient anemic infants. Pediatr. Res. 1996;39:20A(abs.)
99. Sourkes T. L. Influence of specific nutrients on catecholamine synthesis and metabolism. Pharmacol. Rev. 1973;24:359-379
100. Spear A. T., Sherman A. R. Iron deficiency alters DMBA-induced tumor burden and natural killer cell cytotoxicity rats. J. Nutr. 1992;122:46-55
101. Sussman M. Iron and infection. Jacobs A. Worwood A. M. eds. Iron in Biochemistry and Medicine 1974:649-679 Academic Press New York, NY.
102. Taneja V., Mishra K., Agarwal K. N. Effect of early iron deficiency in the rat on gamma aminobutyric acid shunt in brain. J. Neurochem. 1986;46:1670-1674[Medline]
103. Taylor E. M., Crowe A., Morgan E. H. Transferrin and iron uptake by the brain: effects of altered iron status. J. Neurochem. 1991;57:1584-1592[Medline]
104. Thompson C. H., Green Y. S., Ledingham J. G., Radda G. K., Rajagopalan B. The effect of iron deficiency on skeletal muscle metabolism of the rat. Acta Physiol. Scand. 1993;147:85-90[Medline]
105. Viteri F. E., Torun B. Anemia and physical work capacity. Garby L. eds. Clinics in Haematology 1974;3:609-626 W. B. Saunders London, UK.
106. Webb E. C. Enzyme Nomenclature 1992 Academic Press San Diego, CA.
107. Wiesinger J. A., Li N. Q., Beard J. L. Iron deficiency decreases 2,3-cyclic nucleotide 3' phosphorylase activity in developing rats. FASEB J 2000;14:A752(abs.)
108.
Willis W. T., Brooks G. A., Henderson S. A., Dallman P. R. Effects of iron deficiency and training on mitochondrial enzymes in skeletal muscle. J. Appl. Physiol. 1987;62:2442-2446
109. Willis W. T., Ghil K., Brooks G. A., Dallman P. R. Iron deficiency improved exercise performance within 15 hours of iron treatment in rats. J. Nutr. 1990;120:909-916
110. Yehuda S. Neurochemical basis of behavioral effects of brain iron deficiency in animals. Dobbing J. eds. Brain, Behavior and Iron in the Infant Diet 1990:63-82 Springer-Verlag London, UK.
111. Youdim M.B.H. Neuropharmacological and neurobiochemical aspects of iron deficiency. Dobbing J. eds. Brain, Behavior and Iron in the Infant Diet 1990:83-106 Springer-Verlag London, UK.
112. Youdim M.B.H., Ben-Schachar D., Yehuda S. Putative biological mechanisms on the effects of iron deficiency on brain biochemistry. Am. J. Clin. Nutr. 1989;50:607S-617S[Abstract]
113. Youdim M.B.H., Grahame-Smith D. G., Woods H. F. Some properties of human platelet monamine oxidase in iron-deficiency anemia. Clin. Sci. Mol. Med. 1975;50:479-485
114. Youdim M.B.H., Green A. R. Biogenic monoamine metabolism and functional activity in iron-deficient rats: behavioral correlates. Porter R. R. Knight J. eds. Iron Metabolism 1977:201-227 Elseveir Amsterdam, The Netherlands Ciba Foundation Symposium 51 (New Series)
115. Youdim M.B.H., Green A. R. Iron deficiency and neurotransmitter synthesis and function. Proc. Nutr. Soc. 1978;37:173-179[Medline]
116. Youdim M.B.H., Green A. R., Bloomfield M. R., Mitchell B. D., Heal D. J., Grahame-Smith D. G. The effects of iron deficiency on brain biogenic monoamine biochemistry and function in rats. Neuropharmacology 1980;19:259-267[Medline]
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