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Inadequate iron nutrition is thought to affect many aspects of brain development. Iron is a component of enzyme systems in DNA synthesis, the respiratory chain, neurotransmitter and lipid metabolism. The iron content of the striatum increases post-natally, with neuronal differentiation, myelin lipid and receptor formation: Seventy percent of the iron in the brain is associated with myelin. In an attempt to dissociate the global effects of under-and/or malnutrition and to produce exclusively an iron deficiency, we have used the gastrostomy-reared rat pup fed milk substitutes which vary only in their iron content. To ensure the pups did not have adequate iron reserves at birth, dams were fed a meal diet of low iron content (3 ppm) throughout gestation. The pups were then artificially reared on milk with (43 ppm), and without added iron (2.5 ppm) from 6 up to 21 days after birth. At 21 days of age, body weights of iron deficient pups were about 90% those of control animals. At 21 days of age, the pups were weaned, then fed standard laboratory rat chow. Brain was examined at 42 days of age (for young adults) and up to 6 months of age (180 days as mature adults). Morphometric analysis of sagittal sections of the cerebellum at 21 and 63 days of age revealed a deficit in white matter formation in pups fed low-iron at 21 days of age when compared to controls. This deficit was partially recouped by age 63 days. By contrast, animals fed milk supplemented with iron showed greater definition in white matter formation than controls at 21 days of age; indicative of precocious maturation of the white matter tracts. Our findings indicate that iron deficiency, without under/mal-nutrition and other variables, does not result in extensive growth deficits in body and brain weight. However, the iron status profoundly influences the development of myelination in that the process is delayed in iron deficiency.
Cell Mol Biol (Noisy-le-grand) 2000 May
PMID:Dietary iron and the integrity of the developing rat brain: a study with the artificially-reared rat pup. 1087 38

Ferritin (Ft) H and L subunits are independently regulated proteins with both transcriptional and translational regulation in response to cellular iron levels. While the heterogeneous distribution of ferritin and iron in the brain is now well established, the relative response of each subunit to iron deficiency and iron supplementation, is not well defined. Weanling male Sprague-Dawley rats (n=12 per group) were randomly assigned to an iron deficient (3.5 mg Fe/kg diet), control (35 mg Fe/kg diet) or supplemented (350 mg Fe/kg diet) diet for six weeks. The H-/L-ferritin subunit ratio and mRNA levels were determined. Overall, the protein ratio in control rats of H to L was approximately 45:1 compared to a ratio >60:1 in iron deficiency but the absolute amounts of each subunit varied greatly from one brain region to another. The ratio of H-:L-ferritin mRNA was 6:1 and was not affected by dietary iron deficiency in contrast to a potent effect on mRNA levels in liver. Severe iron deficiency reduced brain ferritin H protein levels significantly in all regions, whereas only ferritin L levels in striatum, substantia nigra and pons were affected by iron deficiency. Supplemental dietary iron increased both ferritin subunits, with the largest increase (50%) in the hippocampus. These data indicate that ferritin H and L subunits within the brain respond differently to iron status and suggest post transcription regulation as a key event.
Cell Mol Biol (Noisy-le-grand) 2000 May
PMID:Iron deficiency alters H- and L-ferritin expression in rat brain. 1087 39

Aluminum (Al) is a simple trivalent cation incapable of redox changes. The toxicity of the metal has been the subject of much controversy in the past few decades. Although it has been generally believed that the metal is innocuous to human health, a causal role for Al has been established in dialysis dementia (Alfrey et al., 1976), osteomalacia (Bushinsky et al., 1995) and microcytic anemia without iron deficiency (Touam et al., 1983). Aluminum has also been implicated in Alzheimer's disease (AD) although a direct causal role has not been determined. The exact mechanism of Al toxicity is not known. However, there are several lines of evidence that show the metal's capacity to exacerbate oxidative events. The present review is intended to propose a coherent pathway linking Al-induced oxidative events to Alzheimer's disease. The preliminary segment is an introduction to reactive oxygen species and their potential involvement in the pathogenesis of AD and the generation of an inflammatory response. Evidence on the relation between AD and inflammatory processes is also presented. The epidemiological and clinical evidence of Al neurotoxicity is summarized in the second section of the review. Finally, a hypothesis indicating that aluminum can exacerbate AD by activating ROS generation and initiation of an inflammatory cascade is presented.
Cell Mol Biol (Noisy-le-grand) 2000 Jun
PMID:Aluminum induced oxidative events and its relation to inflammation: a role for the metal in Alzheimer's disease. 1087 35

The mechanism that leads to iron overload in hereditary hemochromatosis is not yet fully understood and genes other than HFE may be involved. Nramp2 is an intestinal iron transporter, upregulated by dietary iron deficiency, which also colocalizes with transferrin in recycling endosomes. The purpose of the present study was to analyze the coding region of the Nramp2 gene in 14 hemochromatosis probands which did not carry any HFE mutations on both chromosomes. We confirmed the existence of a polymorphism (1254 T --> C), which presumably is not associated with hereditary hemochromatosis, but we did not find any mutation. On the other hand, we identified 17 splice variants of the Nramp2 mRNA. Eight corresponded to activation of cryptic splicing sequences between exons 3 and 4. They were observed in a majority of hemochromatosis probands and control subjects. This indicates the existence of an important splicing instability in this region. At this stage, the biological significance of these variants is unclear. Our study did not find evidence for the involvement of the Nramp2 gene in hereditary hemochromatosis. The remaining question is whether hemochromatosis probands in our study have iron overload because of environmental factors or due to mutation in gene(s) other than HFE and Nramp2.
Blood Cells Mol Dis 2000 Aug
PMID:Nramp2 analysis in hemochromatosis probands. 1104 33

A cDNA clone, Ids3 (iron deficiency-specific clone 3), was isolated from an Fe-deficient-root cDNA library of Hordeum vulgare. Ids3 encodes a protein of 339 amino acids with a calculated molecular mass of 37.7 kDa, and its amino acid sequence shows a high degree of similarity with those of plant and fungal 2-oxoglutarate-dependent dioxygenases. One aspartate and two histidine residues for ferrous Fe binding (Asp-211, His-209, His-265) and arginine and serine residues for 2-oxoglutarate binding (Arg-275, Ser-277) are conserved in the predicted amino acid sequence of Ids3. Ids3 expression was rapidly induced by Fe deficiency, and was suppressed by re-supply of Fe. Among eight graminaceous species tested, Ids3 expression was observed only in Fe-deficient roots of H. vulgare and Secale cereale. which not only secrete 2'-deoxymugineic acid (DMA), but also mugineic acid (MA) and 3-epihydroxymugineic acid (epiHMA, H. vulgare), and 3-hydroxymugineic acid (HMA, S. cereale). The Ids3 gene is encoded on the long arm of chromosome 4H of H. vulgare, which also carries the hydroxylase gene that converts DMA to MA. Moreover, the Ids2 gene, which is the plant dioxygenase with the highest homology to Ids3, is encoded on the long arm of chromosome 7H of H. vulgate, which carries the hydroxylase gene that converts MA to epiHMA. The observed expression patterns of the Ids3 and Ids2 genes strongly suggest that IDS3 is an enzyme that hydroxylates the C-2' positions of DMA and epiHDMA, while IDS2 hydroxylates the C-3 positions of MA and DMA.
Plant Mol Biol 2000 Sep
PMID:Two dioxygenase genes, Ids3 and Ids2, from Hordeum vulgare are involved in the biosynthesis of mugineic acid family phytosiderophores. 1111 63

Although iron deficiency poses severe nutritional problems to crop plants, to date iron transporters have only been characterized from the model plant Arabidopsis thaliana. To extend our molecular knowledge of Fe transport in crop plants, we have isolated two cDNAs (LeIRT1 and LeIRT2) from a library constructed from roots of iron-deficient tomato (Lycopersicon esculentum) plants, using the Arabidopsis iron transporter cDNA, IRTI, as a probe. Their deduced polypeptides display 64% and 62% identical amino acid residues to the IRT1 protein, respectively. Transcript level analyses revealed that both genes were predominantly expressed in roots. Transcription of LeIRT2 was unaffected by the iron status of the plant, while expression of LeIRT1 was strongly enhanced by iron limitation. The growth defect of an iron uptake-deficient yeast (Saccharomyces cerevisiae) mutant was complemented by LeIRT1 and LeIRT2 when ligated to a yeast expression plasmid. Transport assays revealed that iron uptake was restored in the transformed yeast cells. This uptake was temperature-dependent and saturable, and Fe2+ rather than Fe3+ was the preferred substrate. A number of divalent metal ions inhibited Fe2+ uptake when supplied at 100-fold or 10-fold excess. Manganese, zinc and copper uptake-deficient yeast mutants were also rescued by the two tomato cDNAs, suggesting that their gene products have a broad substrate range. The gene structure was determined by polymerase chain reaction experiments and, surprisingly, both genes are arranged in tandem with a tail-to-tail orientation.
Plant Mol Biol 2001 Mar
PMID:Two iron-regulated cation transporters from tomato complement metal uptake-deficient yeast mutants. 1135 62

Hereditary hemochromatosis (HH) is a common genetic disorder. Although it is inherited in an autosomal recessive manner, heterozygous individuals are believed to be protected against iron deficiency. Screening to estimate the prevalence of HH was frequently performed among blood donors, not considering that carriers of the HH gene mutations may be present in higher proportion in this population. To examine the allele frequencies of the HH gene (HFE) point mutations, C282Y and H63D genotyping was carried out in 996 consecutive, first-time, and regular Hungarian blood donors by PCR-RFLP techniques. Iron parameters of the first-time donors and the identified C282Y heterozygotes and age, gender, and number of previous blood donation-matched wild-type donors were also determined. We were not able to demonstrate a significant increase in the frequency of C282Y and H63D alleles among regular blood donors, compared to first-time blood donors. However, there was a trend of higher C282Y allele frequency among women with higher number of previous blood donations (2.2 +/- 1.5% in female blood donors with 0-8 previous blood donations compared to 4.8 +/- 2.3% in women with more than 8 previous blood donations, P = 0.06). No detectable phenotypic differences were observed in serum iron, ferritin, and transferrin saturation values between C282Y wild-type and heterozygous groups. However, the single identified C282Y homozygous male (age 21) showed definite signs of iron overload. Our observations suggest that the protective effect of C282Y heterozygosity against iron deficiency may be less significant than other environmental (e.g., iron-rich diet) or genetic factors.
Blood Cells Mol Dis
PMID:Genotype screening for hereditary hemochromatosis among voluntary blood donors in Hungary. 1135 95

C-14 formaldehyde crosses the placenta and enters fetal tissues. The incorporated radioactivity is higher in fetal organs (i.e., brain and liver) than in maternal tissues. The incorporation mechanism has not been studied fully, but formaldehyde enters the single-carbon cycle and is incorporated as a methyl group into nucleic acids and proteins. Also, formaldehyde reacts chemically with organic compounds (e.g., deoxyribonucleic acid, nucleosides, nucleotides, proteins, amino acids) by addition and condensation reactions, thus forming adducts and deoxyribonucleic acid-protein crosslinks. The following questions must be addressed: What adducts (e.g., N-methyl amino acids) are formed in the blood following formaldehyde inhalation? What role do N-methyl-amino adducts play in alkylation of nuclear and mitochondrial deoxyribonucleic acid, as well as mitochondrial peroxidation? The fact that the free formaldehyde pool in blood is not affected following exposure to the chemical does not mean that formaldehyde is not involved in altering cell and deoxyribonucleic acid characteristics beyond the nasal cavity. The teratogenic effect of formaldehyde in the English literature has been sought, beginning on the 6th day of pregnancy (i.e., rodents) (Saillenfait AM, et al. Food Chem Toxicol 1989, pp 545-48; Martin WJ. Reprod Toxicol 1990, pp 237-39; Ulsamer AG, et al. Hazard Assessment of Chemicals; Academic Press, 1984, pp 337-400; and U.S. Department of Health and Human Services. Toxicological Profile of Formaldehyde; ATSDR, 1999 [references 1-4, respectively, herein]). The exposure regimen is critical and may account for the differences in outcomes. Pregnant rats were exposed (a) prior to mating, (b) during mating, (c) or during the entire gestation period. These regimens (a) increased embryo mortality; (b) increased fetal anomalies (i.e., cryptochordism and aberrant ossification centers); (c) decreased concentrations of ascorbic acid; and (d) caused abnormalities in enzymes of mitochondria, lysosomes, and the endoplasmic reticulum. The alterations in enzymatic activity persisted 4 mo following birth. In addition, formaldehyde caused metabolic acidosis, which was augmented by iron deficiency. Furthermore, newborns exposed to formaldehyde in utero had abnormal performances in open-field tests. Disparities in teratogenic effects of toxic chemicals are not unusual. For example, chlorpyrifos has not produced teratogenic effects in rats when mothers are exposed on days 6-15 (Katakura Y, et al. Br J Ind Med 1993, pp 176-82 [reference 5 herein]) of gestation (Breslin WJ, et al. Fund Appl Toxicol 1996, pp 119-30; and Hanley TR, et al. Toxicol Sci 2000, pp 100-08 [references 6 and 7, respectively, herein]). However, either changing the endpoints for measurement or exposing neonates during periods of neurogenesis (days 1-14 following birth) and during subsequent developmental periods produced adverse effects. These effects included neuroapoptosis, decreased deoxyribonucleic acid and ribonucleic acid synthesis, abnormalities in adenylyl cyclase cascade, and neurobehavioral effects (Johnson DE, et al. Brain Res Bull 1998, pp 143-47; Lassiter TL, et al. Toxicol Sci 1999, pp 92-100; Chakraborti TK, et al. Pharmacol Biochem Behav 1993, pp 219-24; Whitney KD, et al. Toxicol Appl Pharm 1995, pp 53-62; Chanda SM, et al. Pharmacol Biochem Behav 1996, pp 771-76; Dam K, et al. Devel Brain Res 1998, pp 39-45; Campbell CG, et al. Brain Res Bull 1997, pp 179-89; and Xong X, et al. Toxicol Appl Pharm 1997, pp 158-74 [references 8-15, respectively, herein]). Furthermore, the terata caused by thalidomide is a graphic human example in which the animal model and timing of exposure were key factors (Parman T, et al. Natl Med 1999, pp 582-85; and Brenner CA, et al. Mol Human Repro 1998, pp 887-92 [references 16 and 17, respectively, herein]). Thus, it appears that more sensitive endpoints (e.g., enzyme activity, generation of reactive oxygen species, timing of exposure) for the measurement of toxic effects of environmental agents on embryos, fetuses, and neonates are more coherent than are gross terata observations. The perinatal period from the end of organogenesis to the end of the neonatal period in humans approximates the 28th day of gestation to 4 wk postpartum. Therefore, researchers must investigate similar stages of development (e.g., neurogenesis occurs in the 3rd trimester in humans and neonatal days occur during days 1-14 in rats and mice, whereas guinea pigs behave more like humans). Finally, screening for teratogenic events should also include exposure of females before mating or shortly following mating. Such a regimen is fruitful inasmuch as environmental agents cause adverse effec
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PMID:Embryo toxicity and teratogenicity of formaldehyde. 1157 72

The alpha subunit of polypeptide chain initiation factor eIF2 can be phosphorylated by a number of related protein kinases which are activated in response to cellular stresses. Physiological conditions which result in eIF2 alpha phosphorylation include virus infection, heat shock, iron deficiency, nutrient deprivation, changes in intracellular calcium, accumulation of unfolded or denatured proteins and the induction of apoptosis. Phosphorylated eIF2 acts as a dominant inhibitor of the guanine nucleotide exchange factor eIF2B and prevents the recycling of eIF2 between successive rounds of protein synthesis. Extensive phosphorylation of eIF2 alpha and strong inhibition of eIF2B activity can result in the downregulation of the overall rate of protein synthesis; less marked changes may lead to alterations in the selective translation of alternative open reading frames in polycistronic mRNAs, as demonstrated in yeast. These mechanisms can provide a signal transduction pathway linking eukaryotic cellular stress responses to alterations in the control of gene expression at the translational level.
Prog Mol Subcell Biol 2001
PMID:Initiation factor eIF2 alpha phosphorylation in stress responses and apoptosis. 1157 61

Sickle cell disease patients who acquire iron deficiency may experience a degree of amelioration from painful crises in terms of frequency, severity, and duration. This observation prompted us to identify the potential utility of iron load reduction in the management of this disease. Thirteen sickle cell patients not ameliorated by conventional treatment entered a weekly venesection protocol. Hematological values and painful crises of all degrees of severity were recorded and compared to those of the last 12 months before venesection for each case separately ("historical controls"). A decrease was noted in the frequency and intensity of several types of painful crises. Reduction of iron load by venesection seems to be a simple, safe, side-effect-free, and efficient way of preventing and ameliorating to a large extent painful crises in sickle cell disease. The biological effects of venesection on other parameters of sickle cell disease remain to be determined.
Blood Cells Mol Dis
PMID:Amelioration of painful crises in sickle cell disease by venesections. 1206 23


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