Brain iron homeostasis

Morris, Christopher M.; Candy, J.; Keith, A.B.; Oakley, Arthur E.; Taylor, Geoffrey A.; Pullen, R. G. L.; Bloxham, C. A.; Gocht, Andreas; Edwardson, J. A.

doi:10.1016/0162-0134(92)84071-t

Cited by 87 publications

(31 citation statements)

References 41 publications

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“…12 This functional defect of HFE protein increases TfR activity and facilitates iron transport into cells. 14,15 Subjects who carry HFE variants are less likely to be iron deficient and can still appropriately downregulate gastrointestinal iron absorption. 27 Downregulation of iron/metal absorption based on body iron stores may occur in lung epithelial cells, as occurs in the intestinal tract, possibly explaining the present findings.…”

Section: Discussionmentioning

confidence: 99%

“…12,13 Because transferrin and TfRs mediate iron transport across cell membranes, the functional defect of HFE proteins increases TfR activity and facilitates iron transport into cells. 14,15 Because iron stores are inversely associated with the gastrointestinal absorption of multiple potentially toxic metals (lead, cadmium, manganese, copper, and cobalt), 16,17 HFE variants may modify the effect of particulate transition metals, and in previous studies, HFE variants were associated with lower blood and bone levels of lead, a toxic divalent metal. 18 We hypothesized that the HFE genetic polymorphism modifies the effect of ambient PM 2.5 on cardiac autonomic function.…”

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confidence: 99%

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HFE Genotype, Particulate Air Pollution, and Heart Rate Variability

et al. 2006

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Background-Particulate air pollution has been associated with cardiovascular mortality and morbidity. Transition metals such as iron bound to the particles may be responsible for those associations. The protein product of the hemochromatosis (HFE) gene modulates uptake of iron and divalent cations from pulmonary sources and reduces their toxicity. Two HFE polymorphisms (C282Y and H63D) associated with increased iron uptake may modify the effect of metal-rich particles on the cardiovascular system. Methods and Results-We investigated the association between particulate matter Յ2.5 m in aerodynamic diameter and heart rate variability in 518 older men from the Normative Aging Study who were examined between November 2000 and December 2004. Linear regression models were fit to evaluate interactions between HFE genotype and particulate matter Յ2.5 m in aerodynamic diameter in relation to heart rate variability, controlling for potential confounders. A 10-g/m 3 increase in particulate matter Յ2.5 m in aerodynamic diameter during the 48 hours before heart rate variability measurement was associated with a 31.7% (95% CI, 10.3% to 48.1%) decrease in the high-frequency component of heart rate variability in persons with the wild-type genotype, whereas no relationship in the high-frequency component was observed in persons with either HFE variant. The difference in effect of particulate matter Յ2.5 m in aerodynamic diameter on the high-frequency component between persons with and without HFE variants was significant (P for interactionϭ0.02). Conclusions-The effect of particles on cardiac autonomic function was shielded in subjects with at least 1 copy of an HFE variant compared with wild-type subjects. Transition metals, including iron, bound to ambient particles and the related oxidative stress may play an important role in cardiac toxicity of particles.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

HFE Genotype, Particulate Air Pollution, and Heart Rate Variability

et al. 2006

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“…The two central assumptions are, first, that iron is stored primarily in one form, namely, ferritin. It is believed that ferritin accounts for the majority of nonheme iron in the brain, but it is not the only form in which iron is found (33,34). Iron is stored in neuromelanin in the substantia nigra, where it can account for 10% to 20% of the nonheme .…”

Section: Discussionmentioning

confidence: 99%

Correlation of R2 with total iron concentration in the brains of rhesus monkeys

Hardy

Gash

Yokel

et al. 2005

Magnetic Resonance Imaging

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Purpose: To estimate the relationship between R 2 ϭ 1/T 2 as measured with a double echo spin echo sequence and total iron concentration in gray matter structures in the brains of aging rhesus monkeys. Materials and Methods:Using a 1.5-T magnetic resonance (MR) imager, we collected double echo spin echo images of the brains of 12 female rhesus monkeys aged between 9 and 23 years. From the double echo images, the transverse relaxation rate R 2 ϭ 1/T 2 was calculated in selected gray matter regions. After the animals were euthanized, their brains were excised and tissue punches were taken of the substantia nigra, globus pallidus, and gray matter regions of the cerebellum. Some of the tissue punches were assayed for total iron using atomic absorption spectroscopy. Results:The range of tissue iron concentration spanned from 15 to 450 g/g wet weight, with the highest levels in the globus pallidus and the lowest levels in the cerebellum. The results show that R 2 was highly correlated with the total iron concentration and that the relationship between R 2 and tissue iron concentration appeared to depend upon the iron concentration. For concentrations above approximately 150 g/g wet weight, R 2 increased with a sensitivity of 0.0484 Ϯ 0.0023 second -1 ( g/g) -1 . In contrast, where the iron concentration was below 150 g/g, R 2 increased at 0.0013 Ϯ 0.0073 second -1 ( g/g) -1 . The bilinear behavior may reflect changes with age in the relative amounts of iron distributed diffusely and in granular form in the globus pallidus and substantia nigra. Histological sections of the tissues stained for iron and ferritin support this hypothesis and indicate that the distribution of ferritin is similar to the distribution of iron. Conclusion:This study reaffirms the value of measuring the MR relaxation rate R 2 for a noninvasive estimate of iron content in the brain and identified limitations in the relationship at low tissue iron concentrations.

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“…Mn is then released from the complex in the endothelial cell interior by endosomal acidification and the apo-Tf Tf complex is returned to the luminal surface (Morris et al, 1992a;Morris et al, 1992b) without the assistance of DMT1 (Divalent Metal Transporter-1) (Moos et al, 2006). Mn released within the endothelial cells is subsequently transferred to the abluminal cell surface for release into the extracellular fluid.…”

Section: Manganese Transport Into Brain Transferrin/transferrin Recepmentioning

confidence: 99%

Manganese neurotoxicity: A focus on the neonate

Erikson

Thompson

Aschner

et al. 2007

Pharmacology & Therapeutics

221

141

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Manganese (Mn) is an essential trace metal found in all tissues, and it is required for normal amino acid, lipid, protein, and carbohydrate metabolism. While Mn deficiency is extremely rare in humans, toxicity due to overexposure of Mn is more prevalent. The brain appears to be especially vulnerable. Mn neurotoxicity is most commonly associated with occupational exposure to aerosols or dusts that contain extremely high levels (> 1-5 mg Mn/m 3 ) of Mn, consumption of contaminated well water, or parenteral nutrition therapy in patients with liver disease or immature hepatic functioning such as the neonate. This review will focus primarily on the neurotoxicity of Mn in the neonate. We will discuss putative transporters of the metal in the neonatal brain and then focus on the implications of high Mn exposure to the neonate focusing on typical exposure modes (e.g., dietary and parenteral). Although Mn exposure via parenteral nutrition is uncommon in adults, in premature infants, it is more prevalent, so this mode of exposure becomes salient in this population. We will briefly review some of the mechanisms of Mn neurotoxicity and conclude with a discussion of ripe areas for research in this underreported area of neurotoxicity.

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Brain iron homeostasis

Cited by 87 publications

References 41 publications

HFE Genotype, Particulate Air Pollution, and Heart Rate Variability

HFE Genotype, Particulate Air Pollution, and Heart Rate Variability

Correlation of R2 with total iron concentration in the brains of rhesus monkeys

Manganese neurotoxicity: A focus on the neonate

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