Several observations suggest that iron is an essential factor in myelination and oligodendrocyte biology. However, the specific role of iron in these processes remains to be elucidated. This role could be as an essential cofactor in metabolic processes or as a transcriptional or translational regulator. In this study, we used animals models each with a unique defect in iron availability, storage, or transfer to test the hypothesis that disruptions in these mechanisms affect myelinogenesis and myelin composition. Disruption of iron availability either by limiting dietary iron or by altering iron storage capacity resulted in a decrease in myelin proteins and lipids but not the iron content of myelin. Among the integral myelin proteins, proteolipid protein was most consistently affected, suggesting that limiting iron to oligodendrocytes results not only in hypomyelination but also in a decrease in myelin compaction. Mice deficient in transferrin must receive transferrin injections beginning at birth to remain viable, and these mice had increases in all of the myelin components and in the iron content of the myelin. This finding indicates that the loss of endogenous iron mobility in oligodendrocytes could be overcome by application of exogenous transferrin. Overall, the results of this study demonstrate how myelin composition can be affected by loss of iron homeostasis and reveal specific chronic changes in myelin composition that may affect behavior and attempts to rescue myelin deficits.

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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Manganese, an essential nutrient, can also elicit toxicity in the central nervous system (CNS). The route of exposure strongly influences the potential neurotoxicity of manganese-containing compounds. Recent studies suggest that inhaled manganese can enter the rat brain through the olfactory system, but little is known about the molecular factors involved. Divalent metal transporter-1 (DMT1) is the major transporter responsible for intestinal iron absorption and its expression is regulated by body iron status. To examine the potential role of this transporter in uptake of inhaled manganese, we studied the Belgrade rat, since these animals display significant defects in both iron and manganese metabolism due to a glycine-to-arginine substitution (G185R) in their DMT1 gene product. Absorption of intranasally instilled 54 Mn was significantly reduced in Belgrade rats and was enhanced in iron-deficient rats compared to iron-sufficient controls. Immunohistochemical experiments revealed that DMT1 was localized to both the lumen microvilli and end feet of the sustentacular cells of the olfactory epithelium. Importantly, we found that DMT1 protein levels were increased in anemic rats. The apparent function of DMT1 in olfactory manganese absorption suggests that the neurotoxicity of the metal can be modified by iron status due to the ironresponsive regulation of the transporter. KeywordsBelgrade rat; iron deficiency INHALATION OF MANGANESE PROMOTES its deposition in the brain and can lead to neurotoxic effects. Clinical cases of manganism are associated with elevated levels of manganese in the basal ganglia accompanied by neuronal loss and an extrapyramidal movement disorder preceded by psychiatric symptoms (1). Occupational exposures that can result in manganism include metalworking, mining, and battery manufacture as well as pesticide use (2,3). Recent debate over potentially harmful effects of low level chronic manganese exposures have been sparked by the use of the fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT) (4-6) and the increased environmental burdens resulting from its combustion (7-9).The route of exposure strongly influences the potential neurotoxicity of manganese-containing compounds (10,11 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript brain through the olfactory pathway (12-15), but little is known about the molecular factors involved. DMT1 is the major transporter responsible for intestinal iron absorption and its expression is regulated by body iron status (16,17). Exogenous expression studies have shown that DMT1 mediates uptake of manganese as well as iron (18,19). To examine the potential role of this transporter in uptake of inhaled manganese, we chose to study the Belgrade (b) rat since its DMT1 gene product contains a glycine-to-arginine substitution at codon 185 (G185R; ref 20). This defective allele encodes a protein with diminished activity in iron uptake assays (21-23). Accordingly, Belgrade rats are not only anemic but also display signif...