Olfactory uptake of manganese requires DMT1 and is enhanced by anemia

Abstract

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...

Manganese transport in eukaryotes: The role of DMT1

“…Immunostaining studies suggest that DMT1 expression is strongest at the brush border of the apical pole of the enterocytes, which is consistent with the role for DMT1 in luminal metal uptake . Moreover, recent immunohistochemical experiments revealed that DMT1 is also expressed in the lumen microvilli and end-feet of the sustentacular cells of the olfactory epithelium, suggesting an alternative route of metal exposure (Thompson et al, 2007). In macrophages, DMT1 is restricted in the phagosomal membrane where red cells are engulfed.…”

“…Mn toxicity from dietary intake is rare; its uptake is tightly regulated, and any excess of ingested Mn is readily excreted via the bile. In contrast, both pulmonary uptake and particulate transport via the olfactory bulb (Saric, 1986;Aschner et al, 1991;Thompson et al, 2007) can lead to deposition of Mn within the striatum and cerebellum and inflammation of the nasal epithelium .Mn plays an important role in the development and functioning of the brain (Prohaska, 1987;Takeda, 2003). Mn deficiency may result in birth defects, poor bone formation and an increased susceptibility to seizures (Aschner, 2000;Aschner et al, 2002).…”

“…Immunostaining studies suggest that DMT1 expression is strongest at the brush border of the apical pole of the enterocytes, which is consistent with the role for DMT1 in luminal metal uptake . Moreover, recent immunohistochemical experiments revealed that DMT1 is also expressed in the lumen microvilli and end-feet of the sustentacular cells of the olfactory epithelium, suggesting an alternative route of metal exposure (Thompson et al, 2007 neocortex, the subcortical white matter and the hippocampus of monkeys (Wang et al, 2001). In the basal ganglia, immunocytochemical experiments indicate dense DMT1 staining in the caudate nucleus, the putamen and the substantia nigra pars reticulata (Huang et al, 2004).…”

“…Additionally, this theory was proven valid in olfactory Mn uptake. A study examining the contribution of olfactory DMT1 in Mn uptake showed that nasal absorption of Mn is significantly reduced in b/b rats and the protein levels of olfactory DMT1 were elevated in iron-deficient rats, suggesting the importance of DMT1 in olfactory Mn absorption that is dependent upon the iron status (Thompson et al, 2007). …”

“…Mn toxicity from dietary intake is rare; its uptake is tightly regulated, and any excess of ingested Mn is readily excreted via the bile. In contrast, both pulmonary uptake and particulate transport via the olfactory bulb (Saric, 1986;Aschner et al, 1991;Thompson et al, 2007) can lead to deposition of Mn within the striatum and cerebellum and inflammation of the nasal epithelium .…”