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. 2007 Jan;21(1):223-30.
doi: 10.1096/fj.06-6710com. Epub 2006 Nov 20.

Olfactory uptake of manganese requires DMT1 and is enhanced by anemia

Khristy Thompson  1 , Ramon M Molina, Thomas Donaghey, James E Schwob, Joseph D Brain, Marianne Wessling-Resnick
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Olfactory uptake of manganese requires DMT1 and is enhanced by anemia (V体育平台登录)

Khristy Thompson et al. FASEB J. 2007 Jan.

Abstract (V体育官网)

Manganese, an essential nutrient, can also elicit toxicity in the central nervous system (CNS) VSports手机版. 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 54Mn 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 iron-responsive regulation of the transporter. .

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Figures

Figure 1
Figure 1
Vascular kinetics of intranasally instilled (A) and i.v. injected (B) 54Mn. Anemic +/b rats (filled circles) were fed an iron-deficient diet (20 ppm iron) while iron-replete +/b rats (filled squares) and Belgrade b/b rats (open circles) were fed iron-supplemented diet (500 ppm iron) for three weeks postweaning. Blood 54Mn levels are expressed as percent of instilled dose or injected dose. Each point is mean ± sem of 5−8 rats. A) *P < 0.05 (iron-replete +/b vs. anemic +/b); **P < 0.01 (b/b vs. anemic +/b rats). B) * P < 0.05 (b/b vs. anemic +/b and b/b vs. iron-replete +/b).
Figure 2
Figure 2
Brain microdissections of intranasally-instilled (A) and i.v.-injected (B) 54Mn. Anemic +/b rats (solid bars) were fed an iron-deficient diet (20 ppm iron) while iron-replete +/b rats (hatched bars) and Belgrade b/b rats (open bars) were fed iron-supplemented diet (500 ppm iron) for 3 wk postweaning. Two weeks after intranasal instillation or iv injection, rats were humanely killed and brains were collected for microdissection. Tissue 54Mn levels are expressed as percentage of instilled dose or injected dose. Each point is mean ± sem of 5−8 rats. A) *P < 0.05 (b/b vs. iron-replete +/b and b/b vs. anemic +/b). B) **P < 0.05 (iron-replete +/b vs. b/b and iron-replete +/b vs. anemic +/b).
Figure 3
Figure 3
DMT1 immunoreactivity in the rat olfactory epithelium. Infrared imaging (Li-Cor Odyssey) was used to detect nickel chloride enhanced 3′3-diaminobenzidine staining for DMT1 immunoreactivity using a modified protocol of Canonne-Hergaux et al. (27, 29) in tissue processed according to the methods of Goldstein and Schwob (27). DMT1 staining (arrows) is found throughout olfactory epithelial regions of the nasal concha.
Figure 4
Figure 4
Colocalization of DMT1 with olfactory epithelial markers. Sustentacular cells were labeled with anti-SUS-4 (arrows A,C), basal cells with anti-cytokeratin (asterisks D,F), and neurons with anti-Hu (asterisks G,I) (40X magnification). Colocalization of SUS-4 (red) with DMT1 (green) is noted in C (arrowheads). DMT1 immunoreactivity is also detected in the mucociliary complex (MC).
Figure 5
Figure 5
DMT1 staining in control and iron-deficient rats. Weanling Sprague Dawley rats were fed an iron-deficient diet (Harlan Teklad TD 99397) or standard chow (Purina 5061) for 3 wk. Olfactory DMT1 staining intensity was increased in iron-deficient rats. Region that includes the sustentacular cell end feet (arrows) shows greatest increase in iron deficiency for DMT1 staining.
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