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Comparative Study
, 897 (1-2), 175-9

Iron Overload Following Manganese Exposure in Cultured Neuronal, but Not Neuroglial Cells

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Comparative Study

Iron Overload Following Manganese Exposure in Cultured Neuronal, but Not Neuroglial Cells

W Zheng et al. Brain Res.

Abstract

Our previous studies show that manganese (Mn) exposure inhibits aconitase, an enzyme regulating the proteins responsible for cellular iron (Fe) equilibrium. This study was performed to investigate whether Mn intoxication leads to an altered cellular Fe homeostasis in cultured neuronal or neuroglial cells as a result of disrupted Fe regulation. Our results reveal a significant increase in the expression of transferrin receptor (TfR) mRNAs and a corresponding increase in cellular 59Fe net uptake by PC12 cells, but not astrocytes, following Mn exposure. These findings suggest that alteration by Mn of cellular Fe homeostasis may contribute to Mn-induced neuronal cytotoxicity.

Figures

Fig. 1
Fig. 1
Effect of Mn on the expression of TfR mRNA in cultured PC12 cells or astrocytes. The cells were incubated with 200 μM Mn (as MnCl2) dissolved in culture medium for 4 days. (A) Northern blot of total RNAs from PC12 cells. (B) Northern blot of purified mRNAs from astrocytes. The optical density of TfR mRNA bands was normalized by the density of β-actin mRNA. Ct: control cells; Mn: Mn-treated cells.
Fig. 2
Fig. 2
Effect of Mn on cellular Fe net uptake in cultured PC12 cells or astrocytes. Cultured PC12 cells or astrocytes were pretreated with 200 μM Mn in culture medium for 3 days. (A). Time course study of PC12 cells. 59Fe as FeCl3 (2 μM) was added into the culture medium at time ‘0’. At the indicated times, cells were washed, homogenized, and counted for radioactivity. There was an overall statistically significant difference in cellular 59Fe net uptake between the control and Mn-treated groups by two-way ANOVA (P<0.001). (B). Dose response study of PC12 cells. Cells were pretreated with 50–200 μM Mn in culture medium for 3 days, followed by incubation with 1.5 μM 59Fe for 2 h. (C). Time course study of astrocytes. All data represent Mean±S.D.
Fig. 3
Fig. 3
Putative mechanism of Mn-induced cytotoxicity. Increased intracellular Mn alters iron regulatory protein (ACO1) in Step 1, leading to the up-regulation of TfR in Step 2 and down-regulation of Fe storage protein ferritin in Step 3. Increased TfR and decreased Fe storage elevate intracellular free Fe as shown in Step 4. The latter catalyzes the formation of highly reactive hydroxyl free radicals via Fenton reaction and provokes oxidative stress, resulting in ultimate cell damage.

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