Alteration at translational but not transcriptional level of transferrin receptor expression following manganese exposure at the blood–CSF barrier in vitro

Li, G. Jane; Zhao, Qiuqu; Zheng, Wei

doi:10.1016/j.taap.2004.10.003

Cited by 39 publications

(57 citation statements)

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“…Research from this laboratory has showed that chronic in vivo exposure to manganese, while reducing blood Fe concentrations, increases iron concentrations in the CSF, suggesting a likely compartment shift of iron from the blood circulation to brain extracellular fluids . Our recent in vitro studies have further demonstrated an increased iron transport at the blood-CSF barrier (Li et al, 2005), a result that may be due to manganese interference on iron regulatory mechanism at the choroid plexus. From the chemistry point of view, manganese ions have many biochemical properties in common with iron including ionic radius, electrical charges in biological matrices, binding affinity for the carrier protein and subcellular accumulation in mitochondria Chen et al, 2001;Zheng et al, 1998).…”

Section: Introductionmentioning

confidence: 76%

“…An increased TfR expression and ensuing elevated iron transport at the BCB may partly explain the disrupted iron status in the CSF (Li et al, 2005). In the current study, we observed that, in addition to action on TfR, manganese exposure increased DMT1 levels in cultured choroidal epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…Noticeably, the IRE structure in TfR mRNA binds specifically to a protein known as iron regulatory protein-1 (IRP1), whose active center contains a [4Fe-4S] cluster. In the Fe-deficient condition, IRP1 binds with a high affinity to IRE containing TfR mRNAs, stabilizes TfR expression and increases intracellular levels of TfR (Andrews, 1999;Klausner et al, 1993;Li et al, 2005). It is unclear, however, whether the cellular levels of DMT1 are regulated in the same fashion as the TfR.…”

Section: Introductionmentioning

confidence: 99%

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Upregulation of DMT1 expression in choroidal epithelia of the blood–CSF barrier following manganese exposure in vitro

Wang

Zheng

2006

Brain Research

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Divalent metal transporter 1 (DMT1), whose mRNA possesses a stem-loop structure in 3′-untranslated region, has been identified in most organs and responsible for transport of various divalent metal ions. Previous work from this laboratory has shown that manganese (Mn) exposure alters the function of iron regulatory protein (IRP) and increases iron (Fe) concentrations in the cerebrospinal fluid (CSF). This study was designed to test the hypothesis that Mn treatment, by acting on protein-mRNA binding between IRP and DMT1 mRNA, altered the expression of DMT1 in an immortalized choroidal epithelial Z310 cell line which was derived from rat choroid plexus epithelia, leading to a compartmental shift of Fe from the blood to the CSF. Immunocytochemistry confirmed the presence of DMT1 in Z310 cell. Following in vitro exposure to Mn at 100 μM for 24 and 48 h, the expression of DMT1 mRNA in Z310 cells was significantly increased by 45.4% (P < 0.05) and 78.1% (P < 0.01), respectively, as compared to controls. Accordingly, Western blot analysis revealed a significant increase of DMT1 protein concentrations at 48 h after Mn exposure (100 μM). Electrophoretic mobility shift assay (EMSA) showed that Mn exposure increased binding of IRP to DMT1 mRNA in cultured choroidal Z310 cells. Moreover, real-time RT-PCR revealed no changes in DMT1 heterogeneous nuclear RNA (hnRNA) levels following Mn exposure. These data suggest that Mn appears to stabilize the binding of IRP to DMT1 mRNA, thereby increasing the expression of DMT1. The facilitated transport of Fe by DMT1 at the blood-CSF barrier may partly contribute to Mn-induced neurodegenerative Parkinsonism.

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Section: Introductionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Upregulation of DMT1 expression in choroidal epithelia of the blood–CSF barrier following manganese exposure in vitro

Wang

Zheng

2006

Brain Research

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“…The half confluent cultures of Z310, RBE4, N27, or PC12 cells were exposed to 100 µM MnCl 2 containing 2.633 nCi 54 Mn/mL for 24 hrs. The exposure concentration was chosen because previous works by this and other laboratories have shown significant toxic outcomes in various cell types (Chen et al, 2001;Crooks et al, 2007;Li et al, 2005;Zheng and Zhao, 2001). Mn treatment was terminated by rapid aspiration of the medium, followed by thorough washes with 5 mL of ice cold PBS for three times.…”

Section: Mn Exposure and Preparation Of Subcellular Fractionsmentioning

confidence: 99%

Manganese accumulates primarily in nuclei of cultured brain cells

2008

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Manganese (Mn) is known to pass across the blood-brain barrier and interact with dopaminergic neurons. However, the knowledge on the subcellular distribution of Mn in these cell types upon exposure to Mn remained incomplete. This study was designed to investigate the subcellular distribution of Mn in blood-brain barrier endothelial RBE4 cells, blood-cerebrospinal fluid barrier choroidal epithelial Z310 cells, mesencephalic dopaminergic neuronal N27 cells, and pheochromocytoma dopaminergic PC12 cells. The cells were incubated with 100 µM MnCl 2 with radioactive tracer 54 Mn in the culture media for 24 hrs. The subcellular organelles, i.e., nuclei, mitochondria, microsomes, and cytoplasm, were isolated by centrifugation and verified for their authenticity by determining the markers specific to cellular organelles. Data indicated that maximum Mn accumulation was observed in PC12 cells, which was 2.8, 5.2 and 5.9 fold higher than that in N27, Z310 and RBE4 cells, respectively. Within cells, about 92%, 72%, and 52% of intracellular 54 Mn were found to be present in nuclei of RBE4, Z310, and N27 cells, respectively. The recovery of 54 Mn in nuclei and cytoplasm of PC12 cells were 27% and 69% respectively. Surprisingly, less than 0.5% and 2.5% of cellular 54 Mn was found in mitochondrial and microsomal fractions, respectively. This study suggests that the nuclei may serve as the primary pool for intracellular Mn; mitochondria and microsomes may play an insignificant role in Mn subcellular distribution.

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“…Previous studies have suggested that Mn 2+ can induce oxidative stress and affect iron metabolism and cellular energy metabolism (Dobson et al, 2004;Erikson et al, 2004a;Hazell, 2002;Li et al, 2005;Lu et al, 2005). Nonetheless, the understanding of the specific mechanisms underlying Mn neurotoxicity in humans remains far from clear.…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells

et al. 2007

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Exposure of adult humans to manganese (Mn) has long been known to cause neurotoxicity. Recent evidence also suggests that exposure of children to Mn is associated with developmental neurotoxicity. Astrocytes are critical for the proper functioning of the nervous system, and they play active roles in neurogenesis, synaptogenesis and synaptic neurotransmission. In this report, to help elucidate the molecular events underlying Mn neurotoxicity, we systematically identified the molecular targets of Mn in primary human astrocytes at a genome-wide level, by using microarray gene expression profiling and computational data analysis algorithms. We found that Mn altered the expression of diverse genes ranging from those encoding cytokines and transporters to signal transducers and transcriptional regulators. Particularly, 28 genes encoding proinflammatory chemokines, cytokines and related functions were up-regulated whereas 15 genes encoding functions involved in DNA replication and repair and cell cycle checkpoint control were down-regulated. Consistent with the increased expression of proinflammatory factors, analysis of common regulators revealed that 16 targets known to be positively affected by the interferon-γ signaling pathway were up-regulated by Mn 2+ . In addition, 68 genes were found to be similarly up-or down-regulated by both Mn 2+ and hypoxia. These results from genomic analysis are further supported by data from realtime RT-PCR, Western blotting, flow cytometric and toxicological analyses. Together, these analyses show that Mn 2+ selectively affects cell cycle progression, the expression of hypoxia-responsive genes, and the expression of proinflammatory factors in primary human astrocytes. These results provide important insights into the molecular mechanisms underlying Mn neurotoxicity.

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Alteration at translational but not transcriptional level of transferrin receptor expression following manganese exposure at the blood–CSF barrier in vitro

Cited by 39 publications

References 50 publications

Upregulation of DMT1 expression in choroidal epithelia of the blood–CSF barrier following manganese exposure in vitro

Upregulation of DMT1 expression in choroidal epithelia of the blood–CSF barrier following manganese exposure in vitro

Manganese accumulates primarily in nuclei of cultured brain cells

Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells

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