Glutamate/aspartate transporter (GLAST), taurine transporter and metallothionein mRNA levels are differentially altered in astrocytes exposed to manganese chloride, manganese phosphate or manganese sulfate

Keith M. Erikson, Robert L. Suber, Michael Aschner

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43 Citations (Scopus)

Abstract

Manganese (Mn)-induced neurotoxicity can occur due to environmental exposure (air pollution, soil, water) and/or metabolic aberrations (decreased biliary excretion). High brain manganese levels lead to oxidative stress, as well as alterations in neurotransmitter metabolism with concurrent neurobehavioral deficits. Based on the few existing studies that have examined brain regional Mn concentration, it is likely that in pathological conditions, Mn concentration can reach between 100 and 500 μM. Environmental Mn exposure as a result of methylcyclopentadienyl manganese tricarbonyl (MMT) combustion is in the form of phosphate or sulfate (MnPO4, MnSO4, respectively). Pharmacokinetic studies have shown that the Mn salt will determine the rate of transport into the brain: MnCl2 > MnSO4 > MnPO4. The salt-specific neurotoxicity of these species is unknown. The primary goal of this study was to examine gene expression of glutamate/aspartate transporter (GLAST), taurine transporter (tau-T), and metallothionein-I (MT-I) in astrocytes exposed to manganese chloride (MnCl2), manganese sulfate (MnSO4), and manganese phosphate (MnPO4). We hypothesized that the effects of MnPO4 and MnSO4 exposure on GLAST expression in astrocytes would be similar to those induced by MnCl2, since irrespective of salt species exposure, once internalized by astrocytes, the Mn ion would be identically complexed. At the same time, we hypothesized that the magnitude of the effect would be salt-dependent, since the chemical speciation would determine the rate of intracellular uptake of Mn. MnCl2 caused a significant overall decrease (P < 0.0001) in astrocytic GLAST mRNA levels with MnSO4 causing a moderate decrease. MnPO4 exposure did not alter GLAST mRNA in astrocytes. We also sought to examine astrocytic metallothionein and taurine transporter gene expression as markers of manganese exposure. Our findings suggest that manganese chloride significantly decreased (P < 0.0001) astrocytic metallothionein mRNA compared to both the sulfate and phosphate species. However, astrocytic taurine transporter mRNA was not affected by Mn exposure, irrespective of the salt species. These data are consistent with the hypothesis that astrocytic neurotoxicity due to Mn exposure is dependent upon its species, with solubility, and by inference, intracellular concentration, representing a major determinant of its neurotoxicity.

Original languageEnglish (US)
Pages (from-to)281-288
Number of pages8
JournalNeuroToxicology
Volume23
Issue number3
DOIs
StatePublished - Sep 2002
Externally publishedYes

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Amino Acid Transport System X-AG
Metallothionein
Manganese
Astrocytes
Messenger RNA
Salts
Brain
Environmental Exposure
Gene expression
Sulfates
manganese sulfate
manganese phosphate
taurine transporter
manganese chloride
Phosphates
Chemical speciation
Gene Expression
Oxidative stress
Pharmacokinetics
Air Pollution

Keywords

  • Astrocytes
  • Glutamate
  • Manganese
  • Metallothionein
  • mRNA
  • Rat
  • Taurine transporter

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neuroscience(all)
  • Toxicology

Cite this

@article{e8da49687ff543a9ae088e29d4e981da,
title = "Glutamate/aspartate transporter (GLAST), taurine transporter and metallothionein mRNA levels are differentially altered in astrocytes exposed to manganese chloride, manganese phosphate or manganese sulfate",
abstract = "Manganese (Mn)-induced neurotoxicity can occur due to environmental exposure (air pollution, soil, water) and/or metabolic aberrations (decreased biliary excretion). High brain manganese levels lead to oxidative stress, as well as alterations in neurotransmitter metabolism with concurrent neurobehavioral deficits. Based on the few existing studies that have examined brain regional Mn concentration, it is likely that in pathological conditions, Mn concentration can reach between 100 and 500 μM. Environmental Mn exposure as a result of methylcyclopentadienyl manganese tricarbonyl (MMT) combustion is in the form of phosphate or sulfate (MnPO4, MnSO4, respectively). Pharmacokinetic studies have shown that the Mn salt will determine the rate of transport into the brain: MnCl2 > MnSO4 > MnPO4. The salt-specific neurotoxicity of these species is unknown. The primary goal of this study was to examine gene expression of glutamate/aspartate transporter (GLAST), taurine transporter (tau-T), and metallothionein-I (MT-I) in astrocytes exposed to manganese chloride (MnCl2), manganese sulfate (MnSO4), and manganese phosphate (MnPO4). We hypothesized that the effects of MnPO4 and MnSO4 exposure on GLAST expression in astrocytes would be similar to those induced by MnCl2, since irrespective of salt species exposure, once internalized by astrocytes, the Mn ion would be identically complexed. At the same time, we hypothesized that the magnitude of the effect would be salt-dependent, since the chemical speciation would determine the rate of intracellular uptake of Mn. MnCl2 caused a significant overall decrease (P < 0.0001) in astrocytic GLAST mRNA levels with MnSO4 causing a moderate decrease. MnPO4 exposure did not alter GLAST mRNA in astrocytes. We also sought to examine astrocytic metallothionein and taurine transporter gene expression as markers of manganese exposure. Our findings suggest that manganese chloride significantly decreased (P < 0.0001) astrocytic metallothionein mRNA compared to both the sulfate and phosphate species. However, astrocytic taurine transporter mRNA was not affected by Mn exposure, irrespective of the salt species. These data are consistent with the hypothesis that astrocytic neurotoxicity due to Mn exposure is dependent upon its species, with solubility, and by inference, intracellular concentration, representing a major determinant of its neurotoxicity.",
keywords = "Astrocytes, Glutamate, Manganese, Metallothionein, mRNA, Rat, Taurine transporter",
author = "Erikson, {Keith M.} and Suber, {Robert L.} and Michael Aschner",
year = "2002",
month = "9",
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TY - JOUR

T1 - Glutamate/aspartate transporter (GLAST), taurine transporter and metallothionein mRNA levels are differentially altered in astrocytes exposed to manganese chloride, manganese phosphate or manganese sulfate

AU - Erikson, Keith M.

AU - Suber, Robert L.

AU - Aschner, Michael

PY - 2002/9

Y1 - 2002/9

N2 - Manganese (Mn)-induced neurotoxicity can occur due to environmental exposure (air pollution, soil, water) and/or metabolic aberrations (decreased biliary excretion). High brain manganese levels lead to oxidative stress, as well as alterations in neurotransmitter metabolism with concurrent neurobehavioral deficits. Based on the few existing studies that have examined brain regional Mn concentration, it is likely that in pathological conditions, Mn concentration can reach between 100 and 500 μM. Environmental Mn exposure as a result of methylcyclopentadienyl manganese tricarbonyl (MMT) combustion is in the form of phosphate or sulfate (MnPO4, MnSO4, respectively). Pharmacokinetic studies have shown that the Mn salt will determine the rate of transport into the brain: MnCl2 > MnSO4 > MnPO4. The salt-specific neurotoxicity of these species is unknown. The primary goal of this study was to examine gene expression of glutamate/aspartate transporter (GLAST), taurine transporter (tau-T), and metallothionein-I (MT-I) in astrocytes exposed to manganese chloride (MnCl2), manganese sulfate (MnSO4), and manganese phosphate (MnPO4). We hypothesized that the effects of MnPO4 and MnSO4 exposure on GLAST expression in astrocytes would be similar to those induced by MnCl2, since irrespective of salt species exposure, once internalized by astrocytes, the Mn ion would be identically complexed. At the same time, we hypothesized that the magnitude of the effect would be salt-dependent, since the chemical speciation would determine the rate of intracellular uptake of Mn. MnCl2 caused a significant overall decrease (P < 0.0001) in astrocytic GLAST mRNA levels with MnSO4 causing a moderate decrease. MnPO4 exposure did not alter GLAST mRNA in astrocytes. We also sought to examine astrocytic metallothionein and taurine transporter gene expression as markers of manganese exposure. Our findings suggest that manganese chloride significantly decreased (P < 0.0001) astrocytic metallothionein mRNA compared to both the sulfate and phosphate species. However, astrocytic taurine transporter mRNA was not affected by Mn exposure, irrespective of the salt species. These data are consistent with the hypothesis that astrocytic neurotoxicity due to Mn exposure is dependent upon its species, with solubility, and by inference, intracellular concentration, representing a major determinant of its neurotoxicity.

AB - Manganese (Mn)-induced neurotoxicity can occur due to environmental exposure (air pollution, soil, water) and/or metabolic aberrations (decreased biliary excretion). High brain manganese levels lead to oxidative stress, as well as alterations in neurotransmitter metabolism with concurrent neurobehavioral deficits. Based on the few existing studies that have examined brain regional Mn concentration, it is likely that in pathological conditions, Mn concentration can reach between 100 and 500 μM. Environmental Mn exposure as a result of methylcyclopentadienyl manganese tricarbonyl (MMT) combustion is in the form of phosphate or sulfate (MnPO4, MnSO4, respectively). Pharmacokinetic studies have shown that the Mn salt will determine the rate of transport into the brain: MnCl2 > MnSO4 > MnPO4. The salt-specific neurotoxicity of these species is unknown. The primary goal of this study was to examine gene expression of glutamate/aspartate transporter (GLAST), taurine transporter (tau-T), and metallothionein-I (MT-I) in astrocytes exposed to manganese chloride (MnCl2), manganese sulfate (MnSO4), and manganese phosphate (MnPO4). We hypothesized that the effects of MnPO4 and MnSO4 exposure on GLAST expression in astrocytes would be similar to those induced by MnCl2, since irrespective of salt species exposure, once internalized by astrocytes, the Mn ion would be identically complexed. At the same time, we hypothesized that the magnitude of the effect would be salt-dependent, since the chemical speciation would determine the rate of intracellular uptake of Mn. MnCl2 caused a significant overall decrease (P < 0.0001) in astrocytic GLAST mRNA levels with MnSO4 causing a moderate decrease. MnPO4 exposure did not alter GLAST mRNA in astrocytes. We also sought to examine astrocytic metallothionein and taurine transporter gene expression as markers of manganese exposure. Our findings suggest that manganese chloride significantly decreased (P < 0.0001) astrocytic metallothionein mRNA compared to both the sulfate and phosphate species. However, astrocytic taurine transporter mRNA was not affected by Mn exposure, irrespective of the salt species. These data are consistent with the hypothesis that astrocytic neurotoxicity due to Mn exposure is dependent upon its species, with solubility, and by inference, intracellular concentration, representing a major determinant of its neurotoxicity.

KW - Astrocytes

KW - Glutamate

KW - Manganese

KW - Metallothionein

KW - mRNA

KW - Rat

KW - Taurine transporter

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U2 - 10.1016/S0161-813X(02)00041-4

DO - 10.1016/S0161-813X(02)00041-4

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VL - 23

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