Manganese inhalation by rhesus monkeys is associated with brain regional changes in biomarkers of neurotoxicity

Keith M. Erikson, David C. Dorman, Lawrence H. Lash, Michael Aschner

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

The purpose of this study was to evaluate biochemical markers of neurotoxicity following subchronic manganese sulfate (MnSO4) inhalation. Juvenile rhesus monkeys were exposed to MnSO4 at 0, 0.06, 0.3, or 1.5 mg Mn/m3 for 65 days. Glutamine synthetase (GS), glutamate transporters (glutamate transporter-1 [GLT-1] and glutamate/aspartate transporter [GLAST]) and tyrosine hydroxylase (TH) protein levels, metallothionein (MT), GLT-1, GLAST, TH and GS mRNA levels, and total glutathione (GSH) levels were assessed in known targets (caudate, globus pallidus, putamen) as well as the cerebellum, frontal cortex, and olfactory cortex. All MnSO4-exposed monkeys had decreased pallidal GS protein, decreased caudate GLT-1 mRNA, decreased pallidal GLAST protein, and increased olfactory cortical TH mRNA levels. Monkeys exposed to MnSO4 at 0.06 or 0.3 mg Mn/m3 had significantly increased pallidal mRNA levels for GLT-1, GLAST, and TH. Monkeys exposed to MnSO4 at ≥ 0.3 mg Mn/m3 had several alterations including decreased frontal cortical MT mRNA, decreased caudate, globus pallidus, olfactory cortex, and cerebellum GLT-1 protein, decreased olfactory cortex and cerebellum GLAST protein, increased cerebellar GLAST mRNA, and decreased pallidal TH protein levels. Lastly, GSH levels were significantly increased in the frontal cortex and decreased in the caudate of monkeys exposed to the 1.5-mg Mn/m3 compared to the controls. Overall, as in our previous studies, we observed that increased Mn concentrations due to airborne Mn exposure differentially affects biomarkers in each brain region (e.g., GSH was increased in the frontal cortex and decreased in the caudate despite two- to threefold increases in Mn concentrations in these regions).

Original languageEnglish (US)
Pages (from-to)459-466
Number of pages8
JournalToxicological Sciences
Volume97
Issue number2
DOIs
StatePublished - Jun 2007
Externally publishedYes

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Amino Acid Transport System X-AG
Biomarkers
Manganese
Macaca mulatta
Inhalation
Brain
Tyrosine 3-Monooxygenase
Excitatory Amino Acid Transporter 1
Glutamate-Ammonia Ligase
Messenger RNA
Haplorhini
Proteins
Frontal Lobe
Metallothionein
Cerebellum
Globus Pallidus
Glutathione
Putamen

Keywords

  • Brain
  • Glutamate transporters
  • Glutamine synthetase
  • Glutathione
  • Manganese
  • Monkey

ASJC Scopus subject areas

  • Toxicology

Cite this

Manganese inhalation by rhesus monkeys is associated with brain regional changes in biomarkers of neurotoxicity. / Erikson, Keith M.; Dorman, David C.; Lash, Lawrence H.; Aschner, Michael.

In: Toxicological Sciences, Vol. 97, No. 2, 06.2007, p. 459-466.

Research output: Contribution to journalArticle

Erikson, Keith M. ; Dorman, David C. ; Lash, Lawrence H. ; Aschner, Michael. / Manganese inhalation by rhesus monkeys is associated with brain regional changes in biomarkers of neurotoxicity. In: Toxicological Sciences. 2007 ; Vol. 97, No. 2. pp. 459-466.
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abstract = "The purpose of this study was to evaluate biochemical markers of neurotoxicity following subchronic manganese sulfate (MnSO4) inhalation. Juvenile rhesus monkeys were exposed to MnSO4 at 0, 0.06, 0.3, or 1.5 mg Mn/m3 for 65 days. Glutamine synthetase (GS), glutamate transporters (glutamate transporter-1 [GLT-1] and glutamate/aspartate transporter [GLAST]) and tyrosine hydroxylase (TH) protein levels, metallothionein (MT), GLT-1, GLAST, TH and GS mRNA levels, and total glutathione (GSH) levels were assessed in known targets (caudate, globus pallidus, putamen) as well as the cerebellum, frontal cortex, and olfactory cortex. All MnSO4-exposed monkeys had decreased pallidal GS protein, decreased caudate GLT-1 mRNA, decreased pallidal GLAST protein, and increased olfactory cortical TH mRNA levels. Monkeys exposed to MnSO4 at 0.06 or 0.3 mg Mn/m3 had significantly increased pallidal mRNA levels for GLT-1, GLAST, and TH. Monkeys exposed to MnSO4 at ≥ 0.3 mg Mn/m3 had several alterations including decreased frontal cortical MT mRNA, decreased caudate, globus pallidus, olfactory cortex, and cerebellum GLT-1 protein, decreased olfactory cortex and cerebellum GLAST protein, increased cerebellar GLAST mRNA, and decreased pallidal TH protein levels. Lastly, GSH levels were significantly increased in the frontal cortex and decreased in the caudate of monkeys exposed to the 1.5-mg Mn/m3 compared to the controls. Overall, as in our previous studies, we observed that increased Mn concentrations due to airborne Mn exposure differentially affects biomarkers in each brain region (e.g., GSH was increased in the frontal cortex and decreased in the caudate despite two- to threefold increases in Mn concentrations in these regions).",
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AB - The purpose of this study was to evaluate biochemical markers of neurotoxicity following subchronic manganese sulfate (MnSO4) inhalation. Juvenile rhesus monkeys were exposed to MnSO4 at 0, 0.06, 0.3, or 1.5 mg Mn/m3 for 65 days. Glutamine synthetase (GS), glutamate transporters (glutamate transporter-1 [GLT-1] and glutamate/aspartate transporter [GLAST]) and tyrosine hydroxylase (TH) protein levels, metallothionein (MT), GLT-1, GLAST, TH and GS mRNA levels, and total glutathione (GSH) levels were assessed in known targets (caudate, globus pallidus, putamen) as well as the cerebellum, frontal cortex, and olfactory cortex. All MnSO4-exposed monkeys had decreased pallidal GS protein, decreased caudate GLT-1 mRNA, decreased pallidal GLAST protein, and increased olfactory cortical TH mRNA levels. Monkeys exposed to MnSO4 at 0.06 or 0.3 mg Mn/m3 had significantly increased pallidal mRNA levels for GLT-1, GLAST, and TH. Monkeys exposed to MnSO4 at ≥ 0.3 mg Mn/m3 had several alterations including decreased frontal cortical MT mRNA, decreased caudate, globus pallidus, olfactory cortex, and cerebellum GLT-1 protein, decreased olfactory cortex and cerebellum GLAST protein, increased cerebellar GLAST mRNA, and decreased pallidal TH protein levels. Lastly, GSH levels were significantly increased in the frontal cortex and decreased in the caudate of monkeys exposed to the 1.5-mg Mn/m3 compared to the controls. Overall, as in our previous studies, we observed that increased Mn concentrations due to airborne Mn exposure differentially affects biomarkers in each brain region (e.g., GSH was increased in the frontal cortex and decreased in the caudate despite two- to threefold increases in Mn concentrations in these regions).

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