Details:

Alternative Title:
Neurotoxicology
Personal Author:
Taka, Equar ; Mazzio, Elizabeth ; Soliman, Karam FA ; Reams, R. Renee
Taka, Equar ; Mazzio, Elizabeth ; Soliman, Karam FA ; Reams, R. Renee Less -
Description:
Environmental or occupational exposure to high levels of manganese (Mn) can lead to manganism, a symptomatic neuro-degenerative disorder similar to idiopathic Parkinson's disease. The underlying mechanism of Mn neurotoxicity remains unclear. In this study, we evaluate the primary toxicological events associated with MnCl(2) toxicity in rat PC12 cells using whole genome cDNA microarray, RT-PCR, Western blot and functional studies. The results show that a sub-lethal dose range (38-300 μM MnCl(2)) initiated slight metabolic stress evidenced by heightened glycolytic rate and induction of enolase/aldolase - gene expression. The largest shift observed in the transcriptome was MnCl(2) induction of heme-oxygenase 1 (HO-1) [7.7 fold, p<0.001], which was further corroborated by RT-PCR and Western blot studies. Concentrations in excess of 300 μM corresponded to dose dependent loss of cell viability which was associated with enhanced production of H(2)O(2) concomitant to elevation of gene expression for diverse antioxidant enzymes; biliverdin reductase, arsenite inducible RNA associated protein, dithiolethione-inducible gene-1 (DIG-1) and thioredoxin reductase 1. Moreover, Mn initiated significant reduction of gene expression of mitochondrial glutaryl-coenzyme A dehydrogenase (GCDH), an enzyme involved with glutaric acidemia, oxidative stress, lipid peroxidation and striatal degeneration observed in association with severe dystonic-dyskinetic movement disorder. Future research will be required to elucidate a defined role for HO-1 and GCDH in Mn toxicity.
Subject:
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Animals
Article
CDNA Microarray Whole Genome
Cell Survival
Chlorides
Chromatography, High Pressure Liquid
Dopamine
Dose-Response Relationship, Drug
GCDH
Gene Expression
Gene Expression Profiling
Gene Expression Regulation
Glucose
Heme Oxygenase
Heme Oxygenase-1
Hydrogen Peroxide
Lactic Acid
Manganese
Manganese Compounds
Mitochondria
Oligonucleotide Array Sequence Analysis
Oxidative Stress
PC12 Cells
Rats
RNA, Messenger
Time Factors
Mitochondria

Source:
Neurotoxicology. 33(2):162-168
Pubmed ID:
22281203
Pubmed Central ID:
PMC3348586
Document Type:
Journal Article
Funding:
G12 RR003020/RR/NCRR NIH HHS/United States ; 5S11ES01187-05/ES/NIEHS NIH HHS/United States ; G12 MD007582-28/MD/NIMHD NIH HHS/United States ; U50 TS473408/TS/ATSDR CDC HHS/United States ; S11 ES011182/ES/NIEHS NIH HHS/United States ; ... More +
G12 RR003020/RR/NCRR NIH HHS/United States ; 5S11ES01187-05/ES/NIEHS NIH HHS/United States ; G12 MD007582-28/MD/NIMHD NIH HHS/United States ; U50 TS473408/TS/ATSDR CDC HHS/United States ; S11 ES011182/ES/NIEHS NIH HHS/United States ; P20 MD006738/MD/NIMHD NIH HHS/United States ; G12 MD007582/MD/NIMHD NIH HHS/United States ; S11 ES011182-03/ES/NIEHS NIH HHS/United States ; G12RR 03020/RR/NCRR NIH HHS/United States Less -
Collection(s):
CDC Public Access
Main Document Checksum:
[+]
urn:sha256:59ff04de7e482180585190ff4e34c21ac69cd88481290ca75dea3ba3e84ea6a0
File Type:

Supporting Files

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