Microarray genomic profile of mitochondrial and oxidant response in Manganese Chloride treated PC12 cells

Details

• Alternative Title:
  Neurotoxicology
• Personal Author:
  Taka, Equar ; Mazzio, Elizabeth ; Soliman, Karam FA ; Reams, R. Renee
• 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.
• Subjects:
  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

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• 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 ; 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
• Volume:
  33
• Issue:
  2
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:59ff04de7e482180585190ff4e34c21ac69cd88481290ca75dea3ba3e84ea6a0
• Download URL:
  https://stacks.cdc.gov/view/cdc/41852/cdc_41852_DS1.pdf
• File Type:
  [PDF - 2.80 MB ]