期刊
NEUROTOXICOLOGY
卷 33, 期 2, 页码 162-168出版社
ELSEVIER
DOI: 10.1016/j.neuro.2012.01.001
关键词
Manganese; Dopamine; Heme oxygenase; Mitochondria; cDNA microarray whole genome; GCDH
资金
- Association of Minority Health Professions Schools, Inc. (AMPHS)
- ATS/DR [3U50TS473408-05W1/CFDA, 93.161]
- NIEHS/ARCH [5S11ES01187-05]
- NIH NCRR RCMI [G12RR 03020]
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 MnCl2 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 mu M MnCl2) initiated slight metabolic stress evidenced by heightened glycolytic rate and induction of enolase/aldolase-gene expression. The largest shift observed in the transcriptome was MnCl2 induction of hemeoxygenase 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 mu M corresponded to dose dependent loss of cell viability which was associated with enhanced production of H2O2 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. Published by Elsevier Inc.
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