title: Microarray genomic profile of mitochondrial and oxidant response in manganese chloride treated PC12 cells.
abstract: 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.
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL 32307, USA.
authors.forename: Equar
authors.initials: E
authors.lastname: Taka
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mazzio
authors.forename: Karam F A
authors.initials: KF
authors.lastname: Soliman
authors.forename: R
authors.initials: R
authors.lastname: Renee Reams
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002712:Chlorides / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D019344:Lactic Acid / Q000378:metabolism; D017895:Manganese Compounds / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D018384:Oxidative Stress / Q000187:drug effects*; D016716:PC12 Cells; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013997:Time Factors
chemical_list: D002712:Chlorides; D017895:Manganese Compounds; D012333:RNA, Messenger; D019344:Lactic Acid; D006861:Hydrogen Peroxide; D051547:Heme Oxygenase-1; D005947:Glucose; C025340:manganese chloride