title: Methylmercury can induce Parkinson's-like neurotoxicity similar to 1-methyl-4- phenylpyridinium: a genomic and proteomic analysis on MN9D dopaminergic neuron cells.
abstract: Exposure to environmental chemicals has been implicated as a possible risk factor for the development of neurodegenerative diseases. Our previous study showed that methylmercury (MeHg) exposure can disrupt synthesis, uptake and metabolism of dopamine similar to 1-methyl-4-phenylpyridinium (MPP(+)). The objective of this study was to investigate the effects of MeHg exposure on gene and protein profiles in a dopaminergic MN9D cell line. MN9D cells were treated with MeHg (1-5 μM) and MPP(+) (10-40 μM) for 48 hr. Real-time PCR Parkinson's disease (PD) arrays and high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) were performed for the analysis. PD PCR array results showed that 19% genes were significantly changed in the 2.5 μM MeHg treated cells, and 39% genes were changed in the 5 μM MeHg treated cells. In comparison, MPP(+) treatment (40 µM) resulted in significant changes in 25% genes. A total of 15 common genes were altered by both MeHg and MPP(+), and dopaminergic signaling transduction was the most affected pathway. Proteomic analysis identified a total of 2496 proteins, of which 188, 233 and 395 proteins were differentially changed by 1 μM and 2.5 μM MeHg, and MPP(+) respectively. A total of 61 common proteins were changed by both MeHg and MPP(+) treatment. The changed proteins were mainly involved in energetic generation-related metabolism pathway (propanoate metabolism, pyruvate metabolism and fatty acid metabolism), oxidative phosphorylation, proteasome, PD and other neurodegenerative disorders. A total of 7 genes/proteins including Ube2l3 (Ubiquitin-conjugating enzyme E2 L3) and Th (Tyrosine 3-monooxygenase) were changed in both genomic and proteomic analysis. These results suggest that MeHg and MPP(+) share many similar signaling pathways leading to the pathogenesis of PD and other neurodegenerative diseases.
authors.affiliation: Natural Resources and Environmental Studies Program, University of Northern British Columbia, Canada.
authors.forename: Yueting
authors.initials: Y
authors.lastname: Shao
authors.forename: Daniel
authors.initials: D
authors.lastname: Figeys
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Ning
authors.forename: Ryan
authors.initials: R
authors.lastname: Mailloux
authors.forename: Hing Man
authors.initials: HM
authors.lastname: Chan
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism* / Q000502:physiology; D059290:Dopaminergic Neurons / Q000378:metabolism*; D004734:Energy Metabolism / Q000235:genetics; D016678:Genome / Q000187:drug effects*; D023281:Genomics; D006801:Humans; D008767:Methylmercury Compounds / Q000633:toxicity*; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D010085:Oxidative Phosphorylation; D010302:Parkinson Disease, Secondary / Q000139:chemically induced*; D046988:Proteasome Endopeptidase Complex; D020543:Proteome / Q000187:drug effects*; D040901:Proteomics; D015398:Signal Transduction / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism
chemical_list: D008767:Methylmercury Compounds; D020543:Proteome; D014446:Tyrosine 3-Monooxygenase; D044763:Ubiquitin-Conjugating Enzymes; D046988:Proteasome Endopeptidase Complex; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine