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Mitochondrial dysfunction and loss of Parkinson's disease-linked proteins contribute to neurotoxicity of manganese-containing welding fumes.

Authors
Sriram-K; Lin-GX; Jefferson-AM; Roberts-JR; Wirth-O; Hayashi-Y; Krajnak-KM; Soukup-JM; Ghio-AJ; Reynolds-SH; Castranova-V; Munson-AE; Antonini-JM
Source
FASEB J 2010 Dec; 24(12):4989-5002
NIOSHTIC No.
20037643
Abstract
Welding generates complex metal aerosols, inhalation of which is linked to adverse health effects among welders. An important health concern of welding fume (WF) exposure is neurological dysfunction akin to Parkinson's disease (PD), thought to be mediated by manganese (Mn) in the fumes. Also, there is a proposition that welding might accelerate the onset of PD. Our recent findings link the presence of Mn in the WF with dopaminergic neurotoxicity seen in rats exposed to manual metal arc-hard surfacing (MMA-HS) or gas metal arc-mild steel (GMA-MS) fumes. To elucidate the molecular mechanisms further, we investigated the association of PD-linked (Park) genes and mitochondrial function in causing dopaminergic abnormality. Repeated instillations of the two fumes at doses that mimic approximately 1 to 5 yr of worker exposure resulted in selective brain accumulation of Mn. This accumulation caused impairment of mitochondrial function and loss of tyrosine hydroxylase (TH) protein, indicative of dopaminergic injury. A fascinating finding was the altered expression of Parkin (Park2), Uchl1 (Park5), and Dj1 (Park7) proteins in dopaminergic brain areas. A similar regimen of manganese chloride (MnCl2) also caused extensive loss of striatal TH, mitochondrial electron transport components, and Park proteins. As mutations in PARK genes have been linked to early-onset PD in humans, and because welding is implicated as a risk factor for parkinsonism, PARK genes might play a critical role in WF-mediated dopaminergic dysfunction. Whether these molecular alterations culminate in neurobehavioral and neuropathological deficits reminiscent of PD remains to be ascertained.-Sriram, K., Lin, G. X., Jefferson, A. M., Roberts, J. R., Wirth, O., Hayashi, Y., Krajnak, K. M., Soukup, J. M., Ghio, A. J., Reynolds, S. H., Castranova, V., Munson, A. E., Antonini, J. M. Mitochondrial dysfunction and loss of Parkinson's disease-linked proteins contribute to neurotoxicity of manganese-containing welding fumes.
Keywords
Welding; Metal-workers; Metal-fumes; Inhalants; Neurological-reactions; Nervous-system; Nervous-system-disorders; Neurological-system; Exposure-levels; Manganese-compounds; Author Keywords: brain; DJ-1; neurodegeneration; Park genes; proteasome; ubiquitin-proteasome pathway
Contact
Krishnan Sriram; Toxicology and Molecular Biology Branch, Mailstop L-3014, CDC-NIOSH, 1095 Willowdale Rd., Morgantown, WV 26505, USA
CODEN
FAJOEC
CAS No.
7439-96-5
Publication Date
20101201
Document Type
Journal Article
Email Address
kos4@cdc.gov
Fiscal Year
2011
NTIS Accession No.
NTIS Price
Issue of Publication
12
ISSN
0892-6638
NIOSH Division
HELD
Priority Area
Manufacturing
Source Name
The FASEB Journal
State
WV; NC
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