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Mitochondrial dysfunction and loss of Parkinson's disease-linked proteins contribute to neurotoxicity of manganese-containing welding fumes.
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
FASEB J 2010 Dec; 24(12):4989-5002
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.
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
Krishnan Sriram; Toxicology and Molecular Biology Branch, Mailstop L-3014, CDC-NIOSH, 1095 Willowdale Rd., Morgantown, WV 26505, USA
Issue of Publication
The FASEB Journal
Page last reviewed: September 2, 2020
Content source: National Institute for Occupational Safety and Health Education and Information Division