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

• Published in: The FASEB journal 2010-12, Vol.24 (12), p.4989-5002
• Main Authors: Sriram, Krishnan, Lin, Gary X., Jefferson, Amy M., Roberts, Jenny R., Wirth, Oliver, Hayashi, Yusuke, Krajnak, Kristine M., Soukup, Joleen M., Ghio, Andrew J., Reynolds, Steven H., Castranova, Vincent, Munson, Albert E., Antonini, James M.
• Format: Article
• Language: English
• Subjects: DJ-1; neurodegeneration; Park genes; pro-teasome; train; ubiquitin‐proteasome pathway
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.10.163964

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 ~1 to 5 yr of worker exposure resulted in selective brain accumulation of Mn. This accumulation caused impairment of mitochondrial function and loss of ty‐rosine hydroxylase (TH) protein, indicative of dopa‐minergic injury. A fascinating finding was the altered expression of Parkin (Park2), Uchll (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 neuro‐pathological 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. Mito‐chondrial dysfunction and loss of Parkinson's disease‐linked proteins contribute to neurotoxicity of manganese‐containing welding fumes. FASEB J. 24, 4989–5002 (2010). www.fasebj.org