Mitochondrial dysfunction and loss of Parkinson's disease-linked proteins contribute to neurotoxicity of manganese-containing welding fumes.
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 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 (MnCl(2)) 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
Krishnan
K
Toxicology and Molecular Biology Branch, Mailstop L-3014, CDC-NIOSH, 1095 Willowdale Rd., Morgantown, WV 26505, USA. kos4@cdc.gov
Lin
Gary X
GX
Jefferson
Amy M
AM
Roberts
Jenny R
JR
Wirth
Oliver
O
Hayashi
Yusuke
Y
Krajnak
Kristine M
KM
Soukup
Joleen M
JM
Ghio
Andrew J
AJ
Reynolds
Steven H
SH
Castranova
Vincent
V
Munson
Albert E
AE
Antonini
James M
JM
D000395:Air Pollutants, Occupational / Q000633:toxicity; D000818:Animals; D015153:Blotting, Western; D002712:Chlorides / Q000633:toxicity; D019570:Inhalation Exposure / Q000009:adverse effects; D008297:Male; D008345:Manganese / Q000378:metabolism / Q000633:toxicity*; D017895:Manganese Compounds; D016273:Occupational Exposure / Q000009:adverse effects; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D014896:Welding
D000395:Air Pollutants, Occupational; D002712:Chlorides; D017895:Manganese Compounds; D008345:Manganese; D014446:Tyrosine 3-Monooxygenase; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C489034:UCHL1 protein, rat; D043222:Ubiquitin Thiolesterase; C025340:manganese chloride