Dopaminergic neurotoxicity following pulmonary exposure to manganese-containing welding fumes.
The potential for development of Parkinson's disease (PD)-like neurological dysfunction following occupational exposure to aerosolized welding fumes (WF) is an area of emerging concern. Welding consumables contain a complex mixture of metals, including iron (Fe) and manganese (Mn), which are known to be neurotoxic. To determine whether WF exposure poses a neurological risk particularly to the dopaminergic system, we treated Sprague-Dawley rats with WF particulates generated from two different welding processes, gas metal arc-mild steel (GMA-MS; low Mn, less water-soluble) and manual metal arc-hard surfacing (MMA-HS; high Mn, more water-soluble) welding. Following repeated intratracheal instillations (0.5 mg/rat, 1/week x 7 weeks) of GMA-MS or MMA-HS, elemental analysis and various molecular indices of neurotoxicity were measured at 1, 4, 35 or 105 days after last exposure. MMA-HS exposure, in particular, led to increased deposition of Mn in striatum and midbrain. Both fumes also caused loss of tyrosine hydroxylase (TH) protein in the striatum (~20%) and midbrain (~30%) by 1 day post-exposure. While the loss of TH following GMA-MS was transient, a sustained loss (34%) was observed in the midbrain 105 days after cessation of MMA-HS exposure. In addition, both fumes caused persistent down-regulation of dopamine D2 receptor (Drd2; 30-40%) and vesicular monoamine transporter 2 (Vmat2; 30-55%) mRNAs in the midbrain. WF exposure also modulated factors associated with synaptic transmission, oxidative stress, neuroinflammation and gliosis. Collectively, our findings demonstrate that repeated exposure to Mn-containing WF can cause persistent molecular alterations in dopaminergic targets. Whether such perturbations will lead to PD-like neuropathological manifestations remains to be elucidated.
Sriram
Krishnan
K
Health Effects Laboratory Division, National Institute For Occupational Safety and Health, Morgantown, WV 26505, USA. kos4@cdc.gov
Lin
Gary X
GX
Jefferson
Amy M
AM
Roberts
Jenny R
JR
Chapman
Rebecca S
RS
Chen
Bean T
BT
Soukup
Joleen M
JM
Ghio
Andrew J
AJ
Antonini
James M
JM
D000818:Animals; D004298:Dopamine; D015536:Down-Regulation; D005740:Gases / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D008345:Manganese / Q000378:metabolism*; D008670:Metals / Q000378:metabolism / Q000633:toxicity; D020258:Neurotoxicity Syndromes; D016273:Occupational Exposure; D010300:Parkinson Disease; D051381:Rats; D017207:Rats, Sprague-Dawley; D013232:Steel / Q000633:toxicity; D014896:Welding
D005740:Gases; D008670:Metals; D013232:Steel; D008345:Manganese; D007501:Iron; D004298:Dopamine