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Dopaminergic neurotoxicity following pulmonary exposure to manganese-containing welding fumes.
Sriram K; Lin GX; Jefferson AM; Roberts JR; Chapman RS; Chen BT; Soukup JM; Ghio AJ; Antonini JM
Arch Toxicol 2010 Jul; 84(7):521-540
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 9 7 weeks) of GMA-MS or MMAHS, 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.
Biological-effects; Chemical-hypersensitivity; Chemical-properties; Exposure-assessment; Exposure-levels; Exposure-methods; Fumes; Inhalation-studies; Laboratory-animals; Laboratory-testing; Nerve-function; Neurological-system; Neurotoxic-effects; Occupational-exposure; Physiological-factors; Physiological-testing; Pulmonary-system-disorders; Respiratory-gas-analysis; Respiratory-system-disorders; Statistical-analysis; Toxic-effects; Welders; Welders-lung; Welding; Work-environment; Work-operations; Work-practices; Author Keywords: Brain; Dopaminergic dysfunction; Manganese; Neurotoxicity; Neurodegeneration; Occupational exposure; Parkinsons disease; Parkinsonism
Krishnan Sriram, Health Effects Laboratory Division, National Institute For Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505
Issue of Publication
Archives of Toxicology