Archives of Toxicology

, Volume 84, Issue 7, pp 521–540

Dopaminergic neurotoxicity following pulmonary exposure to manganese-containing welding fumes

  • Krishnan Sriram
  • Gary X. Lin
  • Amy M. Jefferson
  • Jenny R. Roberts
  • Rebecca S. Chapman
  • Bean T. Chen
  • Joleen M. Soukup
  • Andrew J. Ghio
  • James M. Antonini
Inorganic Compounds

DOI: 10.1007/s00204-010-0525-9

Cite this article as:
Sriram, K., Lin, G.X., Jefferson, A.M. et al. Arch Toxicol (2010) 84: 521. doi:10.1007/s00204-010-0525-9

Abstract

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 × 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.

Keywords

Brain Dopaminergic dysfunction Manganese Neurotoxicity Neurodegeneration Occupational exposure Parkinson’s disease Parkinsonism Welding Welding fume 

Abbreviations

BALF

Bronchoalveolar lavage fluid

CCL2

Chemokine–chemokine ligand 2

CXCL2

Chemokine-X-chemokine ligand 2

CNS

Central nervous system

COX

Cycloxygenase

DMT1

Divalent metal transporter 1

DRD2

Dopamine D2 receptor

EMR1

Egf-like module containing mucin-like hormone receptor-like 1

FLISA

Fluorescence-linked immunosorbent assay

GFAP

Glial fibrillary acidic protein

GMA-MS

Gas metal arc-mild steel

HO

Heme-oxygenase

ICP-AES

Inductive coupled plasma atomic absorption spectroscopy

IL6

Interleukin 6

ITGAM

Integrin αM

LDH

Lactate dehydrogenase

MMA-HS

Manual metal arc-hard surfacing

NOS

Nitric oxide synthase

PCR

Polymerase chain reaction

PD

Parkinson’s disease

PMN

Polymorphonuclear leukocyte

SDS

Sodium dodecyl sulfate

TH

Tyrosine hydroxylase

TNF

Tumor necrosis factor

VMAT2

Vesicular monoamine transporter 2

WF

Welding fume

Copyright information

© US Government 2010

Authors and Affiliations

  • Krishnan Sriram
    • 1
  • Gary X. Lin
    • 1
  • Amy M. Jefferson
    • 1
  • Jenny R. Roberts
    • 1
  • Rebecca S. Chapman
    • 1
  • Bean T. Chen
    • 1
  • Joleen M. Soukup
    • 2
  • Andrew J. Ghio
    • 2
  • James M. Antonini
    • 1
  1. 1.Health Effects Laboratory DivisionNational Institute For Occupational Safety and HealthMorgantownUSA
  2. 2.National Health and Environmental Effects Research LaboratoryUnited States Environmental Protection AgencyResearch Triangle ParkUSA