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

Krishnan Sriram, Gary X. Lin, Amy M. Jefferson, Jenny R. Roberts, Oliver Wirth, Yusuke Hayashi, Kristine M. Krajnak, Joleen M. Soukup, Andrew J. Ghio, Steven H. Reynolds, Vincent Castranova, Albert E. Munson, James M. Antonini

Research output: Contribution to journalArticle

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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 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 (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 neuropathological deficits reminiscent of PD remains to be ascertained.

Original languageEnglish (US)
Pages (from-to)4989-5002
Number of pages14
JournalFASEB Journal
Volume24
Issue number12
DOIs
StatePublished - Dec 1 2010

Fingerprint

Welding
Fumes
Manganese
Parkinson Disease
Proteins
Genes
Tyrosine 3-Monooxygenase
Brain
Health
Corpus Striatum
Hard facing
Mitochondrial Genes
Steel
Coordination Complexes
Parkinsonian Disorders
Electron Transport
Aerosols
Inhalation
Carbon steel
Rats

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

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. / Mitochondrial dysfunction and loss of Parkinson's disease-linked proteins contribute to neurotoxicity of manganese-containing welding fumes. In: FASEB Journal. 2010 ; Vol. 24, No. 12. pp. 4989-5002.
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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 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 (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 neuropathological deficits reminiscent of PD remains to be ascertained.",
author = "Krishnan Sriram and Lin, {Gary X.} and Jefferson, {Amy M.} and Roberts, {Jenny R.} and Oliver Wirth and Yusuke Hayashi and Krajnak, {Kristine M.} and Soukup, {Joleen M.} and Ghio, {Andrew J.} and Reynolds, {Steven H.} and Vincent Castranova and Munson, {Albert E.} and Antonini, {James M.}",
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Sriram, K, Lin, GX, Jefferson, AM, Roberts, JR, Wirth, O, Hayashi, Y, Krajnak, KM, Soukup, JM, Ghio, AJ, Reynolds, SH, Castranova, V, Munson, AE & Antonini, JM 2010, 'Mitochondrial dysfunction and loss of Parkinson's disease-linked proteins contribute to neurotoxicity of manganese-containing welding fumes', FASEB Journal, vol. 24, no. 12, pp. 4989-5002. https://doi.org/10.1096/fj.10-163964

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

In: FASEB Journal, Vol. 24, No. 12, 01.12.2010, p. 4989-5002.

Research output: Contribution to journalArticle

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T1 - Mitochondrial dysfunction and loss of Parkinson's disease-linked proteins contribute to neurotoxicity of manganese-containing welding fumes

AU - Sriram, Krishnan

AU - Lin, Gary X.

AU - Jefferson, Amy M.

AU - Roberts, Jenny R.

AU - Wirth, Oliver

AU - Hayashi, Yusuke

AU - Krajnak, Kristine M.

AU - Soukup, Joleen M.

AU - Ghio, Andrew J.

AU - Reynolds, Steven H.

AU - Castranova, Vincent

AU - Munson, Albert E.

AU - Antonini, James M.

PY - 2010/12/1

Y1 - 2010/12/1

N2 - 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 (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 neuropathological deficits reminiscent of PD remains to be ascertained.

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