Manganese and rotenone-induced oxidative stress signatures differ in iPSC-derived human dopamine neurons

M. Diana Neely, Carrie Ann Davison, Michael Aschner, Aaron B. Bowman

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Parkinson's disease (PD) is the result of complex interactions between genetic and environmental factors. Two chemically distinct environmental stressors relevant to PD are the metal manganese and the pesticide rotenone. Both are thought to exert neurotoxicity at least in part via oxidative stress resulting from impaired mitochondrial activity. Identifying shared mechanism of action may reveal clues towards an understanding of the mechanisms underlying PD pathogenesis. Here we compare the effects of manganese and rotenone in human-induced pluripotent stem cells-derived postmitotic mesencephalic dopamine neurons by assessing several different oxidative stress endpoints. Manganese, but not rotenone caused a concentration and time-dependent increase in intracellular reactive oxygen/nitrogen species measured by quantifying the fluorescence of oxidized chloromethyl 2',7'-dichlorodihydrofluorescein diacetate (DCF) assay. In contrast, rotenone but not manganese caused an increase in cellular isoprostane levels, an indicator of lipid peroxidation. Manganese and rotenone both caused an initial decrease in cellular reduced glutathione; however, glutathione levels remained low in neurons treated with rotenone for 24h but recovered in manganese-exposed cells. Neurite length, a sensitive indicator of overall neuronal health was adversely affected by rotenone, but not manganese. Thus, our observations suggest that the cellular oxidative stress evoked by these 2 agents is distinct yielding unique oxidative stress signatures across outcome measures. The protective effect of rasagiline, a compound used in the clinic for PD, had negligible impact on any of oxidative stress outcome measures except a subtle significant decrease in manganesedependent production of reactive oxygen/nitrogen species detected by the DCF assay.

Original languageEnglish (US)
Pages (from-to)366-379
Number of pages14
JournalToxicological Sciences
Volume159
Issue number2
DOIs
StatePublished - Oct 1 2017

Fingerprint

Rotenone
Oxidative stress
Dopaminergic Neurons
Manganese
Neurons
Dopamine
Oxidative Stress
Parkinson Disease
Reactive Nitrogen Species
Glutathione
Assays
Reactive Oxygen Species
Nitrogen
Outcome Assessment (Health Care)
Oxygen
Isoprostanes
Induced Pluripotent Stem Cells
Neurites
Stem cells
Pesticides

Keywords

  • Dopamine neuron
  • Human-induced pluripotent stem cells
  • Manganese
  • Oxidative stress
  • RasagilineRotenone

ASJC Scopus subject areas

  • Toxicology

Cite this

Manganese and rotenone-induced oxidative stress signatures differ in iPSC-derived human dopamine neurons. / Neely, M. Diana; Davison, Carrie Ann; Aschner, Michael; Bowman, Aaron B.

In: Toxicological Sciences, Vol. 159, No. 2, 01.10.2017, p. 366-379.

Research output: Contribution to journalArticle

Neely, M. Diana ; Davison, Carrie Ann ; Aschner, Michael ; Bowman, Aaron B. / Manganese and rotenone-induced oxidative stress signatures differ in iPSC-derived human dopamine neurons. In: Toxicological Sciences. 2017 ; Vol. 159, No. 2. pp. 366-379.
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