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Catecholamine oxidation-mediated transcriptional inhibition in Mn neurotoxicity

Koji Ueda1, Yoshinori Okamoto1, Akira Aoki1

  • 1Faculty of Pharmacy, Meijo University.

The Journal of Toxicological Sciences
|October 5, 2020
PubMed

Insights

Manganese (Mn) poisoning causes manganism by oxidizing adrenaline into adrenochrome, inhibiting cellular transcription and disrupting neuronal function. This novel mechanism highlights Mn

Area of Science:

  • Neuroscience
  • Toxicology
  • Biochemistry

Background:

  • Manganese (Mn) poisoning can lead to manganism, a neurological disorder.
  • The precise neurotoxic mechanisms of Mn are not fully understood.
  • Oxidative stress is a suspected factor due to Mn interactions with neurotransmitters like adrenaline and metals like iron.

Purpose of the Study:

  • To investigate a novel mechanism of Mn neurotoxicity involving catecholamine oxidation and transcriptional inhibition.
  • To compare the effects of Mn and iron on adrenaline oxidation.
  • To determine if Mn-induced neuronal dysfunction is linked to oxidative DNA damage or transcriptional inhibition.

Main Methods:

  • Comparing the oxidation of adrenaline (Ad) by Mn and iron, and identifying the product adrenochrome (AdC).
  • Assessing DNA base oxidation in the presence of Ad, Mn, and iron.
  • Evaluating cell viability and mRNA synthesis in cells treated with AdC or Ad with Mn.
  • Measuring RNA synthesis using T7 RNA polymerase-driven transcription assays.

Main Results:

  • Mn accelerated adrenaline oxidation to adrenochrome (AdC) more effectively than iron.
  • DNA base oxidation increased with Ad, Mn, and iron.
  • Cell viability decreased with AdC or Ad plus Mn, even without iron, indicating a non-DNA oxidative damage mechanism.
  • AdC or Ad pre-incubated with Mn reduced mRNA synthesis in a dose-dependent manner, demonstrating transcriptional inhibition.

Conclusions:

  • Manganese disrupts neuronal function through catecholamine oxidation.
  • The primary mechanism involves Mn-induced catecholamine oxidation leading to transcriptional inhibition.
  • This study reveals a novel pathway for Mn neurotoxicity independent of direct oxidative DNA damage.
Keywords:
AminochromeManganeseNeurotoxicityTranscription

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