Molecular mechanisms of Mn induced neurotoxicity: RONS generation, genotoxicity, and DNA-damage response
Article first published online: 14 MAR 2013
© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Molecular Nutrition & Food Research
Volume 57, Issue 7, pages 1255–1269, July 2013
How to Cite
Bornhorst, J., Meyer, S., Weber, T., Böker, C., Marschall, T., Mangerich, A., Beneke, S., Bürkle, A. and Schwerdtle, T. (2013), Molecular mechanisms of Mn induced neurotoxicity: RONS generation, genotoxicity, and DNA-damage response. Mol. Nutr. Food Res., 57: 1255–1269. doi: 10.1002/mnfr.201200758
- Issue published online: 1 JUL 2013
- Article first published online: 14 MAR 2013
- Manuscript Accepted: 23 JAN 2013
- Manuscript Revised: 14 JAN 2013
- Manuscript Received: 14 NOV 2012
- Graduate School of Chemistry
- Infant formula;
- Oxidative stress;
In industrial countries dietary manganese (Mn) intake is well above the estimated average requirement. Moreover, exposure to high Mn levels is known to cause adverse neurological effects in humans, which are yet mechanistically not well understood.
Methods and results
This study aimed to identify early modes of action of Mn induced toxicity in mammalian brain cells. In primary porcine brain capillary endothelial cells induction of reactive oxygen and nitrogen species was identified as the most sensitive endpoint (≥0.5 μM MnCl2). In cultured human astrocytes MnCl2 was rapidly bioavailable, induced a slight increase of cellular reactive oxygen and nitrogen species levels and a slight decrease of ATP levels (1–100 μM MnCl2), while no genotoxic effects were observed. However, MnCl2 (≥1 μM) efficiently disturbed DNA-damage-induced poly(ADP-ribosyl)ation in human astrocytes, which indicates sensitization of cells to genotoxic treatment. Additionally, we determined Mn levels in infant formula, which are generally massively supplemented with Mn and thus might pose an important source for Mn overexposure.
The observed inhibition of DNA-damage-induced poly(ADP-ribosyl)ation in human astrocytes by exposure-relevant Mn concentrations indicate that in terms of Mn the existing guidelines for infant formula but also drinking water should be critically reconsidered.