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Molecular mechanisms of Mn induced neurotoxicity: RONS generation, genotoxicity, and DNA-damage response


Bornhorst, Julia; Meyer, Sören; Weber, Till; Böker, Carolina; Marschall, Talke; Mangerich, Aswin; Beneke, Sascha; Bürkle, Alexander; Schwerdtle, Tanja (2013). Molecular mechanisms of Mn induced neurotoxicity: RONS generation, genotoxicity, and DNA-damage response. Molecular Nutrition & Food Research, 57(7):1255-1269.

Abstract

SCOPE: 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.

CONCLUSION: 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.

Abstract

SCOPE: 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.

CONCLUSION: 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Veterinary Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
Date:2013
Deposited On:27 Jan 2014 11:39
Last Modified:05 Apr 2016 17:32
Publisher:Wiley-VCH Verlag Berlin
ISSN:1613-4125
Publisher DOI:https://doi.org/10.1002/mnfr.201200758
PubMed ID:23495240

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