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Mechanistic studies on the adverse effects of manganese overexposure in differentiated LUHMES cells

Affiliation
Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Wuppertal, Germany
Nicolai, Merle M.;
Affiliation
Department of Food Chemistry, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
Witt, Barbara;
Affiliation
Department of Food Chemistry, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
Friese, Sharleen;
Affiliation
Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Wuppertal, Germany
Michaelis, Vivien;
Affiliation
Department of Food Chemistry, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
Hölz-Armstrong, Lisa;
Affiliation
Department of Food Chemistry, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
Martin, Maximilian;
Affiliation
Department of Food Chemistry, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
Ebert, Franziska;
ORCID
0000-0002-4873-7488
Affiliation
German Federal Institute for Risk Assessment (BfR), Executive Committee, Berlin, Germany; Department of Food Chemistry, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany; TraceAge DFG Res Unit Interact Essential Trace El, Berlin, Germany
Schwerdtle, Tanja;
Affiliation
Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Wuppertal, Germany
Bornhorst, Julia

Manganese (Mn) is an essential trace element, but overexposure is associated with toxicity and neurological dysfunction. Accumulation of Mn can be observed in dopamine-rich regions of the brain in vivo and Mn-induced oxidative stress has been discussed extensively. Nevertheless, Mn-induced DNA damage, adverse effects of DNA repair, and possible resulting consequences for the neurite network are not yet characterized. For this, LUHMES cells were used, as they differentiate into dopaminergic-like neurons and form extensive neurite networks. Experiments were conducted to analyze Mn bioavailability and cytotoxicity of MnCl₂, indicating a dose-dependent uptake and substantial cytotoxic effects. DNA damage, analyzed by means of 8-oxo-7,8-dihydro-2′-guanine (8oxodG) and single DNA strand break formation, showed significant dose- and time-dependent increase of DNA damage upon 48 h Mn exposure. Furthermore, the DNA damage response was increased which was assessed by analytical quantification of poly(ADP-ribosyl)ation (PARylation). Gene expression of the respective DNA repair genes was not significantly affected. Degradation of the neuronal network is significantly altered by 48 h Mn exposure. Altogether, this study contributes to the characterization of Mn-induced neurotoxicity, by analyzing the adverse effects of Mn on genome integrity in dopaminergic-like neurons and respective outcomes.

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