Manganese inhibits poly(ADP-ribosyl)ation in human cells: a possible mechanism behind manganese-induced toxicity?
For humans manganese is both an essential trace element and, at higher doses, a toxic metal. Due to the ubiquitous occurrence of manganese in foodstuff, in industrial countries daily dietary uptake is higher as compared to the estimated daily requirement. Therefore manganese deficiency is extremely rare. In contrast chronic manganese toxicity, affecting primarily the central nervous system, is more prevalent. Thus manganese occupational and dietary overexposure has been shown to cause progressive, permanent, neurodegenerative damage, resulting in syndromes similar to idiopathic Parkinson's disease. To date modes of manganese neurotoxic action are poorly understood and in most studies oxidative stress is postulated as the underlying mechanism. The present study searched on the cellular level for a molecular mechanism behind manganese-induced neurotoxicity and investigated bioavailability, cytotoxicity and genotoxicity of MnCl(2), as well as its impact on the DNA damage response in human cells (HeLa S3) in culture. Whereas up to 10 µM MnCl(2) showed no induction of DNA strand breaks after 24 h incubation, manganese strongly inhibited H(2)O(2)-stimulated poly(ADP-ribosyl)ation at low, completely non-cytotoxic, for certain human exposure, relevant concentrations starting at 1 µM. Thereby inhibition of this essential DNA damage response signalling reaction was not due to a reduced gene expression or protein level of the responsible polymerase PARP-1. Taken together, the results indicate that manganese, under conditions of either overload due to high exposure or disturbed homeostasis, can disturb the cellular response to DNA strand breaks, which has been shown before (S. Katyal and P. J. McKinnon, Mech. Ageing Dev., 2008, 129, 483-491) to result in neurological diseases.
Bornhorst
Julia
J
Graduate School of Chemistry, Westfälische Wilhelms-Universität Münster, 48149, Münster, Germany.
Ebert
Franziska
F
Hartwig
Andrea
A
Michalke
Bernhard
B
Schwerdtle
Tanja
T
D002463:Cell Membrane Permeability; D002470:Cell Survival; D003603:Cytotoxins / Q000378:metabolism / Q000633:toxicity*; D053960:DNA Breaks; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000009:adverse effects; D008345:Manganese / Q000378:metabolism / Q000633:toxicity*; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*
D003603:Cytotoxins; D009153:Mutagens; D008345:Manganese; D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases