TY - JOUR A1 - Pieper, Imke A1 - Wehe, Christoph A. A1 - Bornhorst, Julia A1 - Ebert, Franziska A1 - Leffers, Larissa A1 - Holtkamp, Michael A1 - Höseler, Pia A1 - Weber, Till A1 - Mangerich, Aswin A1 - Bürkle, Alexander A1 - Karst, Uwe A1 - Schwerdtle, Tanja T1 - Mechanisms of Hg species induced toxicity in cultured human astrocytes BT - genotoxicity and DNA-damage response JF - Metallomics N2 - The toxicologically most relevant mercury (Hg) species for human exposure is methylmercury (MeHg). Thiomersal is a common preservative used in some vaccine formulations. The aim of this study is to get further mechanistic insight into the yet not fully understood neurotoxic modes of action of organic Hg species. Mercury species investigated include MeHgCl and thiomersal. Additionally HgCl2 was studied, since in the brain mercuric Hg can be formed by dealkylation of the organic species. As a cellular system astrocytes were used. In vivo astrocytes provide the environment necessary for neuronal function. In the present study, cytotoxic effects of the respective mercuricals increased with rising alkylation level and correlated with their cellular bioavailability. Further experiments revealed for all species at subcytotoxic concentrations no induction of DNA strand breaks, whereas all species massively increased H2O2-induced DNA strand breaks. This co-genotoxic effect is likely due to a disturbance of the cellular DNA damage response. Thus, at nanomolar, sub-cytotoxic concentrations, all three mercury species strongly disturbed poly(ADP-ribosyl)ation, a signalling reaction induced by DNA strand breaks. Interestingly, the molecular mechanism behind this inhibition seems to be different for the species. Since chronic PARP-1 inhibition is also discussed to sacrifice neurogenesis and learning abilities, further experiments on neurons and in vivo studies could be helpful to clarify whether the inhibition of poly(ADP-ribosyl)ation contributes to organic Hg induced neurotoxicity. KW - cell-death KW - poly(ADP-ribose) polymerase-1 KW - neurodegenerative diseases KW - adduct formation KW - thimerosal KW - methylmercury KW - repair KW - neurotoxicity KW - manganese KW - exposure Y1 - 2014 U6 - https://doi.org/10.1039/c3mt00337j SN - 1756-591X SN - 1756-5901 VL - 2014 IS - 6 SP - 662 EP - 671 ER - TY - GEN A1 - Pieper, Imke A1 - Wehe, Christoph A. A1 - Bornhorst, Julia A1 - Ebert, Franziska A1 - Leffers, Larissa A1 - Holtkamp, Michael A1 - Höseler, Pia A1 - Weber, Till A1 - Mangerich, Aswin A1 - Bürkle, Alexander A1 - Karst, Uwe A1 - Schwerdtle, Tanja T1 - Mechanisms of Hg species induced toxicity in cultured human astrocytes BT - genotoxicity and DNA-damage response N2 - The toxicologically most relevant mercury (Hg) species for human exposure is methylmercury (MeHg). Thiomersal is a common preservative used in some vaccine formulations. The aim of this study is to get further mechanistic insight into the yet not fully understood neurotoxic modes of action of organic Hg species. Mercury species investigated include MeHgCl and thiomersal. Additionally HgCl2 was studied, since in the brain mercuric Hg can be formed by dealkylation of the organic species. As a cellular system astrocytes were used. In vivo astrocytes provide the environment necessary for neuronal function. In the present study, cytotoxic effects of the respective mercuricals increased with rising alkylation level and correlated with their cellular bioavailability. Further experiments revealed for all species at subcytotoxic concentrations no induction of DNA strand breaks, whereas all species massively increased H2O2-induced DNA strand breaks. This co- genotoxic effect is likely due to a disturbance of the cellular DNA damage response. Thus, at nanomolar, sub-cytotoxic concentrations, all three mercury species strongly disturbed poly(ADP-ribosyl)ation, a signalling reaction induced by DNA strand breaks. Interestingly, the molecular mechanism behind this inhibition seems to be different for the species. Since chronic PARP-1 inhibition is also discussed to sacrifice neurogenesis and learning abilities, further experiments on neurons and in vivo studies could be helpful to clarify whether the inhibition of poly(ADP-ribosyl) ation contributes to organic Hg induced neurotoxicity. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - paper 171 KW - adduct formation KW - cell-death KW - exposure KW - manganese KW - methylmercury KW - neurodegenerative diseases KW - neurotoxicity KW - poly(ADP-ribose) polymerase-1 KW - repair KW - thimerosal Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-74379 SP - 662 EP - 671 ER -