Imke Pieper, Christoph A. Wehe, Julia Bornhorst, Franziska Ebert, Larissa Leffers, Michael Holtkamp, Pia Höseler, Till Weber, Aswin Mangerich, Alexander Bürkle, Uwe Karst, Tanja Schwerdtle
- 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.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.…
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MetadatenAuthor details: | Imke Pieper, Christoph A. Wehe, Julia BornhorstORCiDGND, Franziska EbertORCiDGND, Larissa Leffers, Michael Holtkamp, Pia Höseler, Till Weber, Aswin MangerichORCiDGND, Alexander Bürkle, Uwe Karst, Tanja SchwerdtleORCiDGND |
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DOI: | https://doi.org/10.1039/c3mt00337j |
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ISSN: | 1756-591X |
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ISSN: | 1756-5901 |
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Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/24549367 |
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Title of parent work (English): | Metallomics : integrated biometal science |
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Subtitle (English): | genotoxicity and DNA-damage response |
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Publisher: | Royal Society of Chemistry |
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Place of publishing: | Cambridge |
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Publication type: | Article |
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Language: | English |
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Date of first publication: | 2014/02/03 |
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Publication year: | 2014 |
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Publishing institution: | Universität Potsdam |
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Release date: | 2015/03/25 |
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Tag: | adduct formation; cell-death; exposure; manganese; methylmercury; neurodegenerative diseases; neurotoxicity; poly(ADP-ribose) polymerase-1; repair; thimerosal |
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Volume: | 2014 |
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Issue: | 6 |
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Number of pages: | 10 |
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First page: | 662 |
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Last Page: | 671 |
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Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft |
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DDC classification: | 5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften |
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Peer review: | Referiert |
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Publishing method: | Open Access |
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Grantor: | RSC |
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License (English): | Creative Commons - Namensnennung 3.0 Unported |
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External remark: | Zweitveröffentlichung als Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe ; 171 |
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