7436
2014
2014
eng
662
671
10
6
2014
article
1
--
2014-02-03
--
Mechanisms of Hg species induced toxicity in cultured human astrocytes
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.
Metallomics
genotoxicity and DNA-damage response
10.1039/c3mt00337j
1756-591X
1756-5901
online registration
Au-006613
<a href="http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-74379">Zweitveröffentlichung als Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe ; 171</a>
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
eng
uncontrolled
cell-death
eng
uncontrolled
poly(ADP-ribose) polymerase-1
eng
uncontrolled
neurodegenerative diseases
eng
uncontrolled
adduct formation
eng
uncontrolled
thimerosal
eng
uncontrolled
methylmercury
eng
uncontrolled
repair
eng
uncontrolled
neurotoxicity
eng
uncontrolled
manganese
eng
uncontrolled
exposure
Chemie und zugeordnete Wissenschaften
Institut für Chemie
Referiert
Open Access
RSC
Universität Potsdam
7437
2014
2014
eng
662
671
10
postprint
1
2015-03-25
2014-02-03
--
Mechanisms of Hg species induced toxicity in cultured human astrocytes
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.
genotoxicity and DNA-damage response
urn:nbn:de:kobv:517-opus4-74379
online registration
Au-006613
Metallomics (2014) 6, S. 662-671. - DOI: 10.1039/c3mt00337j
<a href="http://publishup.uni-potsdam.de/opus4-ubp/frontdoor/index/index/docId/7436">Bibliographieeintrag der Originalveröffentlichung/Quelle</a>
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
Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
paper 171
eng
uncontrolled
adduct formation
eng
uncontrolled
cell-death
eng
uncontrolled
exposure
eng
uncontrolled
manganese
eng
uncontrolled
methylmercury
eng
uncontrolled
neurodegenerative diseases
eng
uncontrolled
neurotoxicity
eng
uncontrolled
poly(ADP-ribose) polymerase-1
eng
uncontrolled
repair
eng
uncontrolled
thimerosal
Chemie und zugeordnete Wissenschaften
open_access
Institut für Chemie
Referiert
Open Access
Universität Potsdam
https://publishup.uni-potsdam.de/files/7437/pmnr171.pdf