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
38305
2014
2014
eng
662
671
10
3
6
article
Royal Society of Chemistry
Cambridge
1
--
--
--
Mechanisms of Hg species induced toxicity in cultured human astrocytes: genotoxicity and 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.
Metallomics : integrated biometal science
10.1039/c3mt00337j
24549367
1756-5901
1756-591X
wos:2014
WOS:000333565800028
Schwerdtle, T (reprint author), Univ Munster, Inst Food Chem, Corrensstr 45, D-48149 Munster, Germany., Tanja.Schwerdtle@uni-potsdam.de
Imke Pieper
Christoph A. Wehe
Julia Bornhorst
Franziska Ebert
Larissa Leffers
Michael Holtkamp
Pia Hoeseler
Till Weber
Aswin Mangerich
Alexander Buerkle
Uwe Karst
Tanja Schwerdtle
Institut für Ernährungswissenschaft
Referiert
38016
2014
2014
eng
1909
1916
8
7
406
article
Springer
Heidelberg
1
--
--
--
On-line species-unspecific isotope dilution analysis in the picomolar range reveals the time- and species-depending mercury uptake in human astrocytes
In order to reveal the time-depending mercury species uptake by human astrocytes, a novel approach for total mercury analysis is presented, which uses an accelerated sample introduction system combined on-line with an inductively coupled plasma mass spectrometer equipped with a collision/reaction cell. Human astrocyte samples were incubated with inorganic mercury (HgCl2), methylmercury chloride (MeHgCl), and thimerosal. After 1-h incubation with Hg2+, cellular concentrations of 3 mu M were obtained, whereas for organic species, concentrations of 14-18 mu M could be found. After 24 h, a cellular accumulation factor of 0.3 was observed for the cells incubated with Hg2+, whereas the organic species both showed values of about 5. Due to the obtained steady-state signals, reliable results with relative standard deviations of well below 5 % and limits of detection in the concentration range of 1 ng L-1 were obtained using external calibration and species-unspecific isotope dilution analysis approaches. The results were further validated using atomic fluorescence spectrometry.
Analytical & bioanalytical chemistry
10.1007/s00216-013-7608-4
24442014
1618-2642
1618-2650
wos:2014
WOS:000333111700013
Karst, U (reprint author), Univ Munster, Inst Inorgan & Analyt Chem, Corrensstr 28-30, D-48149 Munster, Germany., uk@uni-muenster.de
Christoph A. Wehe
Imke Pieper
Michael Holtkamp
Georgina M. Thyssen
Michael Sperling
Tanja Schwerdtle
Uwe Karst
eng
uncontrolled
Mercury
eng
uncontrolled
Thimerosal
eng
uncontrolled
Astrocytes
eng
uncontrolled
ICP-MS
eng
uncontrolled
Isotope dilution analysis
eng
uncontrolled
Automation
Institut für Biochemie und Biologie
Referiert