7623
2014
2014
eng
456
464
postprint
1
2015-04-29
2014-05-30
--
Toxicity of arsenite and thio-DMAV after long-term (21 days) incubation of human urothelial cells: cytotoxicity, genotoxicity and epigenetics
This study aims to further mechanistically understand toxic modes of action after chronic inorganic arsenic exposure. Therefore long-term incubation studies in cultured cells were carried out, to display chronically attained changes, which cannot be observed in the generally applied in vitro short-term incubation studies. Particularly, the cytotoxic, genotoxic and epigenetic effects of an up to 21 days incubation of human urothelial (UROtsa) cells with pico- to nanomolar concentrations of iAsIII and its metabolite thio-DMAV were compared. After 21 days of incubation, cytotoxic effects were strongly enhanced in the case of iAsIII and might partly be due to glutathione depletion and genotoxic effects on the chromosomal level. These results are in strong contrast to cells exposed to thio-DMAV. Thus, cells seemed to be able to adapt to this arsenical, as indicated among others by an increase in the cellular glutathione level. Most interestingly, picomolar concentrations of both iAsIII and thio-DMAV caused global DNA hypomethylation in UROtsa cells, which was quantified in parallel by 5-medC immunostaining and a newly established, reliable, high resolution mass spectrometry (HRMS)-based test system. This is the first time that epigenetic effects are reported for thio-DMAV; iAsIII induced epigenetic effects occur in at least 8000 fold lower concentrations as reported in vitro before. The fact that both arsenicals cause DNA hypomethylation at really low, exposure-relevant concentrations in human urothelial cells suggests that this epigenetic effect might contribute to inorganic arsenic induced carcinogenicity, which for sure has to be further investigated in future studies.
urn:nbn:de:kobv:517-opus4-76239
online registration
Au-006423
The Royal Society of Chemistry, 2014, 3, 456–464. DOI: 10.1039/C4TX00036F
<a href="http://publishup.uni-potsdam.de/opus4-ubp/frontdoor/index/index/docId/7622">Bibliographieeintrag der Originalveröffentlichung/Quelle</a>
Marlies Unterberg
Larissa Leffers
Florian Hübner
Hans-Ulrich Humpf
Konstantin Lepikhov
Jörn Walter
Franziska Ebert
Tanja Schwerdtle
Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
178
eng
uncontrolled
induced malignant-transformation
eng
uncontrolled
genomic dna methylation
eng
uncontrolled
vitro toxicological characterization
eng
uncontrolled
thio-dimethylarsinic acid
eng
uncontrolled
bladder-cancer
eng
uncontrolled
methyltransferases dnmt3a
eng
uncontrolled
cytosine methylation
eng
uncontrolled
carcinogen exposure
eng
uncontrolled
mass-spectrometry
eng
uncontrolled
gene-expression
Chemie und zugeordnete Wissenschaften
open_access
Institut für Chemie
Referiert
Open Access
Universität Potsdam
https://publishup.uni-potsdam.de/files/7623/pmnr178.pdf
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