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Metallomics Vol - 6 Issue - 2

Mechanisms of Hg species induced toxicity in cultured human astrocytes: genotoxicity and DNA-damage response

Content Provider	Royal Society of Chemistry (RSC)
Author	Pieper, Imke Karst, Uwe Bornhorst, Julia Wehe, Christoph A. Ebert, Franziska Leffers, Larissa Höseler, Pia Weber, Till Schwerdtle, Tanja Mangerich, Aswin Bürkle, Alexander Holtkamp, Michael
Copyright Year	2014
Abstract	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.
Starting Page	662
Ending Page	671
Page Count	10
File Format	HTM / HTML PDF
ISSN	17565901
Volume Number	6
Issue Number	3
Journal	Metallomics
DOI	10.1039/c3mt00337j
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	Hydrogen peroxide Thiomersal PARP1 Project Mercury Cytotoxicity Vaccine Astrocyte Bioavailability Neurogenesis Alkylation Neurotoxicity Preservative DNA Methylmercury
Content Type	Text
Resource Type	Article
Subject	Chemistry Medicine Metals and Alloys Biochemistry Biomaterials Biophysics

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