title: Mechanisms of Hg species induced toxicity in cultured human astrocytes: genotoxicity and DNA-damage response.
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.
authors.affiliation: Institute of Food Chemistry, University of Münster, Corrensstr. 45, 48149 Münster, Germany.
authors.forename: Imke
authors.initials: I
authors.lastname: Pieper
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Wehe
authors.forename: Julia
authors.initials: J
authors.lastname: Bornhorst
authors.forename: Franziska
authors.initials: F
authors.lastname: Ebert
authors.forename: Larissa
authors.initials: L
authors.lastname: Leffers
authors.forename: Michael
authors.initials: M
authors.lastname: Holtkamp
authors.forename: Pia
authors.initials: P
authors.lastname: Höseler
authors.forename: Till
authors.initials: T
authors.lastname: Weber
authors.forename: Aswin
authors.initials: A
authors.lastname: Mangerich
authors.forename: Alexander
authors.initials: A
authors.lastname: Bürkle
authors.forename: Uwe
authors.initials: U
authors.lastname: Karst
authors.forename: Tanja
authors.initials: T
authors.lastname: Schwerdtle
mesh_terms: D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D053960:DNA Breaks / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008767:Methylmercury Compounds / Q000633:toxicity*; D009153:Mutagens / Q000633:toxicity*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000032:analysis / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013849:Thimerosal / Q000633:toxicity*
chemical_list: D008767:Methylmercury Compounds; D009153:Mutagens; D013849:Thimerosal; D011064:Poly Adenosine Diphosphate Ribose; D006861:Hydrogen Peroxide; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases