title: Toxicological properties of the thiolated inorganic arsenic and arsenosugar metabolite thio-dimethylarsinic acid in human bladder cells.
abstract: Thio-dimethylarsinic acid (thio-DMA(V)) has recently been identified as human metabolite after exposure toward both the human carcinogen inorganic arsenic and arsenosugars, which are the major arsenical constituents of marine algae. This study aims to get further insight in the toxic modes of action of thio-DMA(V) in cultured human urothelial cells. Among others effects of thio-DMA(V) on eight cell death related endpoints, cell cycle distribution, genotoxicity, cellular bioavailability as well as for the first time its impact on DNA damage induced poly(ADP-ribosyl)ation were investigated and compared to effects induced by arsenite. The data indicate that thio-DMA(V) exerts its cellular toxicity in a similar or even lower concentration range, however most likely via different mechanisms, than arsenite. Most interestingly, thio-DMA(V) decreased damage-induced cellular poly(ADP-ribosyl)ation by 35,000-fold lower concentrations than arsenite. The inhibition of this essential DNA-damage induced and DNA-repair related signaling reaction might contribute to inorganic arsenic induced toxicity, at least in the bladder. Therefore, and also because thio-DMA(V) is to date by far the most toxic human metabolite identified after arsenosugar intake, thio-DMA(V) should contemporary be fully (also in vivo) toxicologically characterized, to assess risks to human health related to inorganic arsenic but especially arsenosugar dietary intake.
authors.affiliation: Institute of Food Chemistry, University of Muenster, Corrensstraße 45, 48149 Muenster, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Ebert
authors.affiliation: Institute of Food Chemistry, University of Muenster, Corrensstraße 45, 48149 Muenster, Germany; Graduate School of Chemistry, University of Muenster, Wilhelm-Klemm-Straße 10, 48149 Muenster, Germany.
authors.forename: Larissa
authors.initials: L
authors.lastname: Leffers
authors.affiliation: Institute of Food Chemistry, University of Muenster, Corrensstraße 45, 48149 Muenster, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Weber
authors.affiliation: Institute of Food Chemistry, University of Muenster, Corrensstraße 45, 48149 Muenster, Germany.
authors.forename: Svenia
authors.initials: S
authors.lastname: Berndt
authors.affiliation: Molecular Toxicology Group, Department of Biology, University of Konstanz, Universitaetsstraße 10, 78464 Konstanz, Germany.
authors.forename: Aswin
authors.initials: A
authors.lastname: Mangerich
authors.affiliation: Institute of Veterinary Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 260, 8057 Zurich, Switzerland.
authors.forename: Sascha
authors.initials: S
authors.lastname: Beneke
authors.affiliation: Molecular Toxicology Group, Department of Biology, University of Konstanz, Universitaetsstraße 10, 78464 Konstanz, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bürkle
authors.affiliation: Institute of Food Chemistry, University of Muenster, Corrensstraße 45, 48149 Muenster, Germany; Graduate School of Chemistry, University of Muenster, Wilhelm-Klemm-Straße 10, 48149 Muenster, Germany. Electronic address: Tanja.Schwerdtle@uni-muenster.de.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schwerdtle
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001149:Arsenates / Q000378:metabolism* / Q000633:toxicity*; D001151:Arsenic / Q000633:toxicity*; D001152:Arsenicals; D001682:Biological Availability; D002101:Cacodylic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D053143:Caspase 2 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation; D006026:Glycoside Hydrolases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D009005:Monosaccharides / Q000378:metabolism* / Q000633:toxicity*; D009243:NAD / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000633:toxicity*; D001743:Urinary Bladder / Q000187:drug effects* / Q000473:pathology*; D000097642:GADD45 Proteins
chemical_list: D000246:Adenosine Diphosphate Ribose; D001149:Arsenates; D001151:Arsenic; D001152:Arsenicals; D002101:Cacodylic Acid; D053143:Caspase 2; D018797:Cell Cycle Proteins; D006026:Glycoside Hydrolases; D006861:Hydrogen Peroxide; D009005:Monosaccharides; D009243:NAD; D009687:Nuclear Proteins; D011065:Poly(ADP-ribose) Polymerases; D011994:Recombinant Proteins; D013438:Sulfhydryl Compounds; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C449161:arsenosugar; C523062:thio-dimethylarsinate; C022407:poly ADP-ribose glycohydrolase
keywords: Arsenite; Cellular bioavailability; Genotoxicity; Poly(ADP-ribosyl)ation; Thio-dimethylarsinic acid