caa a22 4500 445853182 CHVBK 20180317145419.0 cr unu---uuuuu 170323e20111201xx s 000 0 eng 10.1007/s00204-011-0716-z doi (NATIONALLICENCE)springer-10.1007/s00204-011-0716-z Genotoxic effects of the cyanobacterial hepatotoxin cylindrospermopsin in the HepG2 cell line [Elektronische Daten] [Alja Štraser, Metka Filipič, Bojana Žegura] The cyanobacterial alkaloid cylindrospermopsin (CYN) is being increasingly identified in drinking water supplies worldwide. It is a potent protein synthesis inhibitor and causes human intoxications and animal mortality. The few genotoxicity studies available indicate that CYN is genotoxic, generally implying that it is pro-genotoxic. We evaluated CYN genotoxicity in the human hepatoma cell line, HepG2, analyzing the induction of DNA strand breaks, with the alkaline comet assay, and micronuclei (MNi), nuclear bud (NBUD), and nucleoplasmic bridge (NPB) formation, with the cytokinesis block micronucleus (CBMN) assay. In addition, changes in the expression of genes involved in the response to DNA damage (P53, CDKN1A, GADD45α, and MDM2) and genes presumably involved in CYN metabolism (genes from the Cytochrome P450 family: CYP1A1 and CYP1A2) were determined, using quantitative real-time PCR. Non-cytotoxic concentrations of CYN induced increased DNA damage after 12 and 24h of exposure and increased the frequency of MNi, NBUDs, and NPBs after 24h exposure. Moreover, CYN up-regulated the expression of the CYP1A1 and CYP1A2 genes. Although no changes in the expression of the P53 tumor-suppressor gene were found, CYN up-regulated the expression of the P53 downstream-regulated genes CDKN1A, GADD45α, and MDM2. Our results provide new evidence that CYN is genotoxic and strongly suggest that it needs to be considered in the human health risk assessment. Springer-Verlag, 2011 Cylindrospermopsin nationallicence DNA damage nationallicence Micronucleus nationallicence Nuclear bud nationallicence Nucleoplasmic bridge nationallicence Gene expression nationallicence BaP : Benzo[a]pyrene nationallicence BNC : Binucleated cells nationallicence CYN : Cylindrospermopsin nationallicence CYP450 : Cytochrome p-450 nationallicence CBMN : Cytokinesis block micronucleus assay nationallicence MNed : Micronucleated nationallicence MNi : Micronuclei nationallicence MTT : 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide nationallicence NDI : Nuclear division index nationallicence NBUD : Nuclear bud nationallicence NPB : Nucleoplasmic bridge nationallicence Štraser Alja Department for Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000, Ljubljana, Slovenia aut Filipič Metka Department for Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000, Ljubljana, Slovenia aut Žegura Bojana Department for Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000, Ljubljana, Slovenia aut Archives of Toxicology Springer-Verlag 85/12(2011-12-01), 1617-1626 0340-5761 85:12<1617 2011 85 204 https://doi.org/10.1007/s00204-011-0716-z text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00204-011-0716-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Štraser Alja Department for Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000, Ljubljana, Slovenia aut NATIONALLICENCE 700 1- Filipič Metka Department for Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000, Ljubljana, Slovenia aut NATIONALLICENCE 700 1- Žegura Bojana Department for Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000, Ljubljana, Slovenia aut NATIONALLICENCE 773 0- Archives of Toxicology Springer-Verlag 85/12(2011-12-01), 1617-1626 0340-5761 85:12<1617 2011 85 204 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer