title: Role of nitric oxide in the genotoxic response to chronic microcystin-LR exposure in human-hamster hybrid cells.
abstract: Microcystin-LR (MC-LR) is the most abundant and toxic microcystin congener and has been classified as a potential human carcinogen (Group 2B) by the International Agency for Research on Cancer. However, the mechanisms underlying the genotoxic effects of MC-LR during chronic exposure are still poorly understood. In the present study, human-hamster hybrid (AL) cells were exposed to MC-LR for varying lengths of time to investigate the role of nitrogen radicals in MC-LR-induced genotoxicity. The mutagenic potential at the CD59 locus was more than 2-fold higher (p<0.01) in AL cells exposed to a cytotoxic concentration (1 μmol/L) of MC-LR for 30 days than in untreated control cells, which was consistent with the formation of micronucleus. MC-LR caused a dose-dependent increase in nitric oxide (NO) production in treated cells. Moreover, this was blocked by concurrent treatment with the NO synthase inhibitor NG-methyl-L-arginine (L-NMMA), which suppressed MC-LR-induced mutations as well. The survival of mitochondrial DNA-depleted (ρ0) AL cells was markedly decreased by MC-LR treatment compared to that in AL cells, while the CD59 mutant fraction was unaltered. These results provided clear evidence that the genotoxicity associated with chronic MC-LR exposure in mammalian cells was mediated by NO and might be considered as a basis for the development of therapeutics that prevent carcinogenesis.
authors.affiliation: Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui, China; Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui, China. Electronic address: wxf1985@mail.ustc.edu.cn.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui, China. Electronic address: peih84@163.com.
authors.forename: Pei
authors.initials: P
authors.lastname: Huang
authors.affiliation: Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Du
authors.affiliation: Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui, China.
authors.forename: Xinan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui, China.
authors.forename: Meimei
authors.initials: M
authors.lastname: Wang
authors.affiliation: Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui, China.
authors.forename: Yichen
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Radiological Research, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Tom K
authors.initials: TK
authors.lastname: Hei
authors.affiliation: Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Wu
authors.affiliation: Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui, China. Electronic address: anxu@ipp.ac.cn.
authors.forename: An
authors.initials: A
authors.lastname: Xu
mesh_terms: D000818:Animals; D006224:Cricetinae; D004249:DNA Damage / Q000187:drug effects*; D006801:Humans; D006825:Hybridomas / Q000187:drug effects*; D008387:Marine Toxins; D052998:Microcystins / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D009569:Nitric Oxide / Q000378:metabolism*
chemical_list: D008387:Marine Toxins; D052998:Microcystins; D009569:Nitric Oxide; C057862:cyanoginosin LR
keywords: Chronic exposure; Genotoxicity; Microcystin-LR (MC-LR); Nitric oxide