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Major changes of cell function and toxicant sensitivity in cultured cells undergoing mild, quasi-natural genetic drift.
Gutbier, Simon; May, Patrick; Berthelot, Sylvie; Krishna, Abhimanyu; Trefzer, Timo; Behbehani, Mehri; Efremova, Liudmila; Delp, Johannes; Gstraunthaler, Gerhard; Waldmann, Tanja; Leist, Marcel.
Afiliação
  • Gutbier S; Department for in vitro toxicology and biomedicine (Doerenkamp-Zbinden chair), University of Konstanz, PO Box M657, 78457, Konstanz, Germany.
  • May P; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
  • Berthelot S; Department for in vitro toxicology and biomedicine (Doerenkamp-Zbinden chair), University of Konstanz, PO Box M657, 78457, Konstanz, Germany.
  • Krishna A; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
  • Trefzer T; Department for in vitro toxicology and biomedicine (Doerenkamp-Zbinden chair), University of Konstanz, PO Box M657, 78457, Konstanz, Germany.
  • Behbehani M; Department for in vitro toxicology and biomedicine (Doerenkamp-Zbinden chair), University of Konstanz, PO Box M657, 78457, Konstanz, Germany.
  • Efremova L; Department for in vitro toxicology and biomedicine (Doerenkamp-Zbinden chair), University of Konstanz, PO Box M657, 78457, Konstanz, Germany.
  • Delp J; Department for in vitro toxicology and biomedicine (Doerenkamp-Zbinden chair), University of Konstanz, PO Box M657, 78457, Konstanz, Germany.
  • Gstraunthaler G; Division of Physiology, Innsbruck Medical University, Schöpfstraße 41/1, 6020, Innsbruck, Austria.
  • Waldmann T; Department for in vitro toxicology and biomedicine (Doerenkamp-Zbinden chair), University of Konstanz, PO Box M657, 78457, Konstanz, Germany.
  • Leist M; Department for in vitro toxicology and biomedicine (Doerenkamp-Zbinden chair), University of Konstanz, PO Box M657, 78457, Konstanz, Germany. Marcel.Leist@uni-konstanz.de.
Arch Toxicol ; 92(12): 3487-3503, 2018 12.
Article em En | MEDLINE | ID: mdl-30298209
Genomic drift affects the functional properties of cell lines, and the reproducibility of data from in vitro studies. While chromosomal aberrations and mutations in single pivotal genes are well explored, little is known about effects of minor, possibly pleiotropic, genome changes. We addressed this question for the human dopaminergic neuronal precursor cell line LUHMES by comparing two subpopulations (SP) maintained either at the American-Type-Culture-Collection (ATCC) or by the original provider (UKN). Drastic differences in susceptibility towards the specific dopaminergic toxicant 1-methyl-4-phenylpyridinium (MPP+) were observed. Whole-genome sequencing was performed to identify underlying genetic differences. While both SP had normal chromosome structures, they displayed about 70 differences on the level of amino acid changing events. Some of these differences were confirmed biochemically, but none offered a direct explanation for the altered toxicant sensitivity pattern. As second approach, markers known to be relevant for the intended use of the cells were specifically tested. The "ATCC" cells rapidly down-regulated the dopamine-transporter and tyrosine-hydroxylase after differentiation, while "UKN" cells maintained functional levels. As the respective genes were not altered themselves, we conclude that polygenic complex upstream changes can have drastic effects on biochemical features and toxicological responses of relatively similar SP of cells.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: 1-Metil-4-fenilpiridínio / Deriva Genética / Neurônios Dopaminérgicos / Sequenciamento Completo do Genoma Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Humans Idioma: En Revista: Arch Toxicol Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: 1-Metil-4-fenilpiridínio / Deriva Genética / Neurônios Dopaminérgicos / Sequenciamento Completo do Genoma Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Humans Idioma: En Revista: Arch Toxicol Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Alemanha