First in vitro approaches to address repeat dose long-term toxicity


Prof. Dr. Marcel Leist

Doerenkamp-Zbinden Chair for Alternative in vitro Methods

University of Konstanz, Germany

Project description:

The project was designed to test the hypothesis that many compounds with a different primary mode of action would trigger developmental toxicity by a common mechanism: a change of how the genetic information of a cell is stored and accessed. This is described in scientific terms as 'epigenetic change'. The project uses differentiating pluripotent human stem cells as model system to examine such epigenetic changes. Knowledge of such changes could be used to define new universal endpoints for in vitro toxicity testing, and thereby help to replace animal experiments in the field of reproductive toxicity testing.


Outcome (preliminary; until IV/2013):

Balmer NV, Weng M, Zimmer B, Ivanova VN, Chambers SM, Nikolaeva E, Jagtap S, Sachinidis A, Hescheler J, Waldmann T, Leist M (2012). Epigenetic changes and disturbed neural development in a human embryonic stem cell-based model relating to the fetal valproate syndrome. Hum Mol Genet 21, 4104-4114

Leist M, Lidbury BA, Yang C, Hayden PJ, Kelm JM, Ringeissen S, Detroyer A, Meunier JR, Rathman JF, Jackson GR, Stolper G, Hasiwa N (2012) Novel technologies and an overall strategy to allow hazard assessment and risk prediction of chemicals, cosmetics and drugs with animal-free methods. ALTEX 29, 373-388

Leist M, Hasiwa N, Daneshian M (2013) Summary and validation of new animal-free toxicity tests. ALTEX Proceedings 2, 27-37

Weng M, Zimmer B, Pöltl D, Brög M, Wüllner U, Waldmann T, Leist M (2012). Extensive transcriptional regulation of chromatin modifiers during human neurodevelopment. PlosOne, 7, e36708