A Tanscriptomics Study to Elucidate the Toxicological Mechanism of Methylmercury Chloride in a Human Stem Cell Based In Vitro Test

The developing nervous system is often targeted by xenobiotics but the prediction of human prenatal toxicity is problematic as the concordance among the toxicological responses of different laboratory animal species can be low. This shortcoming in safety assessments might be overcome by the establishment of relevant human cellular models. Here we report for the first time on a reproducible cellular model based on human embryonic stem cells that mimics aspects of human neurulation and as such allows the identification of chemical effects on neural induction during embryogenesis. The reliability and robustness of the model was supported by the establishment of a panel of neural and pluripotency marker genes acting as quality standards. In order to obtain a first insight into the relevance of the model, the test system was challenged with Methylmercury chloride, known to interact with the embryonic development in vivo. Quantitative changes in the mRNA expression profiles demonstrated the sensitivity of the cellular model to detect hazards on the developing offspring and its qualification for a transcriptomics study screening changes in the expression profile of the complete human genome of MeHgCl-treated human neural cells. Potential biomarkers were identified and these candidate marker genes as well as their involvement in a possible toxic mechanism of MeHgCl during the human neurulation process are hereby introduced. The study confirmed the hypothesis that a cellular model based on a human stem cell line can be applied for elucidating unknown mode of actions of developmental toxicantsJRC.I.5-Systems Toxicolog