Title:A Transcriptomics Study to Elucidate the Toxicological Mechanism of Methylmercury Chloride in a Human Stem Cell Based In Vitro Test
VOLUME: 19 ISSUE: 36
Author(s):K. Vojnits, R. Ensenat-Waser, J. A. Gaspar, K. Meganathan, S. Jagtap, J. Hescheler, A. Sachinidis and S. Bremer-Hoffmann
Affiliation:European Commission Joint Research Centre (JRC), Institute for Health and Consumer Protection (IHCP) Systems Toxicology Unit, EURL-ECVAM, TP 580, Via Fermi 2749, 21027 Ispra, Italy.
Keywords:Biomarker identification, stem cells, In vitro toxicity test, methymercury chloride, molecular pathways, neuronal precursor
differentiation, ESNATS
Abstract:Traditional approaches in evaluating the hazard of drug candidates on the developing offspring are often time-consuming and
cost-intensive. Moreover, variations in the toxicological response of different animal species to the tested substance cause severe
problems when extrapolating safety dosages for humans. Therefore, more predictive and relevant toxicological systems based on human
cell models are required. In the presented study the environmental toxicant methylmercury chloride (MeHgCl), known to cause structural
developmental abnormalities in the brain, was used as reference compound to develop a concept contributing to a mechanistic
understanding of the toxicity of an investigated substance. Despite the fact, that there are significant data available from animal studies
and from poisonings in Japan and Iraq, uncertainties on the mechanism of MeHgCl during human development are still remaining and
qualify the substance for further analysis. Transcriptomics analysis in combination with a human cell based in vitro model has been used
in order to elucidate the toxicity of MeHgCl at molecular level. Differentiating neural precursor cells that have been exposed
continuously to non- and low-cytotoxic concentrations of MeHgCl were investigated. Quantitative change in the mRNA expression
profiles of selected genes demonstrated the sensitivity of the cell model 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 toxicants.
