Delphine Peric: Post-doctoral Fellow (Inserm)
Karine Giraud-Triboult: Associate engineer (CECS)
Aims and background:
In the development of products for human use, it is vital to identify compounds with toxic properties at an early stage, in order to avoid spending time and resources on unsuitable and potentially unsafe candidate products. Nowadays, there is a general agreement that the classical predictive toxicology testing has reached clear limitations, its experimental tools having little changed since the 1920’s when the LD50 test was established. The current working hypothesis is shifting to the paradigm of “toxicity pathways”, defined as normal cellular response pathways that are perturbed by toxicants in a way that results – in a dose-dependent manner – in adverse health effects.
Presently, human pluripotent stem cells (hPSCs) are the most powerful cellular resource to challenge this complete reassessment of the scientific bases and goals of toxicity testing, since they present a unique opportunity to develop a wide variety of human cell-based physiological test systems because they may be expanded indefinitely and triggered to differentiate into any cell type, offering additionally the possibility to represent the human population diversity.
Strategy, means and methods:
Our project relies on the use of hPSCs attributes to develop in vitro cell-based models to explore mechanisms of chronic subacute toxicity and thus contribute to define its related Toxome. For that purpose, we will make use of the biological and technological skills developed at I-Stem by specialized teams and focus on the muscular and keratinocytic lineages. For each these lineage, we will develop a miniaturized model of repeated subacute toxicity over at least 2 weeks and use innovative technologies (omics, HCS …) to identify specific biomarkers. The most relevant biomarker(s) will then be monitored in a functional genomic modifier screen in order to highlight genes regulating its status, thus driving toward the toxicity pathways (Toxome) involved in repeated subacute exposure systems.