Human Ipsc-Based Signaling Disruption Reporter Assay for Teratogenic Toxicity of Chemicals

Abstract

The number of man-made chemicals has increased exponentially in recent decades, and some of them induce foetal malformations. Because complex and precisely programmed signaling pathways play important roles in developmental processes, their disruption by external chemicals often triggers developmental toxicity. However, highly accurate and high-throughput screening assays for the teratogenic potential of various chemicals are currently lacking. In this study, we propose a reporter assay that utilises human induced pluripotent stem cells (iPSCs) to detect changes in fibroblast growth factor signaling, which is essential for limb morphogenesis. The dynamics of this signaling after an exposure to a chemical were integrated to estimate the degree of signaling disruption, which afforded a good prediction of the capacity of chemicals listed in the ECVAM International Validation Study to induce limb malformation. Our results indicate that the human iPSC-based signaling disruption assay could be useful for the initial screening of potentially teratogenic chemicals.