Integrated fibroblast growth factor signal disruptions in human iPS cells for prediction of teratogenic toxicity of chemicals

Abstract

The number of man-made chemicals has increased rapidly in recent decades, with certain chemicals potentially causing malformations in fetuses. Although the toxicities of chemicals have been tested in animals, chemicals that are not teratogenic in rodents can cause severe malformations in humans, owing to the differences in the susceptibility to the teratogenicity of chemicals among species. One possible cause of such species differences, other than pharmacokinetics, could be the difference in sensitivity to such chemicals at the cellular level. Therefore, a human cell-based high-throughput assay system is needed for detecting potential teratogenic chemicals. In this study, we proposed a signal reporter assay using human induced pluripotent stem cells (iPSCs). Because developmental processes are governed by highly intricate and precisely programmed signaling pathways, external chemical-induced disruption of these pathways often triggers developmental toxicities. The reporter assay using hiPSCs was used to detect changes in the fibroblast growth factor (FGF) signaling pathway, a pathway essential for limb morphogenesis. The method was based on monitoring and time-accumulation of the signal disruption over time, rather than the classical endpoint detection of the signal disruption. This approach was useful for detecting signal disruptions caused by the malformation chemicals listed in the ICH S5 guideline, including thalidomide. The human iPSC-based signal disruption assay could be a promising tool for the initial screening of developmental toxicants.

Keywords: Fibroblast growth factor; Pluripotent stem cells; Signal disruption; Signal reporter assay; Teratogenicity.