The use of embryonic stem cells for developmental toxicity testing

Congenital abnormalities represent a severe problem, given that approximately 3% of all human newborns are affected. About 20% of these defects are associated with gene mutations and another 5% with chromosomal aberrations. Approximately 5-10% of the remaining abnormalities are known to be caused by teratogenic agents. It is thus mandatory in toxicological safety assessment of chemicals and drugs to evaluate adverse effects on reproduction and embryonic development according to certain OECD test guidelines or so-called segment studies encompassing three crucial periods of pre- and postnatal development and fertility (ICH, 1993). All of these guidelines generally specify time-consuming and expensive in vivo experiments mostly performed with mammalian species such as rats or rabbits. The implementation of the new chemical legislation REACH adopted in the European Union is expected to create a dramatic increase in the number of toxicological studies that rely on animal experimentation. It has been estimated that reproductive and developmental toxicity testing alone would account for approximately 60% of all animals used for safety assessments under REACH. Thus, for both economical and ethical reasons there is a global demand for alternatives to living mammals in testing of chemical-induced adverse effects on reproduction and development. Over the past 30 years, a wide spectrum of in vitro models has been developed to detect teratogenic effects of chemicals. These test systems either utilize dissociated cells from limb buds and brains of rat embryos (micromass test) or whole embryos of frogs (Frog Embryo Teratogenesis Assay-Xenopus (FETAX)) and rats (whole embryo culture test). In recent years, embryonic stem (ES) cells became more important and shifted into focus. The ability to differentiate into a wide range of different cell types has made ES cells a popular system to study gene function and developmental processes during differentiation in vitro. For instance, the embryonic stem cell test (EST) established by Spielmann et al. (1997), makes use of this capacity to detect developmental toxicants during stem cell differentiation into cardiomyocytes. Currently, many research groups are committed to propose and to work-out additional murine and human stem cell based approaches to discover predictive biomarkers of developmental toxicity. An overview of the current activities in this field will be presented.