Human embryonic stem cells as a model for embryotoxicity screening

Reproductive toxicity encompasses harmful effects of various agents on all aspects and stages of the reproductive cycle, including infertility and the induction of adverse effects in the embryo/fetus. In developing a model for reproductive toxicity screening, it is important to define the stage of the human reproductive cycle that this specific model is going to recreate in vitro and to identify molecular targets that are critical for this stage of development. In this review, we focus our discussion on modeling pre-implantation embryotoxicity. The rationale for this is that despite advances on both clinical and biological levels, many unresolved infertility cases may be due to our lack of knowledge regarding environmental influences on this short, but critical stage of development. Data from in vitro fertilization practice suggest that the early-dividing embryo is very sensitive to numerous factors present in its microenvironment. In vivo, as the embryo travels down the oviduct, physical or chemical insults can directly damage the embryo and/or prevent implantation, and cause infertility. Multiple lines of evidence point to the differences between mouse and human pre-implantation development and between mouse and human embryonic stem cells (hESCs). In light of these data we present the case that hESCs and their derivatives are better suited as in vitro models for human pre-implantation development than their mouse counterparts. We then describe some of the most promising hESC-based systems that are used today to model certain aspects of development in the human pre-implantation embryo and that have the potential to be used for embryo toxicity screening tests in the near future. Described systems model two major events during differentiation of the human pre-implantation embryo: differentiation of the trophectoderm and segregation of the inner cell mass into epiblast and hypoblast. The first event is replicated in vitro by triggering either direct or indirect (through embryoid body stage) differentiation into trophectoderm. The second event can be modeled using the recently described system of high-throughput generation of embryoid bodies that recapitulate segregation of inner cell mass. We conclude by discussing the potential of these existing models in toxicology studies and the possibilities for their improvement in the future.