Use of human embryonic stem cell-based models for male reproductive toxicity screening

Male reproductive toxicity examines harmful effects of various agents on all aspects and developmental stages of the male reproductive system, including germ cell development and spermatogenesis. In developing a model for reproductive toxicity screening it is important to define the developmental stage that this model is going to recreate in vitro and to identify critical molecular targets of this stage. In this review we focus our discussion on the potential for using embryonic stem cell (ESC)-derived models for male reproductive toxicity screening. The rationale for developing novel toxicity models is that despite significant advances in our biological understanding and clinical treatment of infertility, many unresolved cases still remain. This is likely due to our lack of knowledge about environmental influences on the critical stages of gamete development. Many practical and ethical difficulties are associated with the collection of human tissue samples to explore the unknown causes of infertility. Thus, a readily available in vitro model that mimics human gamete development would be an extremely valuable research tool for establishing novel toxicity assays. ESC exhibit a high degree of similarity with primordial germ cells (PGC) at the level of gene expression and molecular signaling. In addition, recent evidence shows that ESC can be differentiated into PGC and spermatids in culture. Multiple lines of evidence point to the differences between mouse and human ESC (hESC). In light of these data, we present the case that hESC are better suited as in vitro toxicity screening models than their mouse counterparts. We then describe some of the most promising hESC-based systems that are used today to model certain aspects of male gamete development and that have a potential to be used for toxicity screening. We conclude by discussing the potential of these existing models in toxicology studies and the possibilities for their improvement in the future.