In vitro models of the male reproductive system: applications for developmental and reproductive toxicology

There is a paucity of in vitro models to study the male reproductive system. Proper function of the reproductive system is critical for endocrine function, growth and development, and fertility. Without practical in vitro screening models, reproductive toxicities can be missed in early drug development or standard toxicological batteries. Successful in vitro models of the male reproductive system need to recapitulate the dynamic nature of the testis, considering the formation of the testicular niches from gonadal differentiation through puberty and the post-pubertal activity of the paracrine and endocrine signals that support spermatogenesis. In vitro approaches are reviewed that model primordial germ cell differentiation, gonadal morphogenesis, fetal steroidogenesis, neonatal reproductive development, and adult testicular niche dynamics to present opportunities for inclusion of male reproductive toxicity screening within a toxicological battery. The utility of cells derived from model organisms, differentiated from induced pluripotent stem cells, and obtained from donated human tissue is discussed. The field of reproductive and developmental toxicology is primed for expansion in in-vitro model availability as complex in-vitro model development continues to accelerate, and fit-for-purpose model approaches are adopted in toxicological and drug development pipelines. This review highlights the current limitations and emerging opportunities in male reproductive in vitro models, providing a roadmap for integrating these systems into toxicology testing and drug development workflows. It highlights the need for developmentally benchmarked, physiologically relevant, and multicellular models to fill existing gaps and improve translatability.