Testicular Cancer in Relation to Testicular Dysgenesis Syndrome

This article focuses on testicular cancer and its relation to testicular dysgenesis syndrome (TDS) and reviews the current evidence of environmental factors in TDS pathogenesis. Testicular germ cell tumors (TGCT), cryptorchidism, as well as some forms of hypospadias and male infertility are all components of TDS, and it was proposed that these disorders share a common etiology and pathogenesis. Links between these conditions are provided by epidemiological clues and from direct biological evidence that disruption of early testis development and impaired differentiation of cell populations are common features. Main advances in our understanding of human TDS have arisen from studies of germ cell neoplasia in situ (GCNIS), cells with features of transformed gonocytes which failed to differentiate, most likely due to a functional insufficiency of the somatic niche during fetal development. Direct evidence linking specific chemical exposures and disruption of early testis development is sparse. However the potential for direct impacts of chemical exposures and for interactions between the changing environment and the genomic landscape to result in heritable epigenetic changes in the germline are being explored. Molecular markers indicate that testicular development and differentiation rely on largely conserved processes, so information gained from studies of nonhuman species is highly relevant for understanding human testicular cancer. To date, most available evidence in humans comes from the occurrence of genital malformations, especially cryptorchidism, which occur in early childhood. Toxicological studies of human adult manifestations, especially TGCT, are difficult for ethical reasons, highlighting the need for suitable animal models, such as rabbits or dogs. Although rodents are crucial for studying fundamental processes, their windows of susceptibility to endocrine disrupters appear different and TGCTs of the 'human type' do not develop. Further advances will arise from efforts to integrate knowledge of (1) the signaling mechanisms that govern key steps in the development and maturation of testicular cells, (2) the effects of toxicants on these processes in animal models and large case-control studies of human subjects with TDS, and (3) the common and species-specific features of normal and disrupted testicular growth. Herein, several of these facets are briefly reviewed and discussed.