Project 172913

Proper positioning of the testes within the scrotum constitutes an essential step of the male sex differentiation process. Testicular descent is a hormonally-regulated biphasic process that occurs during fetal life. Two hormones are involved, both secreted by testicular Leydig cells: INSL3 regulates the first phase while the second phase is dependent on testosterone. Failure of testicular descent is called cryptorchidism. The incidence of cryptorchidism has been steadily rising in the past decades and it is the most prevalent pediatric disorder affecting around 5% of full-term boys. If not adequately treated, cryptorchidism leads to impaired spermatogenesis and increased prevalence of testicular cancer. Although the exact causes of cryptorchidism remain poorly understood, recent studies have revealed that maternal exposure during pregnancy to excess estrogens (medication, obesity since fat tissue is an important source of estrogens) and to phthalates (an endocrine disrupting chemical used as plasticizer in cosmetics, nail polish, toys, tubing and bags used in hospitals, etc) increases the risk to give birth to cryptorchid boys. Using animal models, it was shown that estrogens and phthalates decrease expression of INSL3 in testicular Leydig cells thus causing cryptorchidism. Therefore the goal of the present project is to understand how certain endocrine disruptors found in our everyday life negatively impact expression INSL3 in Leydig cells leading to impaired testicular descent. Understanding this process will provide important new insights into the molecular mechanisms of estrogen- and phthalate-induced cryptorchidism and LC dysfunction and hopefully will allow for the development of new therapeutic and/or preventive measures.