GROWTH CONTROL IN THE TESTIS AND MOLECULAR MECHANISMS OF TESTICULAR HOMEOSTASIS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Children born small for gestational age (SGA) have a significantly elevated risk of cardiovascular and metabolic diseases in adulthood; however, data is limited on how SGA may impact reproductive development. Studies indicate that altered intrauterine growth increases the risk of congenital hypospadias, cryptorchidism, and testicular cancer approximately 2- to 3- fold. Evidence for these outcomes points towards alterations in the normal function of both the Sertoli and Leydig cells. Animal and human studies suggest that impaired peri-pubertal growth can affect testis size and function into adulthood. Therefore, elucidating signaling networks which modulate testis growth and identifying environmental toxicants which impinge upon these pathways will significantly impact environmental health. Our lab focuses on the Akt1 signaling pathway and its role in maintaining peri-pubertal testicular homeostasis. We have found a striking sensitivity to germ cell apoptosis in vivo in the testis of Akt1-deficient mice exposed to mono-2- ethylhexyl-phthalate (MEHP), a peri-pubertal Sertoli cell toxicant; and a reduction in testis size and reproductive potential in mice exposed to 6-N-propylthiouracil (PTU), a thyroid toxicant which targets Sertoli cell proliferation and differentiation. Based on these findings, we hypothesize that the Akt gene family plays a critical role in peri-pubertal testis homeostasis and that toxicants which target the Sertoli cell at this developmental window provide a crucial link between the environment and the etiology of male reproductive disease.