Gene Networks in Peri-pubertal Sertoli Cell Injury

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DESCRIPTION (provided by applicant): 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 gonadal development and reproductive health. Epidemiological studies and registry surveys demonstrate that altered intrauterine growth increases the risks of congenital hypospadias, cryptorchidism and testicular cancer approximately 2- to 3-fold. Evidence for these outcomes points towards alterations in the normal functions of Sertoli and Leydig cells. Both animal and human studies suggest that impaired peri-pubertal growth can affect testis size and function into adulthood. A study by Main et al., examined testis growth from birth to 3 months of age in healthy Finnish and Danish newborns and found a significant correlation between weight for gestational age and testis size. Therefore, elucidating signaling networks which modulate peri-pubertal testis growth and identifying environmental toxicants which impinge upon these pathways will significantly impact environmental health. The Akt gene family effects testis growth. Akt1 -deficient mice are born small for gestational age and have significantly smaller testis throughout their lifetime. Preliminary data indicate that the Akt1 signaling pathway plays a significant role in maintaining peri-pubertal testicular homeostasis. A striking sensitivity is observed in vivo for germ cell apoptosis in testis of Akt1-deficient mice exposed to MEHP, a peri-pubertal Sertoli cell toxicant, and a reduction in testis 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, it is hypothesized that the Akt gene family plays a critical role in peri- pubertal testis development 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. The hypothesis will be tested through the following Specific Aims: 1.) Identify the mechanisms by which Akt1 suppresses Sertoli cell mediated germ cell apoptosis following MEHP exposure. 2.) Identify the mechanisms by which Akt1 promotes testis growth and development following PTU exposure, and 3.) Identify relevant Sertoli cell toxicant-induced stress response networks. Relevance: This research will define critical signaling networks targeted by peri-pubertal reproductive toxicants and delineate how they impact male reproductive health.