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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES015704-04
Application #
7780326
Study Section
Special Emphasis Panel (ZES1-LWJ-E (CG))
Program Officer
Balshaw, David M
Project Start
2007-07-17
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$360,920
Indirect Cost
Name
Brown University
Department
Pathology
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Moyer, Benjamin; Hixon, Mary L (2012) Reproductive effects in F1 adult females exposed in utero to moderate to high doses of mono-2-ethylhexylphthalate (MEHP). Reprod Toxicol 34:43-50
Gualberto, A; Hixon, M L; Karp, D D et al. (2011) Pre-treatment levels of circulating free IGF-1 identify NSCLC patients who derive clinical benefit from figitumumab. Br J Cancer 104:68-74
LaRocca, Jessica; Boyajian, Alanna; Brown, Caitlin et al. (2011) Effects of in utero exposure to Bisphenol A or diethylstilbestrol on the adult male reproductive system. Birth Defects Res B Dev Reprod Toxicol 92:526-33
LaRocca, Jessica; Pietruska, Jodie; Hixon, Mary (2011) Akt1 is essential for postnatal mammary gland development, function, and the expression of Btn1a1. PLoS One 6:e24432
Santos-Ahmed, Jeena; Brown, Caitlin; Smith, Stuart Duncan et al. (2011) Akt1 protects against germ cell apoptosis in the postnatal mouse testis following lactational exposure to 6-N-propylthiouracil. Reprod Toxicol 31:17-25
Juergens, Heribert; Daw, Najat C; Geoerger, Birgit et al. (2011) Preliminary efficacy of the anti-insulin-like growth factor type 1 receptor antibody figitumumab in patients with refractory Ewing sarcoma. J Clin Oncol 29:4534-40
Gualberto, Antonio; Dolled-Filhart, Marisa; Gustavson, Mark et al. (2010) Molecular analysis of non-small cell lung cancer identifies subsets with different sensitivity to insulin-like growth factor I receptor inhibition. Clin Cancer Res 16:4654-65
Brown, Caitlin; LaRocca, Jessica; Pietruska, Jodie et al. (2010) Subfertility caused by altered follicular development and oocyte growth in female mice lacking PKB alpha/Akt1. Biol Reprod 82:246-56
Hixon, Mary; Moyer, Ben (2009) Visions: the art of science. Mol Reprod Dev 76:601
Rogers, Rachel; Ouellet, Gregory; Brown, Caitlin et al. (2008) Cross-talk between the Akt and NF-kappaB signaling pathways inhibits MEHP-induced germ cell apoptosis. Toxicol Sci 106:497-508