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Akt1 protects against germ cell apoptosis in the post natal mouse testis following lactational exposure to 6-N-propylthiouracil
Citation:
Ahmed, J. S., C. Brown, S. D. Smith, M. E. GILBERT, M. L. Hixon, T. Rasoulpour, AND P. Weston. Akt1 protects against germ cell apoptosis in the post natal mouse testis following lactational exposure to 6-N-propylthiouracil. REPRODUCTIVE TOXICOLOGY. Elsevier Science Ltd, New York, NY, 31(1):17-25, (2011).
Impact/Purpose:
Thyroid hormone regulates gene expression during critical periods of development in a number of organ systems. In the reproductive tract, thyroid hormone inhibits proliferation of Sertoli cells in the rodent testis during the early postnatal period. Neonantal thyroid hormone insufficiency extends the Sertoli cell proliferative window resulting in larger number of Sertoli cells with a concomitant increase in germ cells, Leydig cells, and a larger testis. The increase in testis weight has recently been demonstrated to primarily occur through activation of the thyroid receptor alpha 1 (TRa 1), but the mechanism whereby this occurs remains unclear. Aktl is a gene implicated in both cell number and cell size in the establishment oforgan size. The present experiment investigated the role of thyroid hormone in Aktl gene signaling pathways and male reproductive function using an Aktl knockout mouse model. We have recently provided data implicating Aktl in the response to testicular injury following exposure to phthalates. The present study was designed to examine the role of developmental hypothyroidism on germ cell apoptosis and testis growth. Our results demonstrate that Aktl is protective to germ cells following developmental hypothyroidism. Akt l-deficiency alone did not result in decreased T4 levels, however, Aktl-deficiency produced a more dramatic drop in thyroid hormones than in Aktl +/+ and Aktl +/-animals. Hypothyroidism was also accompanied by a 2-fold increase in mRNA of Akt3 that persists to adulthood following a transient developmental hypothyroidism in wildtype mice suggesting that Akt3 may also playa functional role in the postnatal testis. In summary, thyroid hormone regulation of Akt signaling pathways may represent a sensitive target for environmental toxicants on male reproductive function.
Description:
Lactational exposure to 6-propyl-2-thio-uracil (PTU), a neonatal goitrogen, leads to increased testis size and sperm production in rodents. Aktl, a gene involved in cell survival and proliferation is also phosphorylated by thyroxine (T4). Therefore, we examined the requirement for Aktl in germ cell survival/proliferation following PTU-induced hypothyroidism. Experiments were performed using Aktl+/+, Akt1+/-, and Aktl-/-mice. PTU was administered (0.01% w/v) via the drinking water ofdams. At PND15, thyroxine (T4)serum levels were similar in all control groups, and significantly lower in all exposed groups with a dramatic decrease in Aktl-/mice. Aktl-/-testes displayed smaller tubules, increased apoptosis, and delayed lumen formation following PTU. Relative adult testis weights were similar in all exposure groups; however, no increase in daily sperm production was observed in PTU-exposed Akt1-/-mice. In conclusion, Akt l contributes to the effects of thyroid hormone on postnatal testis development and protects against germ cell apoptosis.
