Regulation of neonatal Sertoli cell development by thyroid hormone receptor α1

Neonatal hypothyroidism increases adult Sertoli cell populations by extending Sertoli cell proliferation. Conversely, hyperthyroidism induces premature cessation of Sertoli cell proliferation and stimulates maturational events like seminiferous tubule canalization. Thyroid hormone receptors alpha 1 and beta 1, which are commonly referred to as TR alpha 1 and TR beta 1, respectively, are expressed in neonatal Sertoli cells. We determined the relative roles of TR alpha 1 and TR beta 1 in the thyroid hormone effect on testicular development and Sertoli cell proliferation using Thra knockout (TR alpha KO), Thrb knockout (TR beta KO), and wild-type (WT) mice. Triiodothyronine (T,) treatment from birth until Post-natal Day 10 reduced Sertoli cell proliferation to minimal levels in WT and TR beta KO mice versus that in their untreated controls, whereas T-3 had a diminished effect on TR alpha KO Sertoli cell proliferation. Seminiferous tubule patency and luminal diameter were increased in T-3-treated WT and TR beta KO testes. In contrast, T-3 had no effect on these parameters in TR alpha KO mice. In untreated adult TR alpha KO mice, Sertoli cell number, testis weight, and daily sperm production were increased or trended toward an increase, but the increase in magnitude was smaller than that seen in WT mice following neonatal hypothyroidism. Conversely, in TR beta KO mice, Sertoli cell number, testis weight, and daily sperm production were similar to those in untreated WT mice. In addition, Sertoli cell number and testis weight in adult WT and TR beta KO mice showed comparable increases following hypothyroidism. Our results show that TR alpha KO mice have testicular effects similar to those seen in WT mice following neonatal hypothyroidism and that TR beta KO mice, but not TR alpha KO mice, have normal Sertoli cell responsiveness to T-3. Thus, effects of exogenous manipulation of T-3 on neonatal Sertoli cell development are predominately mediated through TR alpha 1.