Regulation of Neonatal Sertoli Cell Development by Thyroid Hormone Receptor (alpha)1

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 (T3) treatment from birth until Postnatal Day 10 reduced Sertoli cell proliferation to minimal levels in WT and TR(beta)KO mice versus that in their untreated controls, whereas T3 had a diminished effect on TR(alpha)KO Sertoli cell proliferation. Seminiferous tubule patency and luminal diameter were increased in T3-treated WT and TR(beta)KO testes. In contrast, T3 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 T3. Thus, effects of exogenous manipulation of T3 on neonatal Sertoli cell development are predominately mediated through TR(alpha)1.