CONSEQUENCES OF THYROID-HORMONE DEFICIENCY INDUCED BY THE SPECIFIC ABLATION OF THYROID-FOLLICLE CELLS IN ADULT TRANSGENIC MICE

The herpes simplex type 1 virus thymidine kinase (HSV1-TK) reporter ge ne was coupled to a bovine thyroglobulin promoter (TG-tk construct). W ithin the thyroid glands of transgenic mice expression was confined to thyroid follicle cells. Infusion of Ganciclovir (9-[(1,3-dihydroxy-2- propoxy)methyl]guanine) to 8 to 12 week transgenic females led to the complete loss of thyroid HSV1-TK activity (at 3 to 4 days) and thyroid follicles (between 7 and 14 days). During the first 5 days of treatme nt a single reciprocal oscillation in circulating thyroxine (T-4) and TSH levels occurred. By 14 days the circulating triiodothyronine (T-3) and T-4 levels of all treated animals were below the detection limits of the assays, while TSH levels were elevated ten-fold and continued to increase thereafter. During 14 days of treatment the thyroids regre ssed, protein content fell by 80-90% and the C cells, normally dispers ed within the central region of each gland, came together in aggregate s. Pituitary GH levels in females rose and fell back to normal within 14 days and between 14 and 28 days fell to a level comparable with tha t of GH-deficient lit/lit mice. The levels of hepatic GH receptor mRNA and the predominant 6.6 kb T-3 receptor mRNA were unaffected by thyro cyte ablation. Thyrocyte ablation had no effect on the level of prolac tin (Prl) receptor mRNA in females, but increased Prl receptor mRNA le vels in males and eliminated group 1 major urinary protein (MUP) mRNA in females. T-4 replacement reversed the effects of thyrocyte ablation on MUP mRNA in females and on Prl receptor mRNA in males. Despite the many physiological changes induced by thyrocyte ablation, ablated mic e have been maintained for up to 1 year without thyroid hormone supple mentation. T-4-deficient females were normally fertile and carried pup s to term. Although transgenic males expressed HSV1-TK ectopically in spermatids and spermatozoa at levels similar to thyrocyte levels, a ra te of Ganciclovir infusion which successfully ablated the thyrocytes d id not affect the testis. As an alternative to infusion by minipump, t hyrocyte ablation could be achieved by 6 twice-daily injections of Gan ciclovir, at a level of 112 mu g Ganciclovir/g body weight per day, an d fetuses in utero could be thyrocyte ablated by administering 50 or 1 5 mu g/g body weight per day to pregnant females between days 14 and 1 8 of gestation. These data demonstrate the potential value of transgen ic thyrocyte ablation in the study of the effects of thyroid hormone d eprivation.