While thyroid hormone is critically important for normal postnatal growth and development, fetal hypothyroidism results in few clinical sequelae. The mechanisms protecting the fetus during periods of altered thyroid status are the focus of the present proposal. Several important observations require further investigation in order to understand the unique aspects of fetal thyroid physiology. The principal biologically active thyroid hormone is 3,3',5 triiodothyronine (T3) which is derived from the inactive precursor thyroxine (T4) via monodeiodination. A related inactive metabolite, 3,3',5' triiodothyronine (rT3) is also a product of T4 monodeiodination. In the adult, conversion of T4 to T3 occurs mainly in peripheral tissues; this conversion accounts for over 85% of circulating T3 levels. Fetal thyroid hormone metabolism is quite different in several respects. The predominant fetal metabolite resulting from peripheral deiodination is inactive rT3. However, fetal T3 and rT3 production only account for about 35% of total T4 production. Recent reports suggest that the predominant fetal thyroid hormone metabolites are sulfoconjugates of T4, T3, and rT3. Using the fetal sheep as a model for human thyroid metabolism, the present proposal includes experiments to provide a mechanism for the maintenance of T3 sulfate levels (in preference to circulating T3 and T4 levels) during fetal hypothyroidism as well as investigations determining the contribution of thyrosulfoconjugates to fetal tissue levels of active thyroid hormones. Further studies are proposed to document the influence of maternal thyroid hormones on fetal thyrosulfoconjugate levels and subsequent fetal thyroid system effects. Finally, expansion of intriguing preliminary observations suggesting that fetal thyroid hormone metabolites are present in the maternal circulation may allow for sampling of maternal blood in order to document the status of fetal thyroid function.
