Fetal-to-Maternal Transfer of Thyroid Hormone Metabolites in Late Gestation in Sheep

Abstract

3,3=-diiodothyronine sulfate (T 2 S) derived from T 3 of fetal origin is transferred to the maternal circulation and contributes significantly to the maternal urinary pool. The present study quantitatively assesses the fetal to maternal transfer of T 4 metabolites compared with those of T 3 . Labeled T 4 or T 3 was infused intravenously to four singleton fetuses in utero in each group at gestational age 138 Ϯ 3 d. Maternal and fetal serum and maternal urine samples were collected hourly for 4 h and at 24 h (serum) or in pooled 4 -24 h samples (urine). Radioactive metabolites were identified by HPLC and by specific antibody in serum and urine extracts and expressed as percentage infusion dose per liter. The results demonstrate a rapid clearance of labeled T 3 from fetal serum (disappearance T 1/2 of 0.7 h versus 2.4 h for T 4 in the first 4 h). The metabolites found in fetal serum after labeled T 3 infusion were T 2 S Ͼ T 3 Ͼ T 3 S; in maternal urine, T 2 S Ͼ unconjugated iodothyronines (UI) Ͼ T 3 S Ͼ unknown metabolite (UM). After labeled T 4 infusion, the metabolites in fetal serum were rT 3 Ͼ T 3 Ͼ T 2 S Ͼ T 4 S in the first 4 h, and rT 3 ϭ T 3 ϭ T 4 S ϭ T 2 S Ͼ T 3 S at 24 h; in maternal urine we found T 2 S Ͼ UM Ͼ UI Ͼ T 4 S Ͼ T 3 S in the first 4 h and UM Ͼ T 2 S Ͼ UI in 4 -24 h pooled sample. In conclusion, the conversion of T 3 to T 2 S followed by fetal to maternal transfer of T 2 S and other iodothyronines appears to contribute importantly to maintaining low fetal T 3 levels in late gestation. (Pediatr Res 59: 102-106, 2006) K inetic studies in fetal sheep in late gestation (Ͼ135 d of gestational age; term, 150 d) showed that mean fetal T 4 CR and PR are significantly higher than the corresponding values in adult sheep (1). The ratio of mean PR of rT 3 to T 4 is similar in fetal and adult sheep, whereas the PR ratio of T 3 to T 4 in fetal sheep is much lower than that in adult sheep. These data in the ovine fetus indicate that the prevailing low serum T 3 concentration is due both to increased CR and decreased PR, whereas the elevated serum rT 3 levels are due to decreased CR and increased PR. We and others showed that sulfated iodothyronines, including T 4 S, T 3 S, rT 3 S, and 3,3=-T 2 S are major T 4 metabolites in ovine fetuses (2,3). The PR of T 4 S, T 3 S, rT 3 S, and rT 3 significantly exceed the PR of T 3 .Thus, peripheral thyroid hormone metabolism in the ovine fetus, in contrast to the adult, is shunted to inactivation rather than production of active hormone.In a recent study, we showed that a significant amount of 3,3=-diiodothyronine (T 2 ), the inner-ring deiodinated metabolite of fetal T 3 , is found in maternal urine as sulfated T 2 when 125 I-T 3 is infused in venously catheterized fetuses (4,5). In contrast, when a supraphysiological dose of T 3 , about 200-fold the fetal T 3 PR, was infused into fetuses, both T 2 S and T 3 S were found in maternal urine (6). To exclude the possibility that the observed fetal-to-maternal transfer of metabolites could be a pharmacological dose...

Thyroid hormones in small ruminants: effects of endogenous, environmental and nutritional factors

“…In fact, type I deiodinase activity in the liver and kidney of foetus up to the fourth month was lower than that in pre-term foetus or in the newborn (Wu et al, 1992). Low foetal T3 levels are maintained also by sulphation and deiodination (Wu et al, 2006). In the foetus, low T3 levels allow anabolic processes to prevail, despite the high rate of foetal T4 secretion, which resulted eight-fold than maternal one during the last one-third period of gestation (Dussault et al, 1971).…”

Compound W, a 3,3′-Diiodothyronine Sulfate Cross-Reactive Substance in Serum from Pregnant Women—A Potential Marker for Fetal Thyroid Function

“…In sheep, a precocial species similar to humans, it has been shown that a significant amount of T 3 formed in the fetal circulation is converted to T 2 S and transferred to the maternal compartment for deiodination/excretion (22,23). This process may serve to maintain low circulating T 3 levels in the fetus.…”

3′-Monoiodothyronine Sulfate and Triac Sulfate Are Thyroid Hormone Metabolites in Developing Sheep

“…The PR for T 4 and T 3 are 46 and Ͻ1.5 g/kg/d, respectively, in the euthyroid third trimester fetus while the PR for rT 3 S, T 4 S, and T 3 S are 12, 10, and 2 g/kg/d, respectively (18,26). The kinetic studies predicted that 3,3=-T 2 S also is a major thyroid hormone metabolite and this was later confirmed qualitatively (25). 3,3=-T 2 S was also found to be the major metabolite in maternal circulation following the fetal infusion of radioactive T 3 (26); a similar immunoreactive product, Compound W, was found peaked at term in pregnant women disappearing 7-10 d after delivery (4,27).…”

“…From the high potency of 3=-T 1 in inhibiting sulfoconjugation of 3,3=-T 2 in human SULT1A1 and SULT1A3, 3=-T 1 may be an excellent substrate to be sulfated (24). After the infusion of outer-ringlabeled T 3 in the euthyroid fetus, 3,3=-T 2 S was found to be the predominant metabolite, followed by lesser amounts of 3,3=-T 2 and T 3 S; but no 3=-T 1 or its sulfoconjugate was seen (25). The kinetics of labeled T 3 in Tx ovine fetuses have not been studied with HPLC or other available RIAs specific to sulfated iodothyronines developed recently (7).…”