Sing-Yung Wu

Fetal-to-maternal transfer of thyroid hormone metabolites in late gestation in sheep

3,3′-diiodothyronine sulfate (T2S) derived from T3 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 T4 metabolites compared with those of T3. Labeled T4 or T3 was infused intravenously to four singleton fetuses in utero in each group at gestational age 138 ± 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 T3 from fetal serum (disappearance T1/2 of 0.7 h versus 2.4 h for T4 in the first 4 h). The metabolites found in fetal serum after labeled T3 infusion were T2S > T3 > T3S; in maternal urine, T2S > unconjugated iodothyronines (UI) > T3S > unknown metabolite (UM). After labeled T4 infusion, the metabolites in fetal serum were rT3 > T3 > T2S > T4S in the first 4 h, and rT3 = T3 = T4S = T2S > T3S at 24 h; in maternal urine we found T2S > UM > UI > T4S > T3S in the first 4 h and UM > T2S > UI in 4–24 h pooled sample. In conclusion, the conversion of T3 to T2S followed by fetal to maternal transfer of T2S and other iodothyronines appears to contribute importantly to maintaining low fetal T3 levels in late gestation.

Compound W, a 3,3'-diiodothyronine sulfate cross-reactive substance in serum from pregnant women--a potential marker for fetal thyroid function.

Compound W, a 3,3′-diiodothyronine sulfate (T2S) cross-reactive material in maternal serum, was found to be useful as a marker for fetal hypothyroidism. In the present report, we explored its biochemical properties and studied its concentrations in cord and in maternal serum obtained from various gestational periods and at term from different continents. Mean W concentrations, expressed as nmol/L T2S-equivalent, in maternal serum during gestation showed a moderate increase at 20–26 wk (1.57 nmol/L) and an accelerated increase to 34–40 wk (3.59 nmol/L). The mean serum level was relatively low in nonpregnant women (0.17 nmol/L). Compound W levels in cord and maternal serum at term were not significantly different among samples obtained from Taiwan compared with samples from the United States. The mean cord serum “corrected” (by hot acid digestion) concentrations of W were significantly higher than maternal serum concentrations at birth and were also higher in venous than in paired arterial samples, suggesting that the placenta may play a role in its production. We compared a total of 45 iodothyronine analogs by antibody, gel filtration, and HPLC chromatographic studies and found only one compound, N,N-dimethyl-T2S, that has close similarities to Compound W. Further studies are needed.

3,3'-Diiodothyronine sulfate excretion in maternal urine reflects fetal thyroid function in sheep.

We have shown that there is significant fetal-to-maternal transfer of sulfated metabolites of thyroid hormone after fetal infusion of a pharmacologic amount of 3,3′,5-triiodothyronine (T3) or sulfated T3 in late pregnancy in sheep (Am J Physiol 277:E915, 1999). The transferred iodothyronine sulfoconjugate, i.e. 3,3′-diiodothyronine sulfate (T2S), of fetal origin appears in maternal sheep urine. The present study was carried out to assess the contribution of T2S of fetal origin to the urinary pool in ewes. Eighteen date-bred ewes (mean gestational age of 115 d) and their twin fetuses were divided into four groups. In group I (control, n = 5), both ewes (M) and their fetuses (F) were sham operated for thyroidectomy (Tx). In group II, the ewes (MTx, n = 4) and, in group III, the fetuses (FTx, n = 4) were subjected to Tx. In group IV (MTx ·FTx, n = 5), both the ewe and fetus had Tx. After 10–12 d, fetal and/or maternal hypothyroidism were confirmed by serum thyroxine (<15 nmol/L) measurements. In addition, we infused radioactive T3 without disturbing the T3 pool in three singleton near-term fetuses and assessed the amount of radioactive iodothyronine that appeared in maternal urine (MU). After infusing [125I-3′],3,5-T3 via fetal vein to the near-term normal fetuses, radioactive T2S was identified as the major metabolite in MU by HPLC and T2S-specific antibody. MU T2S excretion (pmol/mmol creatinine) was significantly reduced by FTx and MTx ·FTx but not by MTx. In addition, positive correlations (p < 0.01) were found between MU T2S excretion and fetal serum thyroxine and T3 concentrations but not with maternal serum thyroxine or T3 levels. T2S of fetal origin contributes significantly to the MU pool.

Iodothyronine Sulfotransferase Activity in Rat Uterus During Gestation

In developing mammals, we and others demonstrated that sulfation is an important pathway in the metabolism of thyroid hormone, and there is significant fetal-maternal transfer of sulfated iodothyronine. In the present study, we characterized a novel iodothyronine sulfotransferase (IST) in pregnant rat uterus. 125I-labeled 3,3′-diiodothyronine (T2), T3, rT3, and T4 were used as substrates with unlabeled 3′-phosphoadenosine-5′-phosphosulfate (PAPS) as the sulfate donor. Sulfated iodothyronine products were separated by Sephadex LH-20 column and further identified on reverse phase HPLC. We measured IST activity in pregnant rat uterus by incubating 1 μM substrate, 50 μM PAPS, and 50 μg cytosol protein, pH 7.2, 30 min at 37°C. The results show that the substrate preference of the uterine IST activity is: T2 > rT3 > T3> T4; the pH optimum is 6.0 for T2. The Km and Vmax (for gestational day 21 uterus) for T2 are 0.62 μM and 3466 pmol/mg protein/h, respectively; for PAPS the values are 2.6 μM and 1523 pmol/mg protein/h, respectively. During pregnancy, the total activities exhibit a U-shaped curve with minimum activity at day 13 of gestation; while a thermostable activity increases significantly near term. In summary, there is significant uterine IST that varies during pregnancy. The role of this uterine sulfotransferase activities in regulating the bioavailability of thyroid hormone in the developing fetus remains to be elucidated.

3,3'-Diiodothyronine sulfate cross-reactive material (compound W) in human newborns.

Background:Thyrosulfoconjugation appears to facilitate fetal-to-maternal transfer of 3,3′-diiodothyronine-sulfate (T2S). Elevated maternal levels of T2S cross-reactive material (compound W) are found in humans, with higher levels found in venous cord blood than in arterial samples. These findings are consistent with the postulate that the placenta plays an essential role in compound W production.Methods:Serum compound W levels were measured by a T2S-specific radioimmunoassay in 60 serum samples from newborns with hyperbilirubinemia, age 1–30 d. In addition, 59 maternal serum samples, from day 1 to day 7 after uneventful deliveries, were studied.Results:As compared with day 1, at day 5, the mean (±SE) compound W level fell to 43.5 ± 6.8% (decay half-life (t1/2) = 4.12 d) and to 33.7 ± 4.6% (decay t1/2 = 2.82 d) in the newborn and maternal groups, respectively. In the mothers, the level continued to decline along the same slope through day 7. In the newborns, however, the mean compound W level entered a slower phase of decay after the fifth day with a decay t1/2 = 10.9 d.Conclusion:Compound W is cleared at similar rates in newborn and postpartum maternal sera. This is consistent with the postulate that compound W is produced in the placenta.

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

We used novel 3′-monoiodothyronine sulfate (3′-T1S) and 3,3′,5-triiodothyroacetic acid sulfate (TriacS) RIAs to characterize sulfation pathways in fetal thyroid hormone metabolism. 3′-T1S and TriacS levels were measured in serum samples obtained from fetal (n = 21, 94–145 d gestational age), newborn (NB, n = 5), and adult sheep (AD, n = 5) as well as from fetuses after total thyroidectomy (Tx), or sham-operated twin fetuses controls, conducted at gestational age 110–113 d (n = 5). Peak levels (expressed as ng/dL) of both 3′-T1S and TriacS occurred at 130 d gestation. These levels in fetuses were higher than those in NB and AD. In Tx fetuses, there was a significant decrease in the mean serum level of 3′-T1S, but not TriacS. The decrease in 3′-T1S in Tx is similar to that observed for thyroxine sulfate (T4S) and 3,3′,5′-triiodothyronine sulfate (rT3S), whereas TriacS levels were not altered in the hypothyroid state, similarly to 3,3′,5-triiodothyronine sulfate (T3S). These data demonstrate that 3′-T1S and TriacS are normal thyroid hormone metabolites in ovine serum and that TriacS is likely derived from T3S or from the same precursor(s) as T3S.