Placental Iodothyronine Deiodinase Expression in Normal and Growth-Restricted Human Pregnancies

Abstract

We have described the expression of specific iodothyronine deiodinase mRNAs (using quantitative RT-PCR) and activities in normal human placentas throughout gestation and compared our findings to those in placentas from pregnancies affected by intrauterine growth restriction (IUGR). The predominant deiodinase expressed in placenta was type III (D3); type II (D2) was also present. In general terms, the activities of the enzymes D2 and D3 (and mRNAs encoding these enzymes) were higher earlier in gestation (<28 wk) than at term and displayed an inverse relationship with the duration of gestation (P < 0.05). Comparison of the relative expressions of mRNAs encoding D2 and D3 as well as their activities in placentas associated with IUGR (early and late gestational groups) with findings from normal placentas of similar gestational ages revealed no significant differences. Immunolocalization of D2 and D3 in syncytiotrophoblast (including syncytial sprouts) and cytotrophoblast of human placentas was demonstrated at both early and late gestation. Treatment of primary cultures of term cytotrophoblast cells in vitro with increasing doses of T(3) (1, 10, and 100 nM) resulted in increased expression of mRNAs encoding both D2 and D3 at 100-nM concentrations (P < 0.01) compared with control. Experiments with JEG-3 choriocarcinoma cells demonstrated a similar effect on D3 mRNA at 10 and 100 nM T(3) (P < 0.01). The demonstrated changes in iodothyronine deiodinase expression in the placenta across pregnancy are likely to contribute to regulation of the thyroid hormone supply to the developing fetus. The lack of difference in deiodinase expression in normal placentas and those found in IUGR argues against placental deiodinases being responsible for the hypothyroxemia in circulating fetal thyroid hormones observed in this condition.

Thyroid hormones in fetal growth and prepartum maturation

“…Therefore, as an enzymatic barrier, placental D3 limits the exposure of the fetus to maternal thyroid hormones. In the human placenta, the enzyme activity, and mRNA and protein expression, of D2 are greatest in the first trimester compared with term, but significantly lower than those of D3 at all gestational ages studied (Koopdonk-Kool et al 1996, Chan et al 2003. These findings suggest that local production of T 3 may be important for early placental development, but is unlikely to contribute significantly to circulating T 3 concentrations in the fetus.…”

Placental Transport of Thyroid Hormone and Iodide

“…In contrast, D3 has been localised to the villous ST cells and syncytial sprouts with expression in villous CTs focal and weak. In the third trimester villous ST expressed D2 and D3, whilst villous CTs were stronger for D2 than D3 (Chan et al 2003). The localisation of the deiodinases suggests that they may regulate the amount of maternal TH reaching fetal circulation.…”

“…Of the three deiodinating enzymes, only D2 and D3 have been identified in the placenta (Koopdonk-Kool et al 1996). Placental D3 activity is much greater (~200 times in first trimester and ~400 times at term) than D2 activity, however the activity and expression of both D2 and D3 falls as gestation progresses (Chan, et al 2003;Koopdonk-Kool et al 1996;Stulp, et al 1998). D2 is an outer ring deiodinase (Nelson, et al) found primarily in brain, pituitary, brown adipose tissue, thyroid and placenta with a preference for T 4 > rT 3 as a substrate (Figure 1).…”

“…T 2 and rT 3 were previously considered inactive metabolites because they do not bind TH receptors, however more recently rT 3 has been implicated in actin polymerisation (Farwell, et al 2005) and T 2 in stimulation of mitochondrial respiration (O'Reilly and Murphy 1992). D2 and D3 have been found to be present in the placenta throughout gestation (Chan et al 2003). D2 has been localised to the villous cytotrophoblasts cells in the first trimester with expression in villous syncytiotrophoblasts (ST) variable and weak.…”

Management of subclinical hypothyroidism in pregnancy: are we too simplistic?

“…The expression of deiodinases on the maternal side of the placenta may have consequences also on maternal TH levels as we know from consumptive forms of hypothyroidism that high expression of D3 in tumour tissue may lead to a substantial decrease in TH concentrations even in adulthood (63). According to immunohistochemical studies in human placenta, there is lower D3 expression in cytotrophoblasts compared with syncytiotrophoblasts, whereas D2 expression is more prominent in cytotrophoblasts (64,65).…”