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. 2023 May 7;108(10):e944–e948. doi: 10.1210/clinem/dgad243

Effect of the Fetal THRB Genotype on the Placenta

Federico Salas-Lucia 1, Marius N Stan 2, Haleigh James 3, Aadil Rajwani 4, Xiao-Hui Liao 5, Alexandra M Dumitrescu 6,7, Samuel Refetoff 8,9,10,✉
PMCID: PMC10505537  PMID: 37149816

Abstract

Context

Pregnant women with mutations in the thyroid hormone receptor beta (THRB) gene expose their fetuses to high thyroid hormone (TH) levels shown to be detrimental to a normal fetus (NlFe) but not to an affected fetus (AfFe). However, no information is available about differences in placental TH regulators.

Objective

To investigate whether there are differences in placentas associated with a NlFe compared with an AfFe, we had the unique opportunity to study placentas from 2 pregnancies of the same woman with THRB mutation G307D. One placenta supported a NlFe while the other an AfFe.

Methods

Sections of placentas were collected and frozen at −80 °C after term delivery of a NlFe and an AfFe. Two placentas from healthy women of similar gestational age were also obtained. The fetal origin of the placental tissues was established by gDNA quantitation of genes on the X and Y chromosomes and THRB gene. Expression and enzymatic activity of deiodinases 2 and 3 were measured. Expression of following genes was also quantitated: MCT10, MCT8, LAT1, LAT2, THRB, THRA.

Results

The placenta carrying the AfFe exhibited a significant reduction of deiodinase 2 and 3 activities as well as the expression of the TH transporters MCT10, LAT1 and LAT2, and THRA.

Conclusion

We present the first study of the effect of the fetal THRB genotype on the placenta. Though limited by virtue of the rarity of THRB mutations and sample availability, we show that the fetal THRB genotype influences the levels of TH regulators in the placenta.

Keywords: pregnancy, TH transporters, deiodinases, nuclear receptors, resistance to thyroid hormone beta

Thyroid hormone (TH) is essential for vertebrate embryogenesis and fetal maturation with irreversible deleterious effects of TH deficiency and excess (1-3). While maternal free TH levels remain relatively steady throughout pregnancy (4), fetal TH levels increase progressively (5). These changes in fetal TH require placental passage of TH. This is achieved by specific TH membrane transporters and deiodinases that activate (type 2 deiodinase [D2]) or inactivate (D3) TH (6). A third deiodinase, D1, is mainly expressed in the liver, kidney, and thyroid gland but not in the placenta and, thus, plays no role in TH economy (7, 8). As normal gestation progresses, TH transporters become more abundant, and D2 and D3 decrease (9, 10). Studies in pregnancies affecting maternal thyroid status showed changes in the expression of placental TH transporters and deiodinases (8, 11).

Although the fetal thyroid becomes functional on the 16th week of gestation (5), athyreotic fetuses born to euthyroid mothers are normal at birth and develop normally if TH is replaced soon after (12, 13). Yet, maternal hypothyroidism causes neurological abnormalities in fetuses even with intact thyroid glands, indicating the importance of the maternal transplacental supply of TH (14). Individuals with resistance to TH beta (RTHβ) due to heterozygous mutations in the THRB gene maintain euthyroidism at the expense of high serum TH levels (15). When pregnant, their high serum TH is congruent with that of similarly affected fetuses (AfFes) carrying the mutant THRB gene. However, when carrying a normal fetus (NlFe) without a THRB gene mutation, the fetus is exposed to supraphysiologic levels of TH. As a consequence, the fetus may undergo early abortion or be born with low weight and with suppressed TSH (16), similar to patients born from a mother with Graves disease (17). Furthermore, these infants develop later central resistance to TH even though devoid of THRB mutation (18). Conversely, an AfFe with RTHβ inherited from the father, but born to a normal mother (NlMo) without RTHβ, would be potentially exposed to a subphysiological level of TH. These differences in the outcomes of pregnancies when a mother with RTHβ carries an AfFe compared with a NlFe brought into question what role the placenta might play. A major limitation to carry out studies on placentas is their availability given that RTHβ is a rare condition, constraining access to placentas from the same woman carrying an affected and a normal infant, both born at the same gestational age.

We had the rare opportunity to obtain tissue from 2 placentas belonging to the same woman with a heterozygous mutation in the THRB gene while carrying a NlFe and an AfFe harboring the maternal mutation in pregnancies 2 years apart and of the same duration. Our results are compared with placentas from 2 normal women. Despite the limitation of a small sample size, our report constitutes the first evidence of an effect of the fetal THRB genotype on TH regulators in the placenta.

Case Report

The index patient was a woman of White European background who presented for the evaluation of abnormal thyroid tests (elevated thyroxine [T4] and triiodothyronine [T3], with normal and high thyrotropin [TSH], and a thyroidal radioiodine uptake of 78%), detected at the age of 8 years. She was described as “very energetic” and was intermittently placed on antithyroid drugs (propylthiouracil or methimazole). Thyroid abnormalities were documented repeatedly, and similar abnormalities were reported in her father, but no additional information could be obtained.

At age 26, before pregnancy, she had an elevated TSH of 7.2 mU/L (0.40-4.0), with free T4 (FT4) of 1.41 ng/dL (0.46-1.31) and FT3 of 4.6 pg/mL (2.5-3.9). Over the subsequent 7 years, 10 FT4 determinations ranged from 108% to 165% the upper limit of normal (ULN) of 100, and 17 TSH determinations ranged from 3.0 to 19.1 mU/L, with a tendency for TSH values to increase with time. This was likely due to the progression of autoimmune thyroid disease documented by positive TPO antibodies and findings on thyroid ultrasound. A heterozygous mutation in the THRB gene (G307D) was identified. This mutation has been previously described (19) and is of moderate severity (20) based on an average FT4 of 156% ULN calculated by using her values associated with TSH concentrations within the normal range.

After 1 miscarriage, she had 2 pregnancies (at ages 26 and 28 years), resulting in live deliveries with similar gestation age (38 weeks 4 days and 38 weeks 5 days). Amniocentesis at week 20, performed to guide TH management during pregnancy, indicated that she was carrying a NlFe male (first pregnancy). The subsequent pregnancy confirmed an AfFe female harboring the maternal mutation. Thyroid function tests were monitored during her 2 pregnancies. After 65 days of gestation, total T4 (TT4) values were 19.1 µg/dL (4.5-11.2) and total T3 (TT3) 241 ng/day (80-200) when carrying a NlFe, and 13.5 and 206 when carrying an AfFe. After 125 days of gestation, TT4 and TT3 values were 18.4 and 286 in the NlFe and 17.8 and 254 in the AfFe, and at 160 days, values were 20 and 302 and 19.4 and 305, when carrying a NlFe or an AfFe, respectively. This case allowed us to study 2 placentas from the same affected mother (AfMo) carrying a NlFe and an AfFe.

Materials and Methods

The authors confirm that the appropriate ethics approval has been received and that appropriate processes have been followed in accordance with the Declaration of Helsinki as revised in 2013. All subjects gave their informed consent, and the research has been approved by the Ethics Committee of the Mayo Clinic with an IRB number: 16-010250.

Placentas

Infants from the AfMo were delivered at 38 weeks 4 days and 38 weeks 5 days, and the NlFe and AfFe body weights were 3090 and 3104 g, respectively. Five samples from the fetal compartment of both placentas were saved. Placentas from 2 NlMos carrying a NlFe (male and female) delivered at 39 weeks 0 days and 39 weeks 3 days were also sampled as controls. Tissues were kept frozen at −80 °C, and 5 sites of each placenta were sampled for analysis.

Iodothyronine Deiodinases Assays

Placentas were sonicated in 0.25 M sucrose in PE (0.1 M phosphate-buffered saline, 1 Mm EDTA) buffer and processed for deiodinase assays as previously described (21). For measurement of D2 activity, 125I-T3 production from 1 µM 125I-T4 was determined in the presence of 1 Mm propylthiouracil to inhibit the D1-mediated catabolism and 10 Nm T3 to saturate the D3. For measurement of D3 activity, 125I-T2 production from 1 µM 125I-T3 was determined. Iodothyronines were identified by ultra–high-performance liquid chromatography in tandem with a flow scintillator detector. Deiodinase activities were normalized to the DNA concentration and expressed as fractional conversion: fmol/ng of DNA/min. Considering the abundance of blood in the placenta, it is more reliable to use the DNA than protein concentration because DNA mainly represents placental tissue, while a great proportion of the protein comes from nonnucleated red blood cells (22).

Quantitative Reverse Transcription Polymerase Chain Reaction

Total RNA was extracted from placentas, and mRNAs were treated with DNase and measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR) as previously described (18). Data were analyzed using the 2−ΔΔCT method and expressed relative to the values obtained from the NlMo carrying the NlFe. The expression of the indicated deiodinases, TH transporters, and TH nuclear receptors was determined using specific primers. The mean expression of 3 housekeeping genes, RNA polymerase II subunit A, β-actin, and glyceraldehyde 3-phosphate dehydrogenase, was used as the internal control.

Genomic DNA Quantitation

Genomic DNA was extracted from placentas using Qiagen DNeasy Blood & Tissue Kit, and quantitation PCR was performed and analyzed in the same way as RT-qPCR above. The expression of SERPINA7, SRY, and THRB mutant-specific allele [THRB(mut)] was determined using specific primers. The mean expression of TSHR intron 9 and THRB intron 8 was used as the internal control.

Statistics

Data were analyzed using Prism software (GraphPad) and presented as bar histograms depicting the mean ± SEM. The mean was calculated based on results from samples obtained from 5 different sites of each placenta. A 2-tailed Student's t test was used to perform comparisons, and multiple comparisons were by analysis of variance followed by Tukey's test.

Results

To determine the origin of the placental samples, we took advantage of the differences between THRB genotypes of the fetuses and sex to quantify genomic DNA (gDNA) using specific primers for the mutant THRB, Y chromosome, and X chromosome genes. The placentas from a NlMo and an AfMo carrying a NlFe had undetectable mutant THRB (Fig. 1). We measured the gDNA of the SERPINA7 gene, located in the X chromosome, and the SRY gene, located in the Y chromosome. SERPINA7 was reduced ∼50% in placentas carrying a male fetus compared with that carrying a female fetus (Fig. 1) and 100% relative expression of the SRY gene (not detected in placentas carrying a female). These results confirm that placenta samples were of fetal origin without significant contamination from maternally derived placental tissue.

Figure 1.

Figure 1.

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Determination the origin of the placental tissues by quantitation of the gDNA levels of sex and THRB mutant specific genes. SERPINA7 and SRY identify the sex of the fetus confirming the fetal origin of the placental tissue. The mutant (Mut) THRB identifies the AfFe. The tracer amount (1%) of mutant THRB in the AfMo NlFe likely represents contamination from maternally derived gDNA, likely from blood leukocytes. Values are mean ± SEM of 5 samples from each placenta. NlMo, normal mother; AfMo, affected mother; NlFe, normal fetus; AfFe, affected fetus. n.a, not amplifiable.

Measurement of deiodinases revealed that placentas from an AfMo carrying a NlFe exhibited an increase in D2 and D3 activity (202 ± 70 and 2440 ± 700 fmol/ng DNA, respectively) compared with placentas from a NlMo (D2: 159 ± 84 fmol/ng DNA and D3: 1810 ± 820 fmol/ng DNA; Fig. 2A). The placenta from the AfMo carrying an AfFe showed a reduction in D2 and D3 activity of 59.9 ± 14.9% and 34.7 ± 2.2%, respectively (Fig. 2A) compared with placentas from an AfMo carrying a NlFe. We also measured the mRNA levels of deiodinases 3 (DIO3) and 2 (DIO2) and found that for both genes the differences in mRNA levels between the placentas of the AfMo carrying a NlFe and an AfFe correlated with the corresponding D2 and D3 activities (compare Fig. 2A and 2B). This was not the case for the control placentas from the NlMos, which showed differences in enzyme activity compared with mRNA levels (Fig. 2A and 2B). Deiodinase 1 activity and expression were not detected.

Figure 2.

Figure 2.

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(A) D2 and D3 activities and (B) mRNA levels. Values are mean ± SEM of 5 samples from each placenta. Values from the 2 control NlMo placentas were combined. NlMo, normal mother; AfMo, affected mother; NlFe, normal fetus; AfFe, affected fetus.

Next, we examined whether the placental expression of TH transporters is altered. All placentas had similar MCT8 mRNA levels (Fig. 3A). However, placentas from the AfMo had a 52.9 ± 7.9% reduction in the MCT10 mRNA compared with the NlMo (Fig. 3A). Additionally, the placentas carrying an AfFe had a 45.7 ± 0.4% reduction in the LAT1 and LAT2 mRNA levels (Fig. 3A) compared with that of a NlFe. We also measured the TH nuclear receptors and found that while all the placentas exhibited similar mRNA levels of THRB, the placentas carrying an AfFe exhibited a 39.6 ± 10.0% reduction in the THRA1 mRNA levels compared with that of a NlFe (Fig. 3B).

Figure 3.

Figure 3.

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(A) Quantitation of the mRNA levels of the indicated TH transporters and (B) nuclear receptors. Values are mean ± SEM of 5 samples from each placenta (1 placenta per group). Values from the 2 control NlMo placentas were combined. NlMo, normal mother; AfMo, affected mother; NlFe, normal fetus; AfFe, affected fetus.

Discussion

The discovery that the outcome of RTHβ pregnancies is influenced by the THRB genotype of the fetus (16) raised questions about the potential contributions of the placenta. In this study, we show that the THRB genotype of the fetus influences TH regulators in the placenta of women with RTHβ, including changes in deiodinases, TH transporters, and TH nuclear receptors.

Our study presents several limitations. (1) The study is based on only 2 placentas. (2) The content of deiodinases in the placentas changes with gestational age (22), and this study is limited to placentas at term. (3) The lack of information on the maternal component of the placentas; though in terms of D3, it is by far the dominant deiodinase in both components of the human placenta (23). (4) We could not document changes in placental T4 and T3 content owing to the large content in blood, mostly maternal, caused by the abundant vascularity.

On the other hand, the major strengths of this work are (1) the unique availability of placental tissue from a mother with RTHβ, which is a rare condition; (2) obtaining placental tissue from an affected and a normal infant, born to the same woman with RTHβ and at the same gestational age. The occurrence of (1) and (2) together is vanishingly small, and the insights of this report represent important preliminary data on the TH receptor–dependent differences in placenta gene regulation. It provides the basis for a future prospective study, with detailed planning, including perfusion of the placenta to reduce blood contamination and the sampling of both fetal and maternal regions.

Placentas have a much greater D3 activity than D2 (∼20-200 times). Thus, fluctuations in placental D3 rather than D2 activity influence the placental passage of active TH (22). This was illustrated in a study where inhibiting D3 in an isolated perfused human placenta resulted in a 2700-fold increase in TH passage to the fetal compartment (24). We found a decrease in D2 (30%) and D3 (46%) activities in the fetal component of the placenta of an AfMo carrying an AfFe. However, it is known that the maternal component of the placenta also expresses high D3 levels (23) and TH transporters (25).

When carrying an AfFe, the decrease in D2 could reduce the intracellular pool of D2-generated T3 in the placenta. However, the reduction in D3 is likely to have a more substantial effect. The overall result could be an intracellular build-up of T4 and T3 content in the placenta carrying an AfFe. The decrease in D3 activity and genomic downregulation of DIO3 expression in the AfFe could be explained by the concomitant transcriptional repression of THRA, as shown in TRα knockout mice (26). Intuitively, the higher the placental T4 and T3 content, the greater the passage of TH to the fetus. However, specific TH transporters in the placenta could invalidate this assumption (27). An AfMo carrying an AfFe exhibited a reduction in the expression of MCT10, LAT1, and LAT2 in placentas carrying an AfFe. While theoretically, such reductions could decrease the passage of TH to the fetus, TH transporters are plentiful in the placenta and exhibit a great deal of redundancy, with 7 known types and no single 1 playing a dominant role (28).

Along the same lines, when carrying a NlFe, the observed increase in D2 and D3 activity (and genomic upregulation of DIO2 and DIO3) could decrease the intracellular pool of T4 and T3 in the placenta. These changes may be interpreted as an attempt of the NlFe to reduce in utero exposure to high maternal TH levels. The normal body weight at birth of the NlFe support this possibility. However, these changes may not be sufficient in RTHβ pregnancies caused by more deleterious THRB mutations. That is the case of pregnancies where mothers harbor the R243Q mutation, exhibiting a strong RTHβ phenotype with FT3 and FT4 of 700% and 400% the ULN, respectively (16).

This study identifies a distinct modulatory effect of the fetal THRB genotype on specific TH regulators in the placenta, but the exact mechanism remains unknown. The fetal thyroid function in utero could affect the maternal thyroid function and circulating TH levels, ultimately influencing the placental TH regulators. Also, other TH-derived metabolites could play a role. For instance, the fetus, via a combined sulfoconjugation (T4S, rT3S, T3S, and T2S) and D3-mediated metabolism (conversion of T4 to rT3) reduces TH action. Among these metabolites, T2S was identified as the major fetal iodothyronine in maternal urine of sheep (29), and it is considered a mechanism responsible for reducing serum T3 concentrations in the fetus (T3→T3S + D3→T2S) (30). Thus, it is plausible that these metabolites could also influence the activity and expression of placental TH regulators. Additionally, serum cortisol variations could be in play, as cortisol is known to inhibit placental D2 and D3 (31). Furthermore, insulin-like growth factors and other factors and nutrients could alter the placental developmental programming (32), which includes the expression and activity of TH regulators. Another possibility is that factors of paternal origin may also influence DIO3 expression. DIO3 is a paternally imprinted gene and, thus, a wide range of interfering imprinting mechanisms (eg, exposure to pollutants (33)) could influence the changes observed in D3.

Because of the rare clinical occurrence of a mother with RTHβ carrying an affected and a normal infant born at the same gestational age, the sample size in this retrospective study was restricted to only 1 mother and 2 placentas (5 samples per placenta). Currently, it is not known if the observed decrease in placental deiodinases and TH transporters translates to an increased or reduced passage of TH to the AfFe, as we were unable to determine the placental T4 and T3 contents due to the high content in maternal blood in highly vascularized placental tissue. To address some of these questions, prospective investigations need to include more pregnant women with RTHβ caused by different THRB mutations, with detailed clinical and thyroid function test monitoring throughout pregnancy and collecting perfused placental tissue from both fetal and maternal components.

Acknowledgments

We thank the patients for their willingness to participate in this study.

Abbreviations

AfFe

affected fetus

AfMo

affected mother

D2

type 2 deiodinase

FT3

free triiodothyronine

FT4

free thyroxine

NlFe

normal fetus

NlMo

normal mother

RT-qPCR

quantitative reverse transcription polymerase chain reaction

RTHβ

resistance to TH beta

T3

triiodothyronine

T4

thyroxine

TH

thyroid hormone

THRB

thyroid hormone receptor beta

TSH

thyrotropin

TT3

total triiodothyronine

TT4

total thyroxine

ULN

upper limit of normal

Contributor Information

Federico Salas-Lucia, Departments of Medicine, University of Chicago, Chicago, IL 60637, USA.

Marius N Stan, Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA.

Haleigh James, Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA.

Aadil Rajwani, Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA.

Xiao-Hui Liao, Departments of Medicine, University of Chicago, Chicago, IL 60637, USA.

Alexandra M Dumitrescu, Departments of Medicine, University of Chicago, Chicago, IL 60637, USA; Departments of Molecular Metabolism and Nutrition, University of Chicago, Chicago, IL 60637, USA.

Samuel Refetoff, Departments of Medicine, University of Chicago, Chicago, IL 60637, USA; Departments of Pediatrics, University of Chicago, Chicago, IL 60637; Departments of Committees on Genetics, University of Chicago, Chicago, IL 60637, USA.

Funding

This work was supported in part by grant DK15070 from the National Institutes of Health.

Author Contributions

F.S.-L.: Methodology (equal); formal analysis (equal); writing—original draft (lead)—review and editing (equal); review and editing (equal). M.N.S.: Conceptualization (equal); formal analysis (equal); review and editing (equal). H.J.: Methodology (equal); review and editing (equal). A.R.: Methodology (equal); review and editing (equal). X.-H.L.: Methodology (equal); formal analysis (equal); review and editing (equal). A.M.D.: Conceptualization (equal); formal analysis (equal); review and editing (equal). S.R.: Conceptualization (lead); Writing—formal analysis (equal); review and editing (lead).

Disclosures

The authors have nothing to disclose.

Data Availability

Some of the data are not publicly available but could be obtained from the corresponding author on reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Some of the data are not publicly available but could be obtained from the corresponding author on reasonable request.

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