Abstract
Thyroid hormones (THs) regulate a number of metabolic processes during pregnancy. After implantation, the placenta forms and enhances embryonic growth and development. Dysregulated maternal THs signaling has been observed in malplacentation-mediated pregnancy complications such as preeclampsia, miscarriage, and intrauterine growth restriction (IUGR), but the molecular mechanisms involved in this association have not been fully characterized. In this review, we have discussed THs signaling and its roles in trophoblast proliferation, trophoblast differentiation, trophoblast invasion of the decidua, and decidual angiogenesis. We have also explored the relationship between specific pregnancy complications and placental THs transporters, deiodinases, and THs receptors. In addition, we have examined the effects of specific endocrine disruptors on placental THs signaling. The available evidence indicates that THs signaling is involved in the formation and functioning of the placenta and serves as the basis for understanding the pathogenesis and pathophysiology of dysthyroidism-associated pregnancy complications such as preeclampsia, miscarriage, and IUGR.
Introduction
Thyroid hormones (THs)—3,5,3′,5′-tetraiodothyronine (thyroxine, T4) and 3,5,3′- triiodothyronine (T3)—regulate the growth and development of the various tissues and organs of the body [1]. These hormones are vital for a healthy pregnancy and fetal development. In early gestation, placental and fetal development depends on maternal THs [2]. High incidences of malplacentation-mediated pregnancy complications, such as preeclampsia, miscarriage, and intrauterine growth restriction (IUGR), have been reported in women with abnormal levels of THs [3]. However, the molecular mechanisms involved in this association have not been fully characterized. Therefore, elucidating the molecular interactions between THs and the placenta is crucial to understanding the pathogenesis and pathophysiology of these pregnancy complications.
Overview of placentation
The mammalian placenta is a pregnancy-specific and transient organ that mediates the physiological communication between the mother and the fetus. It is responsible for hormone secretion, fetal nourishment, fetal thermoregulation, fetal waste removal, regulation of fetal gaseous exchange, and fetal protection from the maternal immune system and xenobiotics, thus serving as the fetal liver, kidney, lung, endocrine system, and gastrointestinal system [4–6]. Mammalian placentation is a very remarkable biological process during which diverse trophoblast populations form. Three major trophoblast subtypes with distinct features and functions have been identified in the matured human placenta. They are cytotrophoblast (CTB), syncytiotrophoblast (STB), and extravillous trophoblasts (EVTs) [7, 8]. The CTB is the first trophoblast phenotype that differentiates from trophoblast precursors. Proliferation and differentiation of the CTB cells yield the STB and EVTs [5, 9–12].
CTB cells that are committed to becoming the multinucleated STB undergo the process of syncytialization. During syncytialization, the cell membranes of adjacent cells adhere to one another and then disappear for their protoplasm to get mixed. The STB layer is directly in contact with the maternal blood, has a surface area of about 12–14 m2 at term, covers the entire surface of the villous tree, and performs the hormonal secretion, immune tolerance, and transport functions of the placenta. The retention of a functional STB layer is dependent on the shedding of the protoplasm from its surface into the maternal circulation and on the constant incorporation of newly proliferated and fused CTB cells beneath the STB [5, 9–12]. CTB cells that are committed to the EVT pathway migrate from the tips of the placental villi, proliferate, and then differentiate to form noninvasive proximal column trophoblasts (PCT), which further proliferate and differentiate into the nonproliferative but invasive distal column trophoblasts (DCT). After originating from the DCT, the EVT diffusively invades the decidua and inner third of the myometrium in the form of interstitial extravillous trophoblasts (iEVTs), which further differentiate into endovascular extravillous trophoblasts (evEVTs) and endoglandular extravillous trophoblasts (egEVTs). Endovascular extravillous trophoblasts (evEVTs) invade the uterine glands to facilitate histiotrophic nutrition to the embryo before the establishment of the uteroplacental circulation, while evEVTs invade the spiral arteries, enlarge them, and reduce their resistance against blood flow to establish the uteroplacental circulation. Aggregation and fusion of the iEVTs result in the formation of the multinucleated giant cells (GCs) [5, 9–12].
Abnormalities in placental formation and physiology are implicated in miscarriage, preeclampsia, and IUGR. Some postpartum health challenges of both the mother and fetus have also been partly attributed to placental dysfunction that occurred during pregnancy [3, 13, 14]. Hence, normal formation and functions of the placenta are very important for the success of pregnancy and for the overall health of the mother and fetus, even after birth.
THs signaling in the human placenta
THs are synthesized and released into the blood by the thyroid gland under the control of the hypothalamic–pituitary axis. The thyroid gland produces a high percentage of the biologically less potent hormone T4 and a small percentage of the more potent hormone T3. The ratio of T4 to T3 in the blood is approximately 14:1. T4 has a longer half-life than T3; and within cells, it is converted to T3 by deiodinases. Of the total amount of THs in circulation, only about 0.1% are unbound and hence available to enter cells [15–17]. Since fetal thyroid ontogeny starts around the 10th–12th gestational week, and does not get completed until birth, and besides its production of THs begins around the 18th–20th gestational week, the developing embryo or fetus depends on the maternal supply of THs [18].
Transportation of THs across the placenta
After being released into the maternal blood, THs bind to three different carrier proteins: transthyretin (TTR), thyroxine-binding globulin, and human serum albumin [19, 20]. The THs then enter and exit the placental cells through six THs membrane transporters: large amino acid transporter-1 (LAT1) [21], large amino acid transporter-2 (LAT2) [22], organic anion transporting polypeptide-1A2 (OATP1A2) [23], organic anion transporting polypeptide-4A1 (OATP4A1) [24], monocarboxylate transporter-8 (MCT8) [25], and monocarboxylate transporter-10 (MCT10) [26]. LAT1, MCT8, MCT10, OATP1A2, and OATP4A1 are all expressed in the STB, while MCT8, MCT10, and OATP1A2 are expressed in the CTB. With the exception of LAT2, OATP1A2, and OATP4A1, the expression of these transporters increases with gestational age and peak between the 27th and 34th gestational week. [21–27]. This is consistent with the proposed increase in maternal supply of THs to the fetus during the third trimester despite an increase in fetal THs production [28, 29]. Apart from MCT8, which exclusively and preferentially transports THs, all of these transporters also transport other ligands [27]. The loss of MCT8 expression and functions are compensated by the other transporters [30]. The ontogeny, localization, and the relative affinities of these placental THs transporters to THs are variable, complicated, and still under investigation.
Metabolism of THs in the placenta
Within the placenta, the THs are acted on by deiodinase 2 (D2) and deiodinase 3 (D3). The expression levels of the mRNAs and proteins of these deiodinases correlate negatively with gestation and are significantly higher in preterm placentae than in term placentae [31]. This might reflect a modification in the rate of uteroplacental THs transfer during these trimesters. In the first trimester, while D2 is strongly expressed in the CTB and very weakly in the STB, D3 is weakly expressed in the CTB but strongly in the STB. In the third trimester, the expression of the mRNA and protein of D2 in the CTB and STB become attenuated, while the protein expression of D3 in the STB remains unchanged, although the D3 mRNA expression decreases [31, 32]. These indicate that the degree of posttranscriptional and posttranslational regulation of D2 might be similar, while the degree of posttranscriptional and posttranslational regulation of D3 might exhibit significant variations in the placenta throughout gestation [31]. D2 is predominantly located in the membrane of the endoplasmic reticulum, but D3 is predominantly located in the plasma membrane [33, 34]. While D3 converts some of the T4 and T3 to reverse triiodothyronine (rT3) and diiodothyronine (T2), respectively, D2 converts some of the T4 and rT3 to T3 and T2, respectively. Therefore, the finely tuned system of these peroxidases plays an integral role in the intracellular availability of T3 [35–37]. Placental D3 activity is about 100- to 400-fold greater than D2 activity, and the D3/D2 mRNA ratio has been observed to vary between 0.05 and 52 [38]. A balance of D2 and D3 activities ensure that physiological THs levels are maintained within the placenta. The placental activities of these enzymes have been reported to decrease with the advancement in gestation, especially from the end of the first trimester [31, 38]. D3 activity is always high in the STB [32, 38], but some physiological amounts of T4 are able to cross the placenta to play significant roles in embryonic and fetal development [39, 40]. Interestingly, it has been suggested that T4 possibly has other routes through which it evades D3 effects to reach the embryo or the fetus. T4 can bind to TTR, which is partly produced by the STB, to form TTR–T4 complex. Since TTR can be endocytosed by the STB [41], it is hypothesized that the TTR–T4 complex can also be endocytosed by the STB and then get exocytosed into the fetal circulation [42, 43], thus protecting T4 from D3 inactivation. However, this proposal challenges the “free hormone hypothesis,” which states that “the biological activity of a hormone in vivo can only be predicted” by its unbound form since only unbound hormones are able to enter cells [44]. In view of this, the “free hormone hypothesis” might not be fully applicable to THs physiology. The mechanism of transport and deiodination of THs across the human placenta is displayed in Figure 1.
Transport and deiodination of THs across the human placenta. When T4 and T3 move from the maternal blood and enter the placenta, D3 converts some of the T4 and T3 to rT3 and T2, respectively. D2 converts some of the T4 and rT3 to T3 and T2, respectively. Thus, T4, T3, rT3, and T2 enter the fetal blood. The T4, T3, rT3, and T2 move across the placenta by passing through thyroid hormone transporters located on the apical and basolateral portions of the STB and CTB. Within the CTB, some amount of T3 interacts with the nuclei to induce gene expression.
In addition to deiodination, THs are metabolized by sulfation and glucuronidation reactions, which increase their water solubility to ease their clearance [45]. THs glucuronidation is catalyzed by uridine diphosphate (UDP)-glucuronyltransferases, which use UDP-glucuronic acid as their cofactor [46]. THs sulfation is catalyzed by sulfotransferases (SULTs), while their desulfation is catalyzed by arylsulfatases. The preferred substrates for deiodination are the THs sulfates [47]. Eight SULT isozymes have been identified to perform THs sulfation (SULT1A1, 1A3, 1A5, 1B1, 1B2, 1C1, 1E1, and A1), and among these, SULT1A1 and SULT1A3 are the major isoforms that are present in the human placenta. Thus, several SULT enzymes are expressed in the placenta; yet minimal THs sulfation occurs in the human placenta [48, 49]. THs metabolism requires the protein-mediated transport of the hormones across the cell membrane [50].
Regulation of placentation by THs
THs elicit most of their actions after binding to any of their variant receptors. THs receptors (THRs) are among the family of nuclear receptors. These receptors experience a conformational change, upon binding to THs, and then regulate gene expression, thus functioning as hormone-activated transcription factors. Two genes, designated as alpha and beta, encode these receptors. Each of these genes has two isoforms; therefore, four different THRs are recognized: THRα1, THRα2, THRβ1, and THRβ2 [51]. All the receptors are expressed in the CTB, STB, EVTs, and decidua [52, 53] TH. Four types of THs signaling mechanisms have been characterized in the human body. The first mechanism is the canonical pathway in which liganded THR directly binds to DNA. In the second mechanism, liganded THR is tethered to chromatin-associated proteins but does not bind directly to DNA. The third mechanism involves liganded THR exerting its function without getting recruited to the chromatin in either the cytoplasm or the nucleus; and the fourth mechanism suggests that THs act at the plasma membrane or in the cytoplasm without binding to a THR. In fact, this last type is emerging as a key component of THs signaling [51, 54]. However, as to whether all these signaling mechanisms occur in the placenta, or not, remains to be investigated.
Regulation of trophoblast proliferation by THs
All the trophoblast subtypes, except term CTB, exhibit THs responsiveness. However, the first trimester CTB is the subtype that is mostly targeted by T3 [52, 55], due to the higher levels of D2 mRNA and activity in this layer during the first trimester than in the second and third trimesters [32], as D2 increases the levels of T3 by monodeiodinizing T4 [37]. In vitro investigation of the effects of T3 on cell proliferation, using different cell lines, yielded contrasting reports. While the proliferative ability of the choriocarcinoma cell line, JEG 3, increased when it was treated with T3, the proliferative ability of the EVT-derived cell line, SGHPL-4, decreased when it was treated with T3 [52]. These contrasting results are, perhaps, due to the differences in the cell populations used, as the cells might exhibit differences in their expression of the deiodinases and responsiveness to the THs. It has been reported that, in JEG-3 cells, T3 is transcriptionally regulated by epidermal growth factor (EGF), a potent proliferation inducer, and then works synergistically with it [56, 57]. These suggest a role of THs in the proliferation of CTB cells.
Regulation of trophoblast differentiation by THs
CTB cell fusion and hormone secretion indicate the differentiation of CTB to STB [58]. It has been shown that THs facilitate placental hormone secretion. Exposure of cultured first trimester placental tissues to T3 (10−8 mol/l) resulted in an increase in the daily secretion of human placental lactogen, estradiol-17 beta, progesterone, and human chorionic gonadotropin (hCG). T4 (10−7 mol/l) administration was also able to elicit the same stimulatory effects on the placental tissues. However, treatment of the tissues with higher or lower doses of T3 or T4 attenuated these stimulatory effects [59]. Hence, for the placenta to effectively exhibit its endocrine functions, it needs to be supplied with optimal concentrations of T3 and T4. This confirms the observation made by Nishii and his colleagues. In their study, treatment of the CTB with T3 (10−8 mol/l) led to a significant increase in hCG secretion [60]. These observations suggest the involvement of THs in STB formation, since hCG regulates the process in an autocrine–paracrine manner [61, 62]. The attenuation in hCG production by higher or lower doses of the THs indicates that maternal hypothyroidism and hyperthyroidism can negatively affect syncytialization. As to whether THs only play a role in the replenishment of the STB, but not in their initial formation, is yet to be confirmed since there is no specific report about the effects of THs on CTB cells fusion. Nevertheless, a contrasting report has been made. Treating the CTB with T3 (10−8 mol/l) did not significantly increase hCG secretion [63]. Differences in the culturing procedures adopted by each group of investigators might be responsible for this contradiction.
Regulation of EVT invasiveness and decidual angiogenesis by THs
The molecules that mediate the invasiveness of the EVT comprise cell adhesion molecules like integrins, cadherins [64–66] and fibronectin [67, 68], metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs). During invasion, the EVT firstly migrates and degrades the endometrial extracellular matrix (ECM) with the aid of MMPs [69, 70].
T3 has been found to increase the mRNA expression of MMP2, MMP3, oncofetal fibronectin (onfFN), and integrin α5β1 in cultured early (8–12 weeks) EVTs [71, 72]. This corroborates the in vivo results reported in hypothyroid rats [73]. In hypothyroid rats, the reported increase in the GC layer and the glycogen cell population indicated a possible failure in the migration of these cells toward the decidua [74]. This hypothesis was confirmed by the finding that the migration of EVTs is reduced in hypothyroid pregnancies. The observed attenuation in EVT migration was caused by a reduction in the expression of MMP2, MMP9, placental leptin and the anti-inflammatory cytokine, nitric oxide synthase 2 (NOS2) [73], whose expression by EVTs augments their motility and invasive ability [75]. T3 has also been found to suppress EVT apoptosis through the downregulation of Fas and the Fas ligand, thus facilitating EVT invasion of the decidua [76]. The observation that T3 treatment does not affect the expression of TIMP1 protein in EVT cultures [71] agrees with the report that T3 facilitates trophoblast invasion of the decidua [52].
EVT invasion of the decidua and decidual angiogenesis are also regulated by inflammatory mediators released by the decidua [77–79]; and altered levels of such molecules have been reported in miscarriage [80] and preeclampsia [81]. In hypothyroid conditions, there is a compromise in the establishment of an anti-inflammatory environment in the placenta, as evidenced by a decrease in placental interleukin-10 (IL10), leptin, and NOS2 expression [73]. Similarly, hypothyroid women exhibit reduced expression of interleukin-4 (IL4) and IL10 in the decidua [82]. Treatment of cultured first trimester decidual cells with T3 resulted in an increase in the secretion of vascular endothelial growth factor-A (VEGFA) and angiopoietin-2 (ANGPT2) and a reduction in the secretion of IL10 by the decidua; but when cultured second trimester decidual cells were treated with T3, there was an increase in IL10 and angiogenin (ANG) secretion [83]. This indicates that the decidua responds to T3 in a gestational age-dependent manner. In pregnancies treated with L-thyroxine, there was a sharp increment in the levels of placental IL10 and NOS2 in midgestation, as well as a decrement in the levels of tumor necrosis factor alpha [73].
The release of inflammatory cytokines at the fetomaternal interface depends on the activation of Toll-like receptors (TLRs). Interestingly, placental TLR expression is affected by THs as evidenced by the reported increase in TLR2 levels and a reduction in TLR4 levels in the placenta of hypothyroid pregnancies [73]. The levels of placental angiogenic factors and inflammatory cytokines physiologically fluctuate as pregnancy advances. The circulating levels of chemokines and cytokines significantly fall during midgestation but are high in the first trimester and at the end of gestation [78, 84]. Hyperthyroid pregnancies have been reported to exhibit increased inflammatory cytokines—interferon gamma (IFNγ) and migration inhibitory factor—and expression of proangiogenic factors, such as fetal liver kinase (FLK1) and VEGF at the end of gestation [73, 85]. Hence, these alterations might be involved in the premature labor observed in hyperthyroid pregnancies [86, 87]. Administration with L-thyroxine increased the gene expression of placental growth factor (PGF) and VEGF [85], which, in early gestation, are regarded as the major proangiogenic factors involved in the vascular development of the fetomaternal interface [88]. Similarly, excess T4 resulted in an increased FLK1 expression and decidual angiogenesis, while hypothyroidism led to a reduction in the size of the decidua, possibly due to impaired angiogenesis and spiral arteries’ remodeling [89]. In consonance with this finding is the report that, in hypothyroid states, there is a reduction in the placental expression of VEGF [73, 74]. The observed dilation of the maternal venous sinuses in the placental labyrinth of hypothyroid rats [74] and the increment in placental vascular resistance in dysthyroid women [90] strengthen the veracity of the above reports. Decreased expression of these angiogenic and spiral arteries remodelers obviously lead to abnormal trophoblast invasion of the decidua. Thus, abnormal placental THs availability has the tendency to affect placental vascularity and compromise placental functions to disturb pregnancy. This might account for the high incidence of preeclampsia and miscarriage reported among hypothyroid women [3]. The report that hyperthyroidism is also associated with preeclampsia [91] might be related to dysregulation of the placental deiodinases. The reason is that, when the deiodinases are normally regulated, they protect the placenta from excessive levels of THs by establishing THs homeostasis. Nevertheless, the observation that both hypothyroidism and hyperthyroidism lead to preeclampsia only implies the possible existence of divergent molecular mechanisms in preeclampsia, at least, in the context of THs. The mechanism of regulation of placental development by THs has been shown in Figure 2.
Mechanism of regulation of placental development by THs. T3 acts synergistically with EGF to regulate trophoblast proliferation. Also, T4 and T3 contribute to syncytialization by augmenting the levels of hCG. During trophoblast invasion of the decidua, T4 and T3 promote adhesion of the EVT to the decidua by increasing the expression of onfFN and integrin α5β1; they enhance the degradation of the ECM by upregulating the expression of MMP2, MMP3, and MMP9; and they facilitate spiral arteries remodeling and decidual angiogenesis by increasing the expression of VEGF, PGF, IFNγ, IL4, IL10, NOS2, FLK1, ANG, ANGPT2, and leptin. In addition, T3 decreases the rate of EVT apoptosis by downregulating the expression of Fas and the Fas ligand.
Dysregulation of THs transporters and their associated complications
There are a high number of THs transporters in the placenta, and this signifies the existence of some functional redundancy [43]. LAT2, MCT8, and MCT10 are less essential for fetal development as their deficiencies in experimental mice did not elicit any observable fetal pathology [92–94]. Nevertheless, embryonic lethality was reported in LAT1 knockout mice [95]. This lethality might not be due to a lack of transplacental THs transport since the other transporters were intact. It might be due to an impairment in the transportation of amino acids since LAT1 is also an important amino acid transporter [96]. Possibly, a significant number of THs transporters has to be inactivated before placental THs transport would be significantly compromised [97].
In severe IUGR villous placentae, MCT8 expression is significantly increased while MCT10 expression is significantly decreased. The expression of the other transporters is not altered [25, 27]. The CTB of these placentae is more sensitive to T3 and hence takes up and transports T3 faster than the CTB of normal placentae. The increase in MCT8 expression might account for this observation [27]. The rate of THs uptake and transport might influence the effects that T3 has on the CTB. This is due to the in vitro observation that T3 uptake was higher in IUGR CTB than in normal placenta CTB. Interestingly, the increased T3 uptake and transport in the IUGR CTB did not affect T3 efflux, thus resulting in increased intracellular accumulation of T3 in the IUGR CTB. Alterations in the expression of THs transporters in the CTB, alterations in the T3-binding ability within the CTB, as well as variations in individual cell volumes due to hyper-syncytialization of IUGR CTB might be the reason why T3 accumulates in the CTB [27] and lead to hypothyroidism in the IUGR fetuses [98]. Thus, the hypersensitivity of IUGR CTB to T3, the accumulation of T3 in the CTB, and the increased rate of apoptosis observed in IUGR CTB might be part of the pathophysiology of IUGR [27]. The increased rate of CTB apoptosis, due to excess T3, seems contradictory to the known role of T3 against trophoblast apoptosis. This reflects the dose-dependent manner by which T3 elicits its effects. With increased rate of CTB apoptosis in IUGR, the rate of replenishment of the STB might be affected, resulting in a defective transport of THs and other substances from the mother to the fetus. This might also be associated with the higher incidence of IUGR reported in hyperthyroid women [91]. Investigation of the mechanism of dysregulation of MCT8 and MCT10 in IUGR, as well as the effects of T3 accumulation in the CTB, will enhance our understanding of the pathophysiology of this disease.
Dysregulation of the deiodinases and their associated complications
The main regulator of THs homeostasis in the placenta is D3. Significant levels of THs cannot cross the placenta so long as D3 remains active, since it is responsible for the inactivation of THs. [42, 99]. Abnormal upregulation of the placental D3 gene is, hence, a potential contributor to fetal hypothyroidism and its associated pathologies [100]. However, the report that the mRNA expression, as well as the activities, of each of D2 and D3 does not differ between normal placentae and IUGR placentae argues against the implication of placental deiodinases in the hypothyroidism observed in IUGR fetuses [31].
The effects of D3 on THs signaling occur via two routes in accordance with the availability of oxygen. In the presence of adequate oxygen, D3 moves from its site of synthesis in the endoplasmic reticulum to the Golgi apparatus and cell membrane, whereas in hypoxic states, D3 is redirected to the nucleus so as to be closer to the THRs [101]. Regardless of this, placental D3 mRNA and activities do not differ between preeclamptic women and normotensive pregnant women [32], even though there is a hypoxic state during preeclampsia [102, 103]. Interestingly, it has been observed that there is a differential distribution of D3 activity across the placental bed of normotensive pregnant women but not in their preeclamptic counterparts. This observation suggests that there is a possible blunting of D3 activity in preeclampsia [32]. Further investigation of the deiodinases and pregnancy complications will be needful to enhance our understanding of the pathogenesis and pathophysiology of those diseases.
Dysregulation of THs receptors and their associated complications
Most of the actions of THs are mediated by their receptors [51]. Dysregulation of these receptors will, thus, affect the effectiveness in THs action on the placenta and possibly result in malplacentation and its resultant pregnancy complications. A study revealed that the THR isoforms, THRα1, THRα2, and THRβ1, are upregulated in the placental villi of severe IUGR pregnancies [104] even though the placental deiodinase activities are not altered in this pathology [31]. Such altered expression of the THRs might be associated with the lower levels of THs observed in severe IUGR fetuses [43]. Perhaps, the receptors are upregulated to respond to the accumulated levels of the hormones in the CTB cells. When Ziegelmüller et al. conducted a similar investigation into miscarriage placentae, they observed that THRα1, THRα2, THRβ1, and THRβ2 were downregulated in the villous trophoblasts [53]. This may be associated with the aberrant placentation observed in miscarriage placentae. In view of these reports, it is clear that the pathophysiology of IUGR and miscarriage involve dysregulated placental expression of THRs (Figure 3). However, the mechanism of such dysregulation is yet to be revealed. Similarly, the relationship between the regulation of these receptors and the other pregnancy complications remains unknown.
![Proposed mechanism of hypothyroidism-induced preeclampsia, miscarriage, or IUGR. Maternal hypothyroidism can lead to low levels of placental T4 and T3, resulting in a decreased expression of onfFN, integrin α5β1, MMP2, MMP9, NOS2, VEGF, PGF, IFNγ, IL4, IL10, FLK1, ANG, ANGPT2, and leptin. EVT invasion into the decidua, therefore, becomes shallow, while decidual angiogenesis becomes impaired, leading to preeclampsia, miscarriage, or IUGR. In miscarriage, the shallow invasion and decidual angiogenesis might be mediated by the downregulation of THRα1, THRα2, THRβ1, and THRβ2 in the placenta. Maternal hypothyroidism can result in IUGR. However, the development of IUGR fetuses in euthyroid women reflects other causes of the pathology [116]. During IUGR, there is increased expression of MCT8 but decreased expression of MCT10 with an increase in T3 influx into the CTB and a decrease in T3 efflux from the CTB, resulting in the accumulation of T3 in the CTB. The excess T3 increases the rate of CTB apoptosis, thus affecting the replenishment of the STB. In severe IUGR, there is increased expression of THRα1, THRα2, and THRβ1 in the villi. Consequently, little amount of T3 reaches the fetus, resulting in fetal hypothyroidism and IUGR.](https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/biolreprod/102/1/10.1093_biolre_ioz182/1/m_ioz182f3.jpeg?Expires=1712688314&Signature=nE-m99ZR7XvFOF~H1ickD61Wzl7f3nQJthShge7sC4yWE2tmCW4~cwMEJYZ57Bvn1wDdDGCgfhzrJC~WxZYpwZCt9xE98pHC58lysiJWdpsNVAhoo~S4WG0AiiL9yPtA6EC0VWnzq7-xf-~66Wiqfcro94el2DTTnW8E4xUtd4bNy-426UflRV0QSxowH3oERU666wslj4LpjLDyuRRppafF7o4P0KXIzcMDMoBbT2g8nXQXDdZDtvLPggy1GfjZ8sB4Y0p9rnRrlFXP8GZZH5QlyU13mgyLjOZr-6oMbsQFZ2WFdf4VFFCiAoOAfjxJwajM59sIZTq2QNGu2NrgMg__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
Proposed mechanism of hypothyroidism-induced preeclampsia, miscarriage, or IUGR. Maternal hypothyroidism can lead to low levels of placental T4 and T3, resulting in a decreased expression of onfFN, integrin α5β1, MMP2, MMP9, NOS2, VEGF, PGF, IFNγ, IL4, IL10, FLK1, ANG, ANGPT2, and leptin. EVT invasion into the decidua, therefore, becomes shallow, while decidual angiogenesis becomes impaired, leading to preeclampsia, miscarriage, or IUGR. In miscarriage, the shallow invasion and decidual angiogenesis might be mediated by the downregulation of THRα1, THRα2, THRβ1, and THRβ2 in the placenta. Maternal hypothyroidism can result in IUGR. However, the development of IUGR fetuses in euthyroid women reflects other causes of the pathology [116]. During IUGR, there is increased expression of MCT8 but decreased expression of MCT10 with an increase in T3 influx into the CTB and a decrease in T3 efflux from the CTB, resulting in the accumulation of T3 in the CTB. The excess T3 increases the rate of CTB apoptosis, thus affecting the replenishment of the STB. In severe IUGR, there is increased expression of THRα1, THRα2, and THRβ1 in the villi. Consequently, little amount of T3 reaches the fetus, resulting in fetal hypothyroidism and IUGR.
Influence of endocrine disruptors on placental THs signaling
Placental THs signaling is disrupted by polybrominated diphenyl ethers (PBDEs), 2,4,6-tributyl phosphate, and other halogenated compounds [105, 106] such as polychlorinated biphenyls (PCBs) [107], brominated flame retardants [108], organotin chemicals, and organochlorine pesticides [109]. These compounds act by disrupting the activities of the deiodinases [110] and SULTs [111], reducing TTR levels [110], and disrupting the THRs [112]. PCBs, in particular, might act as an agonist or an antagonist of THs [113].
Exposure to some of these pollutants led to the development of IUGR. When pregnant mice were exposed to fenvalerate throughout pregnancy, fetal IUGR resulted. There was a reduction in the placental THRα1 and THRβ1 mRNAs. Also, there was a suppression of nuclear translocation of placental THRβ1 as well as a downregulation of placental VEGFα and insulin-like growth factor 2 (IGF-2), two proteins involved in THs signaling [114]. This downregulation possibly resulted in aberrant spiral arteries remodeling and decidual angiogenesis, which might have affected the transport of THs from the mother to the fetus. Interestingly, the observed decrease in THRα1 and THRβ1 expression in placentae of fenvalerate-induced IUGR mice pregnancies contradict the observed increased expression of these receptors in IUGR human placentae. Probably, the IUGR induced by fenvalerate involves a mechanism that is different from the IUGR induced by maternal hypothyroidism and other means. Otherwise, the pathophysiology of IUGR in mice and humans differs greatly. Moreover, gestational exposure to di-2-ethylhexyl phthalate (DEHP) inhibited THR-mediated placental VEGF, PGF, IGF1 and IGF2 expression, and increased fetal IUGR incidence in a dose-dependent manner [115]. These findings reveal that fenvalerate and DEHP cause IUGR by impairing placental function and fetal development via the inhibition of THs signaling. Thus, it is advisable for women to protect themselves against such chemicals so as to evade the placental malfunctions and IUGR associated with such chemicals.
Conclusion
THs enter and leave the placenta through their transporters: LAT1, LAT2, OATP1A2, OATP4A1, MCT8, and MCT10. Within the placenta, THs are metabolized through sulfation, glucuronidation, and deiodination. Sulfation and glucuronidation increase the water solubility of the THs to increase the rate of their renal clearance, while deiodination leads to the conversion of some of the THs to rT3 and T2. Once fully formed, all the trophoblast subtypes express THRs and respond directly to THs signaling to facilitate placental morphophysiology. Dysregulation of THRs and transporters has been observed in some pregnancy complications, suggesting their involvement in the pathogenesis and pathophysiology of these diseases. Normal THs signaling enhances the expression of a number of molecules that are involved in trophoblast invasion of the decidua and decidual angiogenesis, while abnormal THs signaling has been found to disrupt the expression of these molecules. This indicates that THs promote trophoblast invasion of the decidua and decidual angiogenesis and that a dysthyroid state impairs these processes to result in malplacentation and its associated pathologies. Hence, we have proposed a possible mechanism by which abnormal THs signaling affects placental formation to cause preeclampsia, miscarriage, or IUGR (Figure 3). This mechanism possibly explains the high incidences of these complications in hypothyroid pregnant women and indicates the need to integrate thyroid function tests into the routine obstetric investigations that form the basis of antenatal care.
Future perspectives
Studies regarding the interaction between THs and the placenta, miscarriage, preeclampsia, and IUGR have been based on cell lines, placental explants, rodent models, and human studies. Findings from the nonhuman and in vitro samples may not be similar to the real biological mechanism of THs signaling in humans; hence extrapolating the findings to humans could be misleading. In view of this, investigation and confirmation of the proposed mechanism in humans are highly recommended. Due to the complexity of these pregnancy complications, prospective studies are recommended to further investigate the expression of THs transporters, the deiodinases, and THRs in normal and pathological human placentae and identify the associated signaling pathways. Also, such studies should focus on the effects of endocrine disruptors on the placental expression of the TH-associated proteins. The findings from these studies will contribute to our understanding of the pathogenesis and pathophysiology of dysthyroidism-mediated malplacentation and pregnancy complications.
Conflict of interest
The authors declare that no conflict of interest exists.
References
Author notes
Grant Support: This work was supported by the National Key Research and Development Program of China (Grant No. 2018 YFC1004401) and the National Natural Science Foundation of China (Grant No. 81671493).
All authors contributed equally to the conception of the ideas and the write-up of the manuscript.
