Maternal T4 Research Articles

Distribution of Polybrominated Diphenyl Ethers (PBDEs) in Placental Tissues of Maternal and Fetal Origin in Exposed Wistar Rats and Associations with Thyroid Hormone Levels.

In utero exposure to polybrominated diphenyl ethers (PBDEs) is linked to adverse pregnancy and fetal health outcomes, including altered thyroid hormone (TH) levels. Despite their phase out, PBDEs are still commonly detected in newborn cord blood. While PBDEs can cross the placenta, few studies have separately assessed PBDEs or THs in the maternal and fetal placental tissues. Additionally, no studies have separately assessed THs in these tissues across mid- and late gestation, during the onset of fetal TH synthesis. To address these gaps, we conducted a study with Wistar rats and examined PBDE accumulation in the maternal and fetal placenta. Pregnant dams were exposed daily to sesame oil vehicle, a low dose, or high dose PBDE mixture. At GD15 and 20, dams were sacrificed and placental tissues were collected. Tissues were analyzed for PBDEs, T3, rT3, and T4 using mass spectrometry. BDE-47, -99, -100, and -209 were frequently detected in both the fetal and maternal placenta. At GD15, higher concentrations of BDE-99, -100, and -209 were measured in the fetal placenta; however, this trend reversed by GD20, with higher maternal placental concentrations. Placental T3 and T4 were significantly impacted by exposure, tissue, and exposure x tissue at GD15, with significant reductions in both THs following low dose exposure in the maternal placenta. By GD20, maternal placental T3 was only significantly reduced in the high exposure groups and there was no effect on placental T4. Overall, these results highlight the rapid developmental changes that occur throughout gestation between the maternal and fetal placenta, and the differential impacts of gestational PBDE exposure on placental T3 and T4 across mid- and late-gestation.

Controlled Antenatal Thyroid Screening Study III: Effects of gestational thyroid status on adolescent brain morphology.

Children born to mothers with gestational hypo- or hyperthyroidism may have increased risk of adverse neurodevelopmental outcomes. However, the effects of maternal thyroid status on offspring brain development are unclear. To establish whether adolescent brain morphology is affected by suboptimal gestational thyroid function (SGTF). The Controlled Antenatal Thyroid Screening (CATS) study randomized mothers with SGTF to levothyroxine or no supplementation from ∼12 weeks' gestation. At age 9, children born to mothers who were over-treated with levothyroxine had a higher risk of conduct and hyperactivity traits. For the current CATS III study, children underwent neuroimaging studies, including T1-weighted structural magnetic resonance imaging (MRI). A total of 85 children aged 11-16 years had usable T1-weighted MRI data (exposed to untreated SGTF (n=21), normal GTF (n=24), or treated SGTF (optimally-treated (n=21), over-treated (n=20)). Primary outcome: to examine the association of SGTF and its treatment with global brain volumes. Secondary and exploratory outcomes: to investigate the association of maternal TSH and free T4 levels with global and subregional brain volumes. Results were adjusted for age, sex and pubertal scores. There were no significant differences in global brain volumetric measures between groups, including total gray matter volume (p=0.373). Weak positive correlations were found between maternal TSH, but not FT4, levels and several brain volumes, but these did not survive testing for multiple comparisons. We found no evidence that SGTF was associated with differences in adolescent brain morphology, and no impact of levothyroxine supplementation.

Gestational hypothyroxinemia induces ASD-like phenotypes in behavior, proinflammatory markers, and glutamatergic protein expression in mouse offspring of both sexes.

The prevalence of autism spectrum disorder (ASD) has significantly risen in the past three decades, prompting researchers to explore the potential contributions of environmental factors during pregnancy to ASD development. One such factor of interest is gestational hypothyroxinemia (HTX), a frequent condition in pregnancy associated with cognitive impairments in the offspring. While retrospective human studies have linked gestational HTX to autistic traits, the cellular and molecular mechanisms underlying the development of ASD-like phenotypes remain poorly understood. This study used a mouse model of gestational HTX to evaluate ASD-like phenotypes in the offspring. To induce gestational HTX, pregnant mice were treated with 2-mercapto-1-methylimidazole (MMI), a thyroid hormones synthesis inhibitor, in the tap-drinking water from embryonic days (E) 10 to E14. A separate group received MMI along with a daily subcutaneous injection of T4, while the control group received regular tap water during the entire pregnancy. Female and male offspring underwent assessments for repetitive, anxious, and social behaviors from postnatal day (P) 55 to P64. On P65, mice were euthanized for the evaluation of ASD-related inflammatory markers in blood, spleen, and specific brain regions. Additionally, the expression of glutamatergic proteins (NLGN3 and HOMER1) was analyzed in the prefrontal cortex and hippocampus. The HTX-offspring exhibited anxious-like behavior, a subordinate state, and impaired social interactions. Subsequently, both female and male HTX-offspring displayed elevated proinflammatory cytokines in blood, including IL-1β, IL-6, IL-17A, and TNF-α, while only males showed reduced levels of IL-10. The spleen of HTX-offspring of both sexes showed increased Th17/Treg ratio and M1-like macrophages. In the prefrontal cortex and hippocampus of male HTX-offspring, elevated levels of IL-17A and reduced IL-10 were observed, accompanied by increased expression of hippocampal NLGN3 and HOMER1. All these observations were compared to those observed in the Control-offspring. Notably, the supplementation with T4 during the MMI treatment prevents the development of the observed phenotypes. Correlation analysis revealed an association between maternal T4 levels and specific ASD-like outcomes. This study validates human observations, demonstrating for the first time that gestational HTX induces ASD-like phenotypes in the offspring, highlighting the need of monitoring thyroid function during pregnancy.

Perinatal maternal exposure to high-dose sodium phenobarbital in the modified Comparative Thyroid Assay: no significant reduction in thyroid hormones in pups despite notable effects in dams.

We propose a modified Comparative Thyroid Assay (CTA, USEPA) utilizing a smaller number of Sprague-Dawley rats (N=10/group) that assesses brain thyroid hormone (TH) concentrations and periventricular heterotopia while maintaining assay sensitivity. Our recent findings demonstrated that a prenatal test cohort of the modified CTA detected a dose-dependent decrease in maternal serum T3 (up to -26%) and T4 (up to -44%) with sodium phenobarbital (NaPB) exposure at 1000 ppm and 1500 ppm, equivalent to intakes of 60 and 84 mg/kg/day, respectively. On gestation day (GD) 20, fetuses exhibited reduced serum (-26%) and brain (-29%) TH concentrations, although these reductions were not dose dependent. The present study expanded the treatment in a postnatal test cohort, with maternal exposure to NaPB (81-93 mg/kg/day) from GD6 to lactation day (LD) 21. We assessed serum and brain TH concentrations, and periventricular heterotopia in pups on postnatal days (PND) 4, 21, and 28. While LD21 dams showed significant reductions in serum T3 (up to -34%) and T4 (up to -54%), the pups did not exhibit significant TH suppression or periventricular heterotopia at any test point. Instead, a compensatory increase in T4 was observed in serum and brain of PND21 pups. The present study confirmed that perinatal maternal exposure to high doses of NaPB leads to a moderate decrease in maternal TH concentrations; however, the exposure of maternal rats to a similar dose of NaPB did not significantly reduce serum or brain TH concentrations in their postnatal offspring.

The Potential Role of Thyroid Hormone Therapy in Neural Progenitor Cell Differentiation and Its Impact on Neurodevelopmental Disorders.

Thyroid hormone (T3) plays a vital role in brain development and its dysregulation can impact behavior, nervous system function, and cognitive development. Large case-cohort studies have associated abnormal maternal T3 during early pregnancy to epilepsy, autism, and attention deficit hyperactivity disorder (ADHD) in children. Recent experimental findings have also shown T3's influence on the fate of neural precursor cells and raise the question of its convergence with embryonic neural progenitors. Our objective was to investigate how T3 treatment affects neuronal development and functionality at the cellular level. In vitro experiments using neural precursor cells (NPCs) measured cell growth and numbers after exposure to varying T3 concentrations. Time points included week 0 (W0) representing NPCs treated with 100nM T3 for 5days, and differentiated cortical neurons assessed at weeks 3 (W3), 6 (W6), and 8 (W8). Techniques such as single-cell calcium imaging and whole-cell patch clamp were utilized to evaluate neuronal activity and function. IHC staining detected mature neuron markers, and RNA sequencing enabled molecular profiling. W6 and W8 neurons exhibited higher action potential frequencies, with W6 showing increased peak amplitudes and shortened inter-spike intervals by 50%, indicating enhanced activity. Transcriptomic analysis revealed that W6 T3-treated neurons formed a distinct cluster, suggesting accelerated maturation. Comparison with the whole transcriptome further unveiled a correlation between W6 neurons treated with T3 and neuronal regulatory elements associated with autism and ADHD. These findings provide insights into T3's impact on neuronal development and potential mechanisms of T3 dysregulation and neurodevelopmental disorders.

OR06-02 Placental Distribution Of Polybrominated Diphenyl Ethers (Pbdes) And Thyroid Hormones Across Gestation In PBDE-exposed Wistar Rats

Abstract Disclosure: S. Gaballah: None. B. Horman: None. G. St Armour: None. K. Hoffman: None. H.B. Patisaul: None. H. Stapleton: None. In utero exposure to polybrominated diphenyl ethers (PBDEs) has been linked to adverse pregnancy and fetal health outcomes, including altered thyroid hormone (TH) levels. Despite their phase out, PBDEs are still measured in newborn cord blood. While evidence suggests that PBDEs can cross the placental barrier, few studies have assessed differences in PBDE or TH accumulation in the maternally and fetally-derived placental tissue layers or studied fetal sex-differences. To address these gaps, we conducted a controlled exposure study in Wistar rats (n=8 per treatment and gestational day (GD)). From GD2, pregnant dams were exposed daily to sesame oil vehicle, a low dose, or high dose mixture of 10 PBDEs. The low dose represents the 95th percentile of PBDEs measured in U.S. house dust, and the high dose is ∼20X higher. At GD15 and GD20, dams were sacrificed and placental tissues were micro-dissected into maternally and fetally-derived layers. Tissues were analyzed for PBDEs and for T3, rT3, and T4 using mass spectrometry. BDEs 47, 99, 100, and 209 were frequently detected in the fetal and maternal tissues. Higher concentrations of BDEs 99, 100, and 209 were measured in the fetal placenta on GD 15; however, this trend flipped at GD20, with higher maternal concentrations of BDEs 47, 99, and 209. This shift appears to be related to changes in the mass of the maternal and fetal layers during gestation and not to different partioning processes. Only BDE 99 was significantly different between the two layers, in both sexes. At both timepoints, T3 levels were several-fold higher in maternal tissues than fetal, but T3 decreased in maternal tissues by GD20. No sex differences were observed. In general, we observed a significant difference in maternal and fetal T3 levels at GD15 and GD20 in control, low, and high dose-exposed animals. At GD15, there was a significant difference between maternal and fetal female placental T4 levels (p=0.0237) and a suggestive difference in males (p=0.081) in the high dose group, as well as a significant effect of sex between the fetal tissues in the low dose group (p=0.0044). T4 was only detected in the fetal side at GD20, with no significant effects of treatment or sex. These results highlight the rapid developmental changes throughout gestation between the maternal and fetal placenta. Overall, these data highlight that PBDE accumulation in Wistar rats changes across gestation, causing disruption of TH levels in maternal and fetal tissues, and that sex-specific differences may be contributing to differential accumulation patterns in male and female-associated placentas. Coupled with rapid morphological changes in the fetal and maternal layers during placental growth, in utero PBDE exposure may result in adverse impacts on placental TH regulation and fetal health. Presentation: Thursday, June 15, 2023

Relationship between infant hypothyroidism and maternal thyroid disease

Background: Due to the very high complications of neonatal hypothyroidism in the country, neonatal screening program is performed for timely diagnosis and treatment of neonates. The aim of this study to investigate the relationship between infant hypothyroidism and maternal thyroid disease. Methods: This cross-sectional study was done on 195 neonates with a diagnosis of hypothyroidism. Necessary data were collected by a checklist and then analyzed by statistical methods in statistical package for the social sciences (SPSS) version 21 by statistical methods. Results: Of all mothers, 21.0% had a history of thyroid disease. There was no statistically significant relationship between maternal age and infant thyroid stimulating hormone (TSH). There was no significant relationship between the history of maternal hypothyroidism and maternal hypothyroidism (during experiments) with the amount of TSH in the newborn. There was a direct and significant relationship between maternal TSH level and maternal free T4. But there was no statistically significant relationship between infant TSH level and maternal TSH level and free T4. There was no significant difference in neonatal TSH levels with maternal anti-TPO status. There was no significant relationship between the history of maternal diabetes and the history of maternal hypertension with neonatal TSH. There was no significant difference in neonatal TSH levels by maternal thyroid status. Conclusions: In the present study, no significant relationship was found between the incidence of neonatal hypothyroidism and the presence of thyroid disease in mothers. The existence of different genetic and environmental factors and the significant impact of each of these factors can justify this result.

Treatment with dexamethasone's effects on pregnant women and their fetuses Guinea pigs' Thyroid and Adrenal Hormones

Among the common small laboratory animals, the guinea pig has a thyroid and adrenal hormone pattern most similar to that in humans. Daily administration of 10mg Dexamethasone s/c from 55 days of pregnancy for 6 days resulted in a depression of fetal body and organ weight and depression of maternal and fetal plasma T4, T3, and cortisol concentration. However, an increase in fetal plasma T4 and T3 concentration rates suggests enhanced de-iodination of T4. In human fetuses, late in gestation, a rise in plasma cortisol may not be necessary for organ maturation. Considerable species differences have been observed concerning the type of hormone secreted by the adrenal cortex. Keywords: Dexamethasone, fetal cortisol, Thyroxin, Triiodothyronine, Guinea pigs.

Maternal hypothyroidism in rats impairs placental nutrient transporter expression, increases labyrinth zone size, and impairs fetal growth

IntroductionHypothyroidism during pregnancy is associated with fetal growth restriction (FGR). FGR is commonly caused by placental insufficiency and yet the role of hypothyroidism in placental regulation of fetal growth is unknown. This study aimed to investigate the effects of maternal hypothyroidism on placental nutrient transporter expression, placental morphology, and placental metabolism. MethodsHypothyroidism was induced in female Sprague-Dawley rats by adding methimazole (MMI) to drinking water at moderate (MOD, MMI at 0.005% w/v) and severe (SEV, MMI at 0.02% w/v) doses from one week prior to pregnancy and throughout gestation. Maternal and fetal tissues were collected on embryonic day 20 (E20). ResultsHypothyroidism reduced fetal weight (PTrt<0.001) despite causing fetal hyperglycaemia (PTrt = 0.016). Placental weight was not affected by hypothyroidism however placental efficiency was reduced (PTrt<0.001), as was the junctional zone (JZ):labyrinth zone (LZ) weight ratio (PTrt = 0.005). LZ glycogen content was increased (PTrt = 0.029) and while mRNA expression of glucose transporters was reduced by hypothyroidism, only GLUT1 protein expression was reduced in male LZs. Maternal hypothyroidism reduced mitochondrial content (PTrt = 0.031), particularly in SEV males relative to CON males (P = 0.004). Protein expression of Complex V (P < 0.001) and Complex III (P = 0.002) of the electron transport chain were also reduced in males. Maternal hypothyroidism reduced LZ (PTrt<0.001) and fetal plasma triglycerides (P = 0.019) while fetal free fatty acids and the expression of LZ lipid transporters was not affected. DiscussionOverall, maternal hypothyroidism may lead to FGR through reduced maternal T4 availability, changes to placental morphology, altered nutrient transporter expression and sex-specific effects on placental metabolism. Changes to LZ glycogen and triglyceride stores as well as mitochondrial content suggest a metabolic shift from oxidative phosphorylation to anaerobic glycolysis in males. These changes also likely impact fetal substrate availability and therefore fetal growth.

Resistance to thyroid hormone induced tachycardia in RTHα syndrome

Mutations in thyroid hormone receptor α1 (TRα1) cause Resistance to Thyroid Hormone α (RTHα), a disorder characterized by hypothyroidism in TRα1-expressing tissues including the heart. Surprisingly, we report that treatment of RTHα patients with thyroxine to overcome tissue hormone resistance does not elevate their heart rate. Cardiac telemetry in male, TRα1 mutant, mice indicates that such persistent bradycardia is caused by an intrinsic cardiac defect and not due to altered autonomic control. Transcriptomic analyses show preserved, thyroid hormone (T3)-dependent upregulation of pacemaker channels (Hcn2, Hcn4), but irreversibly reduced expression of several ion channel genes controlling heart rate. Exposure of TRα1 mutant male mice to higher maternal T3 concentrations in utero, restores altered expression and DNA methylation of ion channels, including Ryr2. Our findings indicate that target genes other than Hcn2 and Hcn4 mediate T3-induced tachycardia and suggest that treatment of RTHα patients with thyroxine in high dosage without concomitant tachycardia, is possible.

In a zebrafish biomedical model of human Allan-Herndon-Dudley syndrome impaired MTH signaling leads to decreased neural cell diversity.

Maternally derived thyroid hormone (T3) is a fundamental factor for vertebrate neurodevelopment. In humans, mutations on the thyroid hormones (TH) exclusive transporter monocarboxylic acid transporter 8 (MCT8) lead to the Allan-Herndon-Dudley syndrome (AHDS). Patients with AHDS present severe underdevelopment of the central nervous system, with profound cognitive and locomotor consequences. Functional impairment of zebrafish T3 exclusive membrane transporter Mct8 phenocopies many symptoms observed in patients with AHDS, thus providing an outstanding animal model to study this human condition. In addition, it was previously shown in the zebrafish mct8 KD model that maternal T3 (MTH) acts as an integrator of different key developmental pathways during zebrafish development. Using a zebrafish Mct8 knockdown model, with consequent inhibition of maternal thyroid hormones (MTH) uptake to the target cells, we analyzed genes modulated by MTH by qPCR in a temporal series from the start of segmentation through hatching. Survival (TUNEL) and proliferation (PH3) of neural progenitor cells (dla, her2) were determined, and the cellular distribution of neural MTH-target genes in the spinal cord during development was characterized. In addition, in-vivo live imaging was performed to access NOTCH overexpression action on cell division in this AHDS model. We determined the developmental time window when MTH is required for appropriate CNS development in the zebrafish; MTH is not involved in neuroectoderm specification but is fundamental in the early stages of neurogenesis by promoting the maintenance of specific neural progenitor populations. MTH signaling is required for developing different neural cell types and maintaining spinal cord cytoarchitecture, and modulation of NOTCH signaling in a non-autonomous cell manner is involved in this process. The findings show that MTH allows the enrichment of neural progenitor pools, regulating the cell diversity output observed by the end of embryogenesis and that Mct8 impairment restricts CNS development. This work contributes to the understanding of the cellular mechanisms underlying human AHDS.

Developmental Exposure to Flame Retardant Toxicants (PBDEs) Produces Autistic-Like Reprogramming of Behavior and Hypothalamic Oxytocin in a Thyroid- and Sex-Dependent Manner

Introduction: The prevalence of psychosocial neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) is rising at an alarming rate. ASD etiology is multifactorial, resulting from sex-specific genetic susceptibilities that may interact with environmental toxicant exposures during critical developmental periods. In humans, PBDEs are thyroid-disrupting chemicals associated with altered socioemotional behavior, decreased IQ and hyperactivity. We have previously demonstrated autistic-like effects produced by perinatal exposure to PBDEs in female mice (Kozlova et al, 2022; PMID: 34687351). Maternal thyroid hormone (TH) status affects fetal brain development and has been linked to ASD. Since thyroid hormones regulate oxytocin (OXT) and/or vasopressin neuroendocrine systems critical for social behavior, PBDEs may produce autistic-like actions via disruption of the thyroid system. Therefore, this study tested the hypothesis that developmental exposure to PBDEs produce neurobehavioral and hypothalamic OXT deficits in a TH-dependent manner. Materials and Methods: C57BL/6N dams were exposed human relevant doses of the penta-PBDE mixture, DE-71, at 0.1 mg/kg/d (L-DE-71), 0.4 mg/kg/d (H-DE-71) or with corn oil vehicle control (VEH/CON) for 10 wks (pre-conception: 4 wk, gestation: 3 wk, lactation: 3 wk). A subset of dams was treated with levothyroxine, a synthetic analogue of thyroxine (T4) (8 μg/100 g bw; GD 12-PND 21). Other dams were administered the thyroid synthesis inhibitor, 6-propyl-2-thiouracil (PTU; 50 mg/L; GD 14-PND 21). Results: Compared to VEH/CON, T4 and insulin-like growth factor-1 were attenuated in L-DE-71 dams at PND 0 but normalized in L-DE-71 + T4. In contrast, dam plasma OXT was not altered by DE-71 and elevated by T4 supplementation. L-DE-71 adult male and female offspring showed deficient social novelty preference; maternal T4 supplementation prevented this only in females. In contrast, T4 supplementation was equally effective at normalizing exaggerated repetitive behavior in L-DE-71 male and female offspring. DE-71 reduced OXT immunofluorescence IOD in the paraventricular nucleus of the hypothalamus (PVH) in male (L- and H-DE-71) and female offspring (L-DE-71) and in supraoptic nucleus (SON) in male offspring (L-DE-71) at PND 30. T4 supplementation normalized OXT content in L-DE-71 female and H-DE-71 male PVH. DE-71 had no effect on plasma OXT but was upregulated in VEH/CON +T4 female and DE-71+T4 male offspring. RT-qPCR analysis performed at PND15-30 showed that L-DE-71 downregulated hypothalamic Trh and cortical Oatp1c1 and Dio3 in females and upregulated hypothalamic Dio2, Esr1 and Esr2 and cortical Oatp1c1 in males. PTU’s actions do not exactly mimic those of DE-71. Conclusions: These results suggest that PBDEs disrupt social behavior and central OXT in a TH-dependent and sex-dependent manner. We provide novel information about possible TH-responsive genes that may contribute to neurodevelopmental disorders such as ASD. This work is supported by a Society of Toxicology Syngenta Fellowship Award in Human Health Applications of New Technologies and University of California President's Pre-Professoriate Fellowship to E.V.K. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Asymmetrical Transport of Thyroxine Across Human Term Placenta.

Background: Fetal development is crucially dependent on thyroid hormone (TH). Maternal-to-fetal transfer of TH is a prerequisite for fetal TH availability, particularly in the first half of pregnancy. The mechanisms of transplacental transport of TH, however, are yet poorly understood. We, therefore, investigated the TH transport processes across human placentas using an ex vivo perfusion system. Methods: Intact cotyledons from term placentas of uncomplicated pregnancies were cannulated within 30 minutes after delivery and the maternal and fetal circulations were re-established. One hundred nanomolar thyroxine (T4) was added to either the maternal or fetal circulation and perfusions run up to three hours during which samples were taken from both circulations at different time points. Variables included addition of iopanoic acid (IOP) to block activity of the deiodinase type 3 (D3) and bovine serum albumin (BSA) to trap released T4. T4 and 3,3',5'-triiodothyronine concentrations in the perfusates were measured by radioimmunoassays. Results: Maternal-to-fetal transfer was slow, with T4 barely detectable in the fetal circulation unless D3 was blocked by IOP. Fetal T4 was detected after three hours perfusion (10.6 ± 0.6 nM) when BSA (34 g/L) was added in the fetal circulation to trap the released T4. In contrast, fetal-to-maternal transfer of T4 was rapid and maternal T4 increased to 43.6 ± 5.5 nM. Conclusions: Maternal-to-fetal T4 transport is limited, whereas fetal-to-maternal transport is rapid indicating that T4 transport across human term placenta is an asymmetrical process. With the high D3 activity, our observations are compatible with a protective role of the placental barrier. Future studies should reveal how the placenta exerts its gatekeeper function in ensuring optimal TH passage to the fetus.

Gestational thyroid hormone concentrations and risk of attention-deficit hyperactivity disorder in the Norwegian Mother, Father and Child Cohort Study.

Maternal thyroid function plays an important role in foetal brain development; however, little consensus exists regarding the relationship between normal variability in thyroid hormones and common neurodevelopmental disorders, such as attention-deficit hyperactivity disorder (ADHD). We sought to examine the association between mid-pregnancy maternal thyroid function and risk of clinically diagnosed ADHD in offspring. We conducted a nested case-control study in the Norwegian Mother, Father and Child Cohort Study. Among children born 2003 or later, we randomly sampled singleton ADHD cases obtained through linkage with the Norwegian Patient Registry (n=298) and 554 controls. Concentrations of maternal triiodothyronine (T3), thyroxine (T4), T3-Uptake, thyroid-stimulating hormone (TSH) and thyroid peroxidase antibody (TPO-Ab) were measured in maternal plasma, collected at approximately 17 weeks' gestation. Indices of free T4 (FT4i) and free T3 (FT3i) were calculated. We used multivariable adjusted logistic regression to calculate odds ratios and accounted for missing covariate data using multiple imputation. We used restricted cubic splines to assess non-linear trends and provide flexible representations. We examined effect measure modification by dietary iodine and selenium intake. In sensitivity analyses, we excluded women with clinically significant thyroid disorders (n=73). High maternal T3 was associated with increased risk of ADHD (5th vs 1st quintile odds ratio 2.27, 95% confidence interval 1.21, 4.26). For FT4i, both the lowest and highest quintiles were associated with an approximate 1.6-fold increase in risk of ADHD, with similar trends found for T4. The FT4i association was modified by dietary iodine intake such that the highest risk strata were confined to the low intake group. Both high and low concentrations of maternal thyroid hormones, although within population reference ranges, increase the risk of ADHD in offspring. Increased susceptibility may be found among women with low dietary intake of iodine and selenium.

W-Compound can be used as a Biomarker for Fetal Thyroid Function and a Potential Tool for Screening Congenital Hypothyroidism

Sulfoconjugation is the major pathway for thyroid hormone (TH) metabolism, converting T4 to inactive metabolites, T4S, rT3S, and T3S in fetus, via sulfotransferases (SULT) and type 3 deiodinase in gestation. Consistent with high production rate of T4S and rT3S, there are high serum sulfated iodothyronine analogs, including T4S, T3S, rT3S, and 3,3’-T2S (T2S), in ovine and human fetal and preterm infants. Fetal TH metabolic pathways predict T2S as the major TH metabolite in the fetus. Since maternal T2S appears to be quantitatively derived from fetal T3 (the active TH), the amount of T2S in the maternal compartment correlates with fetal thyroid function in sheep. In humans, maternal serum contains high levels of radioimmunoassayable T2S; however, it displays as a peak adjacent to but unidentical to synthetic T2S on HLPC and we named it the W-Compound. Levels of W-Compound increase during pregnancy and peak as high as 20-fold to that of nonpregnant women. Maternal serum levels of W-Compound significantly correlate with fetal T4 and W-compound concentrations but not maternal serum T4 in euthyroid or hyperthyroid women, showing a distinct difference between fetal and maternal in TH metabolism. Fetal T2S is actively transferred to the mother via placenta and the quantity of T2S or its metabolite (W-Compound) in maternal compartment reflects fetal thyroid function. Thus, maternal serum W-Compound may be a biomarker for monitoring fetal thyroid function in utero, although more investigations are needed to determine if it can be used as an alternative strategy for screening/managing congenital hypothyroidism due to dysregulated thyroid hormone metabolism.

Nicotine binds to the transthyretin-thyroxine complex and reduces its uptake by placental trophoblasts

BackgroundA supply of maternal thyroid hormone (thyroxine, T4) is essential for normal human fetal development. Human placental trophoblasts synthesize, secrete and take up the T4 binding protein transthyretin, providing a route for maternal T4 to enter the placenta. Transthyretin is also involved in T4 transport in other tissues such as the brain choroid plexus. Nicotine alters transthyretin synthesis and function in rat choroid plexus. If nicotine influences trophoblast turnover of transthyretin, then it may directly affect placental transfer of T4 to the developing fetus and contribute to the negative impacts of smoking on fetal growth, development and placental function. MethodsThe effect of nicotine on trophoblast uptake of Alexa-labelled transthyretin was measured using live cell imaging. The effect of nicotine on protein expression was measured by western blotting. Interactions between transthyretin, T4 and nicotine were investigated using chemical cross-linking techniques and molecular dynamic simulations. ResultsNicotine blocks uptake of transthyretin-T4 by human placental trophoblast cells. Nicotine reduces the expression of the trophoblast scavenger receptor class B type 1 (SR-B1) that plays a role in transthyretin-T4 uptake. Molecular dynamic modelling suggests that when T4 is bound to transthyretin, nicotine binding increases tetramer stability, reducing the ability of the transthyretin-T4 complex to enter trophoblast cells. ConclusionOur data suggest that nicotine exposure during pregnancy reduces transplacental transport of transthyretin and T4 to the placenta and developing fetus. This may contribute to the negative effects of smoking on fetal growth, development and pregnancy viability.

Thyroid Disorders.

Thyroid Disorders.

Association between Maternal Thyroid Hormone Level and Fetal Weight

Aims: Present study is aimed to find out the association between maternal thyroid hormone at delivery and weight of delivered fetus.&#x0D; Study Design: This is a case-control study in which low birth weight was cases and appropriate for gestational age were considered as control.&#x0D; Place and Duration of Study: Study was conducted at National Institute of Pathology (ICMR), New Delhi and Department of Biotechnology, Invertis University, Bareilly from July 2018 to July 2020.&#x0D; Subjects and Methods: A total of 193 maternal blood samples were collected and fetal parameters were recorded as per inclusion criteria. Quantitative estimation of Triiodothyronine (T3), Thyroxine (T4), and Thyroid Stimulating Hormone (TSH) was done in the separated serum samples by pre-coated ELISA kits and data analysis was performed using SigmaStat. Cases include women having full-term deliveries with birth weight &lt; 2.5Kg i.e. Low Birth Weight (LBW) and Controls includes women having Appropriate for Gestational Age (AGA) delivery with birth weight &gt; 2.5Kg.&#x0D; Results: No significant difference was observed in maternal age as well as age at marriage and other demographic parameters, while maternal weight and BMI is significantly less in LBW as compared to AGA i.e. 49.62±5.34 &amp; 53.96±6.92 and 21.32±4.01 and 22.66±1.57 respectively having P&lt;0.001. Pearson correlation coefficient also revealed a significant negative correlation of T4 with both fetal weight and fetal length and a positive correlation of T3 with fetal weight, fetal length, and fetal head circumference, whereas TSH did not show any significant association with fetal parameters.&#x0D; Conclusion: It was concluded that maternal T3 and T4 affects the fetal development during gestational period, TSH did not show any significant association with fetal parameters.

T4-mediated rescue of aortic malformations in hypothyroid rats indicates maternal thyroid status can affect great vessel development

Pexacerfont is a corticotrophin-releasing factor subtype 1 receptor (CRF-1) antagonist developed for potential treatment of anxiety and stress-related disorders. In male rats, pexacerfont caused hepatic enzyme induction leading to increased thyroxine (T4) clearance. When administered to pregnant rats on gestation day 6 to 15, pexacerfont at 300 mg/kg/day (30× mean AUC in humans at 100 mg/day) produced similar effects on thyroid homeostasis with serum T4 and thyroid-stimulating hormone levels that were 0.3–0.5× and 3.3–3.7× of controls, respectively. At this dose, fetuses of pexacerfont-treated dams presented findings associated with maternal hypothyroidism including growth retardation and increased skeletal alterations. Additionally, there were unexpected great vessel malformations that were mostly derived from the 4th pharyngeal arch artery in 5 (4.3%) fetuses from 3 (15.8%) litters. The etiology was unclear whether the vascular malformations were related to insufficient thyroid hormones or another mechanism. To better understand this relationship, pregnant rats were implanted with a subcutaneous L-thyroxine pellet designed to provide a sustained release of T4 throughout organogenesis in rat embryos (GD 6 to 15; the dosing period of pexacerfont). T4 supplementation produced a near euthyroid state in pexacerfont-treated dams and completely prevented the fetal vascular malformations. These results suggest maternal T4 levels during organogenesis may have a role in great vessel morphogenesis associated with patterning and/or regression of pharyngeal arch arteries. Although previous clinical reports have speculated a potential relationship between thyroid hormone homeostasis and early cardiovascular development, this is the first report to experimentally demonstrate this relationship in great vessel morphogenesis.

The inflammatory response after an intestinal inflammatory challenge affects in an opposite manner to the female and male offspring gestated in hypothyroxinemia

Abstract Ulcerative colitis (UC) is a highly frequent inflammatory bowel disease (IBD), which causes are unknown. We have shown that the offspring gestated under thyroxine (T4) deficiency, condition named hypothyroxinemia (HTX), shows inflammatory features at the intestine. Moreover, the offspring gestated under HTX (HTX-offspring) suffers strong experimental autoimmune disease. Suggesting that gestational HTX could imprint their offspring with a high immune response after an inflammatory challenge. Thus, we think that the HTX-offspring will be more prone to suffer IBD. To analyze this hypothesis C57BL6 pregnant mice were induced with gestational HTX during E10 to E15 by giving them methimazole in the tap-drinking water. Then, UC was induced to the HTX-offspring or control at postnatal P55 by giving them dextran sodium sulphate (DSS) in the tap-drinking water for six days. Body weight, pathological score of IBD and hidden blood in stool were analyzed daily. Then, mice were sacrificed at day 10 to evaluate their inflammatory response. For that histological analysis were performed in the intestine; the content of cytokines in serum and intestine by ELISA and the populations of innate and adaptive immune cells at the intestine and spleen by flow cytometry. Our results shown that the male and female offspring developed an opposite immune response to UC. The female HTX-offspring were more resistant and the male HTX-offspring were more sensitive to UC compared to their respective female and male control groups. Thus, our results suggest that the immune response of an individual can be set up during gestation and that the normal level of maternal T4 during gestation is fundamental for the proper function of the offspring immune system.