Disrupt Thyroid Hormone Homeostasis Research Articles

Occurrence of rare earth elements in umbilical cord serum and association with thyroid hormones and birth outcomes in newborns

Rare earth elements (REEs) are emerging contaminants that are increasingly used in high technology products. However, limited information is available regarding exposure to REEs and associated health effects in neonates. This study aimed to investigate the association between REE concentrations and thyroid hormone levels, as well as birth outcomes in 109 newborns in Beijing, China. We measured the concentrations of 16 REEs and thyroid hormones in umbilical cord serum. To assess the impact of exposure to individual REEs and REE mixtures on thyroid hormone levels and birth outcomes, we employed univariate linear regression, least absolute shrinkage and selection operator (LASSO), and weighted quantile sum (WQS) models. We detected 14 REEs at high rates (92.6%–100%), with yttrium exhibiting the highest median (interquartile range) concentration [43.94 (0.33–172.55) ng/mL], followed by scandium [3.64 (0.46–11.15) ng/mL]. Univariate analyses showed that per logarithmic (ln)-unit change of neodymium (Nd) and samarium (Sm) was associated with 0.039 [95% confidence interval (CI): 0.001, 0.007] and 0.031 (95% CI: 0.003, 0.060) increases in free thyroxine (FT4) levels, respectively. Moreover, 14 REEs exhibited significant associations with triiodothyronine (T3) levels, resulting in increases ranging from 0.066 to 0.307. Elevated concentrations of terbium (Tb) [per ln-unit change: −0.021 (95% CI: −0.041, −0.01)] and lutetium (Lu) [-0.023 (95% CI: −0.043, −0.002)] were inversely correlated with birth length in newborns. A further multiple exposure analysis employing the LASSO model identified Sm, Nd, Y, Sc, and Lu as critical factors influencing FT4 and T3 levels. Additionally, WQS analyses showed positive associations between exposure to a mixture of 14 REEs and FT4 (P = 0.046), T3 (P < 0.001), and birth length (P = 0.049). These findings suggest that in utero exposure to REEs might disrupt thyroid hormone homeostasis and impact intrauterine growth. Further studies are warranted to validate these findings and elucidate the underlying mechanisms.

Exposure to MEHP during Pregnancy and Lactation Impairs Offspring Growth and Development by Disrupting Thyroid Hormone Homeostasis.

Mono(2-ethylhexyl) phthalate (MEHP), as a highly toxic and biologically active phthalate metabolite, poses considerable risks to the environment and humans. Despite the existence of in vitro studies, there is a lack of in vivo experiments assessing its toxicity, particularly thyroid toxicity. Herein, we investigated the thyroid-disrupting effects of MEHP and the effects on growth and development of maternal exposure to MEHP during pregnancy and lactation on the offspring modeled by SD rats. We found that thyroid hormone (TH) homeostasis was disrupted in the offspring, showing a decrease in total TH levels, combined with an increase in free TH levels. Nonhomeostasis ultimately leads to weight loss in female offspring, longer anogenital distance in male offspring, prolonged eye-opening times, and fewer offspring. Our findings indicate that maternal exposure to MEHP during pregnancy and lactation indirectly influences the synthesis, transport, transformation, and metabolism of THs in the offspring. Meanwhile, MEHP disrupted the morphology and ultrastructure of the thyroid gland, leading to TH disruption. This hormonal disruption might ultimately affect the growth and development of the offspring. This study provides a novel perspective on the thyroid toxicity mechanisms of phthalate metabolites, emphasizing the health risks to newborns indirectly exposed to phthalates and their metabolites.

The effects of hexabromocyclododecane on the transcriptome and hepatic enzyme activity in three human HepaRG-based models

The disruption of thyroid hormone homeostasis by hexabromocyclododecane (HBCD) in rodents is hypothesized to be due to HBCD increasing the hepatic clearance of thyroxine (T4). The extent to which these effects are relevant to humans is unclear. To evaluate HBCD effects on humans, the activation of key hepatic nuclear receptors and the consequent disruption of thyroid hormone homeostasis were studied in different human hepatic cell models. The hepatoma cell line, HepaRG, cultured as two-dimensional (2D), sandwich (SW) and spheroid (3D) cultures, and primary human hepatocytes (PHH) cultured as sandwich were exposed to 1 and 10 µM HBCD and characterized for their transcriptome changes. Pathway enrichment analysis showed that 3D models, followed by SW, had a stronger transcriptome response to HBCD, which is explained by the higher expression of hepatic nuclear receptors but also greater accumulation of HBCD measured inside cells in these models. The Pregnane X receptor pathway is one of the pathways most upregulated across the three hepatic models, followed by the constitutive androstane receptor and general hepatic nuclear receptors pathways. Lipid metabolism pathways had a downregulation tendency in all exposures and in both PHH and the three cultivation modes of HepaRG. The activity of enzymes related to PXR/CAR induction and T4 metabolism were evaluated in the three different types of HepaRG cultures exposed to HBCD for 48 h. Reference inducers, rifampicin and PCB-153 did affect 2D and SW HepaRG cultures’ enzymatic activity but not 3D. HBCD did not induce the activity of any of the studied enzymes in any of the cell models and culture methods. This study illustrates that for nuclear receptor-mediated T4 disruption, transcriptome changes might not be indicative of an actual adverse effect. Clarification of the reasons for the lack of translation is essential to evaluate new chemicals’ potential to be thyroid hormone disruptors by altering thyroid hormone metabolism.

Associations of bisphenol exposure with thyroid hormones in pregnant women: a prospective birth cohort study in China.

Bisphenols are endocrine disruptor chemicals that disrupt thyroid hormone homeostasis. However, evidence on the effects of bisphenol mixtures on thyroid hormones are insufficient. Therefore, the present study aimed to explore the effects of bisphenol substitutes and bisphenol mixtures on thyroid hormones during pregnancy. The study was conducted among 446 pregnant women in the Guangxi Zhuang Birth Cohort (GZBC), China. In multiple linear regressions, compared with the low-exposure group, bisphenol S (BPS) concentrations in the middle-exposure group led to a 10.90% (95% CI: - 18.16%, - 2.99%) decrease in triiodothyronine (T3) levels in the first trimester; tetrabromobisphenol A (TBBPA) levels in the middle-exposure group led to an 8.26% (95% CI: - 15.82%, - 0.01%) decrease in T3 levels in the first trimester; bisphenol B (BPB) levels in the middle-exposure group led to higher free thyroxine (FT4) levels (9.84%; 95% CI: 1.73%, 18.60%) in the second trimester; bisphenol F (BPF) in the middle-exposure group led to higher FT4 levels (8.59%, 95% CI: 0.53%, 17.31%) in the second trimester; and TBBPA levels in the high-exposure group led to a 9.39% (95% CI: 1.46%, 17.93%) increase in FT4 levels in the second trimester. The Bayesian kernel machine regression (BKMR) and restricted cubic spline (RCS) models showed a U-shaped dose-response relationship between bisphenol A (BPA) and free triiodothyronine (FT3) (p < 0.01) as well as BPS and FT4 (p < 0.05). Nonlinear relationships were also observed between the bisphenol mixture and FT3. Overall, maternal bisphenol exposure affected thyroid hormone levels during pregnancy. This study provides evidence that BPB, BPF, BPS, and TBBPA are unsafe substitutes for BPA, as well as the overall effect of bisphenols on adverse health in human beings.

Developmental toxicity of bromoacetamide via the thyroid hormone receptors-mediated disruption of thyroid hormone homeostasis in zebrafish embryos

Bromoacetamide (BAcAm) is a nitrogenous disinfection by-product. We previously found that BAcAm induced developmental toxicity in zebrafish embryos, but the underlying mechanisms remain to be elucidated. Since thyroid hormones (THs) homeostasis is crucial to development, we hypothesized that disruption of THs homeostasis may play a role in the developmental toxicity of BAcAm. In this study, we found BAcAm exposure significantly increased mortality and malformation rate, decreased hatching rate and body length, inhibited the locomotor capacity in zebrafish embryos. BAcAm elevated TSH, T3 and T4 levels, down-regulated T3/T4 ratios, and up-regulated mRNA expression changes of THs related genes (trh, tsh, tg, nis, tpo, dio1, dio2, ugt1ab，klf9 and rho), but down-regulated mRNA expression changes of TH receptors (tr α and tr β). Up-regulated tr α and tr β mRNAs by rescue treatment confirmed that both tr α and tr β were involved in the developmental toxicity of BAcAm. In conclusion, our study indicates disruption of THs homeostasis via the thyroid hormone receptors was responsible for the developmental toxicity of BAcAm.

Human exposure to a mixture of endocrine disruptors and serum levels of thyroid hormones: A cross-sectional study

Exposure to endocrine disruptors (EDCs) could disrupt thyroid hormone homeostasis. However, human epidemiological studies reported inconsistent observations, and scarce information on the effect of a mixture of chemicals. The aim of the present study was to examine the associations of multiple chemicals with thyroid hormones among adults from China. We measured serum levels of thyroid hormones and urinary levels of 11 EDCs, including six phthalate metabolites, bisphenol A (BPA), bisphenol F (BPF), bisphenol S (BPS), perchlorate, and thiocyanate among 177 healthy adults without occupational exposure. Associations of multiple urinary analytes with serum thyroid hormones were examined by performing general linear regression analysis and bayesian kernal machine regression analysis. These EDCs were detected in almost all samples. After adjusting for various covariates, we observed only BPF significantly associated with total thyroxin (TT4) (β=-0.27, 95% confidence interval (CI) [-0.41, -0.14]), total triiodothyronine (TT3) (β=-0.02 95% CI [-0.03, -0.01]), free T4 (fT4) (β=-0.02, 95% CI [-0.03, -0.01]), and free T3 (fT3) (β=-0.04, 95% CI [-0.07, -0.01]), and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) and monoethyl phthalate (MEP) positively associated with TT4 (β=0.24, 95% CI [0.01, 0.48]) and fT4 (β=0.02, 95% CI [0.01, 0.04]), respectively. Moreover, we observed significant dose-response relationships between TT4 and the mixture of 11 EDCs, and BPF was the main contributor to the mixture effect, suggesting the priority of potential effect of BPF on disrupting thyroid function under a real scenario of human exposure to multiple EDCs. Our findings supported the hypothesis that human exposure to low levels of EDCs could alter thyroid hormones homeostasis among non-occupational healthy adults.

Lycopene ameliorates the effect of Aroclor 1254 on morphology, proliferation, and angiogenesis of the thyroid gland in rat

Aroclor 1254 is a mixture of polychlorinated biphenyls that are reported to disrupt thyroid hormone homeostasis, yet little is known on its effect on thyroid gland microarchitecture. Lycopene is a commonly used potent antioxidant. This study is a biochemical, histological, and immunohistochemical assessment of the effect of Aroclor 1254 on the morphology, proliferation, and angiogenesis of the thyroid gland in rat and to evaluate the possible ameliorating role of lycopene. Twenty-four adult male albino rats were divided into 4 groups; Control, lycopene-treated (4 mg/kg/day orally for 30 days), Aroclor 1254-treated (2 mg/kg/day intraperitoneally for 30 days), and lycopene & Aroclor 1254-treated group. Serum thyroid hormones, thyroid-stimulating hormone (TSH), and tissue malondialdehyde (MDA) were quantified. Thyroid specimens were processed for histological staining with hematoxylin and eosin, periodic acid-Schiff, and Mallory’s trichrome stains as well as immunohistochemical staining for detection of calcitonin, Ki67, and VEGF. In this study, Aroclor 1254-treated animals recorded a significant decline in both serum T3 and T4 coupled with a significant elevation in both TSH and tissue MDA. Histological sections showed small irregular follicles with the formation of hyperplastic and micro follicles. Some follicular and parafollicular cells depicted nuclear and cytoplasmic alterations associating with scanty or absent colloid in addition to signs of inflammation and fibrosis. A significant upregulation in the immunohistochemical expression of calcitonin, Ki67, and VEGF was recorded. Lycopene co-treatment successfully reinstated the values of most studied parameters and retrieved a near-control thyroid morphology. In conclusion, Aroclor 1254 impacted the thyroid hormone homeostasis, morphology, proliferation, and angiogenesis of the thyroid gland in rat, while lycopene efficiently ameliorated these adverse effects.

PM2.5 disrupts thyroid hormone homeostasis through activation of the hypothalamic-pituitary-thyroid (HPT) axis and induction of hepatic transthyretin in female rats 2.5

Fine particulate matter (PM2.5), a ubiquitous environmental pollutant, has been indicated to affect thyroid hormone (TH) homeostasis in women, but the detailed mechanism behind this effect remains unclear. The objective of this study was to evaluate the roles of the hypothalamic-pituitary-thyroid (HPT) axis and hepatic transthyretin in the thyroid-disrupting effects of PM2.5. Sprague Dawley rats were treated with PM2.5 (0, 15 and 30 mg/kg) by passive pulmonary inhalation for 49 days; and recovery experimental group rats were dosed with PM2.5 (30 mg/kg) for 35 days, and no treatment was done during the subsequent 14 days. PM2.5 was handled twice a day by passive pulmonary inhalation throughout the study. After treatment, pathological changes were analyzed by performing haemotoxylin and eosin staining, measuring levels of THs and urine iodine (UI) in serum, plasma, and urine samples using enzyme-linked immunoabsorbent assay, and expression of proteins in the hypothalamus, pituitary, thyroid, and liver tissues of rats were analyzed by immunohistochemistry and Western blotting. The levels of oxidative stress factors, such as reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (Gpx), and nuclear factor-kappa B (NF-κB) in female rats’ plasma were also evaluated by ELISA. The results of these analyses revealed that PM2.5 treatment induced pathologic changes in rat thyroid and liver characterized by increased follicular cavity size and decreased amounts of follicular epithelial cells and fat vacuoles, respectively. Serum levels of triiodothyronine, thyroxine, and thyroid stimulating hormone were significantly decreased, plasma NF-κB level was increased and plasma redox state was unbalanced (enhanced ROS, MDA and Gpx levels; reduced SOD activities) in female rats treated with PM2.5 (P < 0.05). PM2.5 treatment suppressed the biosynthesis and biotransformation of THs by increasing sodium iodide symporter, thyroid transcription factor 1, thyroid transcription factor 2, and paired box 8 protein expression levels (P < 0.05). Additionally, thyroid stimulating hormone receptor and thyroid peroxidase levels were significantly decreased (P < 0.05). Both thyrotropin releasing hormone receptor and thyroid stimulating hormone beta levels were enhanced (P < 0.05). Moreover, transport of THs was inhibited due to reduced protein expression of hepatic transthyretin upon treatment with PM2.5. In summary, PM2.5 treatment could perturb TH homeostasis by affecting TH biosynthesis, biotransformation, and transport, affecting TH receptor levels, and inducing oxidative stress and inflammatory responses. Activation of the HPT axis and altered hepatic transthyretin levels therefore appear to play a crucial role in PM2.5-induced thyroid dysfunction.

Amiodarone bioconcentration and suppression of metamorphosis in Xenopus

Trace concentrations of a number of pharmaceutically active compounds have been detected in the aquatic environment in many countries, where they are thought to have the potential to exert adverse effects on non-target organisms. Amiodarone (AMD) is one such high-risk compound commonly used in general hospitals. AMD is known to alter normal thyroid hormone (TH) function, although little information is available regarding the specific mechanism by which this disruption occurs. Anuran tadpole metamorphosis is a TH-controlled developmental process and has proven to be useful as a screening tool for environmental pollutants suspected of disrupting TH functions. In the present study, our objective was to clarify the effects of AMD on Xenopus metamorphosis as well as to assess the bioconcentration of this pharmaceutical in the liver. We found that AMD suppressed spontaneous metamorphosis, including tail regression and hindlimb elongation in pro-metamorphic stage tadpoles, which is controlled by endogenous circulating TH, indicating that AMD is a TH antagonist. In transgenic X. laevis tadpoles carrying plasmid DNA containing TH-responsive element (TRE) and a 5′-upstream promoter region of the TH receptor (TR) βA1 gene linked to a green fluorescent protein (EGFP) gene, triiodothyronine (T3) exposure induced a strong EGFP expression in the hind limbs, whereas the addition of AMD to T3 suppressed EGFP expression, suggesting that this drug interferes with the binding of T3 to TR, leading to the inhibition of TR-mediated gene expression. We also found AMD to be highly bioconcentrated in the liver of pro-metamorphic X. tropicalis tadpoles, and we monitored hepatic accumulation of this drug using mass spectrometry imaging (MSI). Our findings suggest that AMD imposes potential risk to aquatic wildlife by disrupting TH homeostasis, with further possibility of accumulating in organisms higher up in the food chain.

Gestational and childhood exposure to phthalates and child behavior

BackgroundEarly-life phthalate exposures may adversely influence neurodevelopment by disrupting thyroid hormone homeostasis, altering brain lipid metabolism, or reducing gonadal hormone concentrations. Previous literature examining gestational phthalate exposure and child behavior were inconclusive and few prospective studies have examined childhood phthalate exposure, particularly phthalate mixtures. We investigated whether gestational and childhood phthalate exposures were associated with child behavior. MethodsWe used data from 314 mother–child pairs in the HOME Study, a longitudinal pregnancy and birth cohort that enrolled pregnant women from Cincinnati, Ohio. We quantified urinary concentrations of 11 phthalate metabolites in samples collected twice during gestation from women and six times from their children when they were ages 1, 2, 3, 4, 5, and 8 years. We assessed children’s behavior at ages 2, 3, 4, 5, and 8 years using the Behavioral Assessment System for Children-2. Using linear mixed models, we estimated covariate-adjusted associations of measurement-error-corrected gestational and childhood phthalate metabolite concentrations (per interquartile range increase) with repeated child behavior assessments. We used Weighted Quantile Sum (WQS) regression to estimate the association of phthalate mixtures with child behavior. ResultsGestational mono(3-carboxypropyl) phthalate (MCPP) concentrations were associated with more problem behaviors (internalizing: β = 0.9, 95% confidence interval [CI] = -0.1, 1.9; externalizing: β = 1.0, 95%CI = -0.1, 2.0; behavioral symptoms index [BSI]: β = 1.1, 95%CI = 0.1, 2.1). Higher childhood monobenzyl phthalate (MBzP) (β = 1.4; 95%CI = 0.0, 2.7), monocarboxynonyl phthalate (MCNP) (β = 3.2; 95%CI = 1.6, 4.8), monocarboxyoctyl phthalate (MCOP) (β = 0.9; 95%CI = 0.0, 1.7), MCPP (β = 1.8; 95%CI = 0.2, 3.5), and monoethyl phthalate (MEP) (β = 1.6; 95%CI = 0.1, 3.1) concentrations were associated with higher BSI composite scores. Consistent with this, the weighted childhood phthalate index was associated with more problem behaviors (internalizing: β = 1.5, 95%CI = −0.2, 3.1; externalizing: β = 1.7, 95%CI = 0.1, 3.5; BSI: β = 1.7, 95%CI = 0.2, 3.2); MBzP, MCNP, and MEP largely contributed to these associations. ConclusionOur findings suggest that childhood exposure to phthalate mixtures may be associated with children’s problem behaviors.

Thyroid dysfunction in patients with diabetic retinopathy.

Thyroid disease and diabetes mellitus (DM) are the most common endocrinopathies in clinical practice that interact with each other. On the one hand, thyroid hormones regulate carbohydrate metabolism and pancreas functions, and on the other hand DM affects the function and work of the thyroid gland. Diabetic retinopathy (DR) is a highly specific neurovascular complication of both type 1 and type 2 DM, which is a significant cause of vision loss on a global scale. In DM, the internal blood-retinal barrier is the earliest to be damaged, and changes in neuroretina result from the loss of its adaptation to metabolic disorders. Patients with DM have a higher incidence of thyroid disease compared to people without DM. The coexistence of DM with thyroid disease leads to endothelial damage, and the degree of its dysfunction has a significant impact on the course of macro- and microangiopathic complications in patients. There are few reports in the literature about the impact of thyroid disease and substitution of levothyroxine preparations on the development and course of DR in patients with DM. It is unknown whether the fact that patients with unrecognised hypothyroidism are not treated with levothyroxine preparations disrupts thyroid hormone homeostasis to the extent that it may contribute to a higher incidence of DR. This review discusses recent clinical trials for thyroid dysfunction in patients with DR.

Extrapolating In Vitro Screening Assay Data for Thyroperoxidase Inhibition to Predict Serum Thyroid Hormones in the Rat.

Thyroperoxidase (TPO) is an enzyme essential for thyroid hormone (TH) synthesis and a target site for a number of xenobiotics that disrupt TH homeostasis. An in vitro high-throughput screening assay for TPO inhibition, the Amplex UltraRed-TPO (AUR-TPO), has been used to screen the ToxCast chemical libraries for this action. Output from this assay would be most useful if it could be readily translated into an in vivo response, namely a reduction of TH in serum. To this end, the relationship between TPO inhibition in vitro and serum TH decreases was examined in rats exposed to 2 classic TPO inhibitors, propylthiouracil (PTU) and methimazole (MMI). Serum and gland PTU, MMI, and TH levels were quantified using tandem liquid chromatography mass spectrometry. Thyroperoxidase activity was determined in thyroid gland microsomes treated with PTU or MMI in vitro and ex vivo from thyroid gland microsomes prepared from exposed animals. A quantitative model was constructed by contrasting in vitro and ex vivo AUR-TPO results and the in vivo time-course and dose-response analysis. In vitro:ex vivo correlations of AUR-TPO outputs indicated that less than 30% inhibition of TPO in vitro was sufficient to reduce serum T4 by 20%, a degree of regulatory significance. Although further testing of model estimates using other TPO inhibitors is essential for verification of these initial findings, the results of this study provide a means to translate in vitro screening assay results into predictions of in vivo serum T4 changes to inform risk assessment.

Associations between Exposure to Persistent Organic Pollutants and Thyroid Function in a Case-Control Study of East China.

Animal studies have indicated that persistent organic pollutants (POPs) affect thyroid hormone homeostasis, while epidemiological studies involving human have not shown consistent results. In this study, we investigated the associations between POP exposure and thyroid function among adult population of East China. One hundred eighty-six participants diagnosed with thyroid disease and 186 participants without thyroid disease from Shandong, China were enrolled in the case-control study during 2016 to 2017. We found that POP exposure was significantly and positively associated with the risk of thyroid disease. The association of thyroid disease with a sum of 17 POPs followed a nonmonotonic dose response, with an adjusted odds ratio of 2.09 (95% confidence intervals: 1.13-3.87, p = 0.019) for the second quartile. Among 186 participants in the control group, concentrations of POPs showed negative associations with triiodothyronine (T3), free T3 (FT3), thyroxine (T4), and free T4 (FT4) in males and positive associations with T4 and FT4 in females. Taken together, these findings suggest that POP exposure can disrupt thyroid hormone homeostasis and increase the risk of thyroid disease.

OR23-6 The Impact of PBDE Exposure, Fetal Sex, and Gestational Day on Thyroid Hormone Regulation in the Placenta

During pregnancy, supply of thyroid hormone (TH) is critically important for fetal growth, neural development, metabolism and maintenance of pregnancy. However, when circulating levels of THs in maternal serum are disrupted, there is an increased risk of several adverse pregnancy outcomes, such as neurodevelopmental delays. It is unclear what may be disrupting TH homeostasis, however, numerous studies have shown that environmental contaminants, such as polybrominated diphenyl ethers (PBDEs) could be playing a role. Exposure to PBDEs have been shown to lower circulating free T4 and T3 in animal studies and their metabolites can be inhibitors of deiodinase enzymes. However, no studies to date have investigated potential changes in TH levels in paired maternal serum, placenta, and fetal tissues following exposure to PBDEs during development. Although it is well known that the rat fetus relies on maternal synthesis and delivery of TH until gestational day (GD) 18, it is unclear how levels of TH fluctuate in paired maternal serum, placenta and fetus prior to GD 18 and if there are any sex differences. In this study, pregnant Wistar rats were dosed daily from GD 6 to 15 with a mixture of PBDEs ranging in concentration from 5.3 - 30.4 ug/kg/day. After 10 days, two fetuses per sex per treatment, their paired micro-dissected placenta (isolated fetal and maternal placental tissue) and dam serum were collected. The tissues were extracted, purified and quantified for TH’s (T4, T3, rT3) and PBDE’s. We also examined gene expression of TH transporters in the fetal portion of the placenta using qPCR. Circulating T3 levels in the dosed dams were lower relative to controls, but not significantly different (p=0.1). However, we detected a significant increase in T3 levels in the maternal placental tissues of the dosed dams relative to controls (p=0.037), suggesting the tissue sampled has a significant impact on the direction of TH disruption. Furthermore, we found that the sex of the fetus influenced the levels of T3 in the fetal placental tissues (increased levels of T3 from female fetuses, decreased levels from male fetuses). Preliminary data on TH levels in the fetus thus far suggest changes in TH levels are influenced by both sex and exposure. For example, rT3 levels were lower in females compared to males (p<0.001) and was not influenced by exposure. T3 was also lower in females compared to males (p<0.001) and was significantly reduced by exposure to PBDEs (p=0.027). Furthermore, we observed an upregulation in gene expression for TH transporter MCT8 in the fetal portion of the placenta in males relative to females. Lastly, we also observed significant differences in TH levels based on GD, with levels decreasing from GD 12-15 (p<0.001). This study suggests that even though there are no significant effects of dose on maternal TH levels, there is significant disruption of TH homeostasis in the placenta as well as the fetus.

Exposure to perfluoroalkyl substances and associations with serum thyroid hormones in a remote population of Alaska Natives

Perfluoroalkyl substances (PFASs) are known to accumulate in traditional food animals of the Arctic, and arctic indigenous peoples may be exposed via consumption of subsistence-harvested animals. PFASs are suspected of disrupting thyroid hormone homeostasis in humans. The aim of this study is to assess the relationship between serum PFASs and thyroid function in a remote population of Alaska Natives.Serum samples were collected from 85 individuals from St. Lawrence Island, Alaska. The concentrations of 13 PFASs, as well as free and total thyroxine (T4), free and total triiodothyronine (T3), and thyrotropin (TSH) were quantified in serum samples. The relationships between circulating concentrations of PFASs and thyroid hormones were assessed using multiple linear regression fit with generalized estimating equations.Several PFASs, including perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA), were positively associated with TSH concentrations when modeled individually. PFOS and PFNA were significantly associated with free T3 and PFNA was significantly associated with total T3 in models with PFAS*sex interactive terms; these associations suggested negative associations in men and positive associations in women. PFASs were not significantly associated with concentrations of free or total T4.Serum PFASs are associated with circulating thyroid hormone concentrations in a remote population of Alaska Natives. The effects of PFAS exposure on thyroid hormone homeostasis may differ between sexes.

Association of polybrominated diphenylethers (PBDEs) and hydroxylated metabolites (OH-PBDEs) serum levels with thyroid function in thyroid cancer patients

Polybrominated diphenylethers (PBDE) have been demonstrated to be associated with significant alterations in hormone levels in humans. However, yet few epidemiological human evidence has associated thyroid function with hydroxylated polybrominated diphenylethers (OH-PBDEs), which may be more potent in disrupting thyroid hormone homeostasis. In the present study, the body burdens of 7 PBDEs and 11 OH-PBDEs as well as the serum thyroid status were examined in a cohort of 33 thyroid cancer patients. The levels of ∑PBDEs and ∑OH-PBDEs ranged from 1.07 to 39ng/g lipid, and 0.01–0.46ng/g lipid, respectively. BDE-47, 6-OH-BDE-47 and 3-OH-BDE-47 were the predominant congeners. The associations between these PBDE congeners and thyroid function were not significant after controlling for sociodemographic characteristics, as well as the associations between OH-PBDEs and free T3. There were an inverse association between lg3-OH-BDE-47 and lgFT4 (free T4) but a positive association between lg4'-OH-BDE-49 and TSH. Both lgΣ5OH-PBDEs (the sum of HO-tetra-BDEs) and lgΣOH-PBDEs were significantly and positively associated with lgTSH. Our results are consistent with most human studies, suggesting that OH-PBDEs can alter thyroid function by enhancing the elimination of serum FT4 with elevated TSH levels. To our knowledge, this is the first study to examine and report associations between OH-PBDEs and thyroid function in a cancer population.

Di2-ethylhexyl phthalate disrupts thyroid hormone homeostasis through activating the Ras/Akt/TRHr pathway and inducing hepatic enzymes

Di(2-ethylhexyl) phthalate (DEHP), as a widespread environmental pollutant and an endocrine disruptor, can disturb the homeostasis of thyroid hormones (THs). In order to elucidate roles of the MAPK and PI3K/Akt pathways and hepatic enzymes in thyroid-disrupting effects of DEHP, Sprague-Dawley rats were dosed with DEHP by gavage for 30 consecutive days; Nthy-ori 3-1 cells were treated with DEHP with NAC, k-Ras siRNA or inhibitors (U0126 and wortmannin). Results showed that DEHP led to histopathologic changes in rat thyroid and liver, such as the decrease in thyroid follicular cavity diameter, hepatocyte edema. Triiodothyronine (T3), thyroxine (T4) and thyrotropin releasing hormone (TRH) were reduced. DEHP caused ROS production, oxidative stress and k-Ras upregulation, thereby activating the ERK and Akt pathways in vivo and in vitro. Moreover, TRH receptor (TRHr) level was elevated after the activation of the Akt pathway and was downregulated after the inhibition of the Akt pathway. However, TRHr was not modulated by the ERK pathway. Additionally, hepatic enzymes, including Ugt1a1, CYP2b1, Sult1e1, and Sult2b1, were significantly induced after DEHP exposure. Taken together, DEHP can perturb TH homeostasis and reduce TH levels. The activated Ras/Akt/TRHr pathway and induced hepatic enzymes play vital roles in thyroid-disrupting effects of DEHP.

Prenatal exposure to perfluorinated compounds affects thyroid hormone levels in newborn girls

Introduction Exposure to perfluorinated compunds (PFCs) continues in Asian countries, which is a major public health concern. Various mechanisms by which PFCs that can affect fetal growth have been proposed, like activation of peroxisome proliferators, disruption of thyroid hormones and changes in lipid metabolism. But, the overall evidence of an association with thyroid hormones is not strong. Thus, we studied the effect of various prenatal PFCs on cord blood thyroid hormones: triiodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH) levels and explored the endocrine disruption capacity of these PFCs on thyroid hormones levels in children by gender. Methods Two hundred and seventy-nine pregnant women were selected from the enrolled participants in the Retrospective Ewha Birth &amp; Growth Cohort conducted at Ewha Womans University Hospital, Seoul, Korea between 2006 and 2010. Cord blood was analyzed for PFCs and thyroid hormones. A generalized linear model was constructed to explore the association of prenatal PFCs and cord blood thyroid hormones. Further, an analysis stratified by child’s gender was conducted. Results Our study shows that cord blood perfluorodecanoic acid (PFDA) [β=2.40, p=0.07] and perfluoro n-pentanoic acid (PFPeA) [β=0.27, p&lt;0.01] were positively associated with cord blood T3 and T4 levels, respectively. Gender-specific analysis showed that PFPeA and Perfluorohexane sulfonic acid (PFHxS) exposure significantly increased T4 (β=0.52, p &lt;0.01) and T3 (β=4.28, p=0.03) respectively while perfluorononanoic acid (PFNA) decreased TSH (β= -1.69, p= 0.04) in newborn girls only. Conclusion Thus, prenatal PFCs exposure may have gender specific effect on disruption of thyroid hormone homeostasis in girls. Hence, these results are important in high-risk groups, such as fetuses and children.

Prenatal exposure to perfluorinated compounds affects thyroid hormone levels in newborn girls

Perfluorinated compounds (PFCs) are ubiquitous in the environment and have been detected in humans and wildlife. Exposure to PFCs has decreased in the United States recently, while exposure to PFCs continues in Asian countries, which represents a public health concern. Various mechanisms by which PFCs affect fetal growth have been proposed, such as activation of peroxisome proliferators, disruption of thyroid hormones and changes in lipid metabolism. However, the overall evidence for an association with thyroid hormones is not strong. Therefore, we examined the effect of various prenatal PFCs on cord blood thyroid hormones: triiodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH) levels, and explored the endocrine disrupting effect of these PFCs on thyroid hormone levels in children according to gender. Two hundred and seventy-nine study participants were selected from among the enrolled participants in the Ewha Birth & Growth Retrospective Cohort, a retrospective birth cohort study conducted at Ewha Womans University Hospital, Seoul, Korea between 2006 and 2010. A generalized linear model was constructed to explore the association of PFCs and thyroid hormones. Further, an analysis stratified by gender was conducted. Our study shows that cord blood perfluoro n-pentanoic acid (PFPeA) was positively associated with cord blood T4 (p=0.01) level. Gender-specific analysis showed that prenatal PFCs: PFPeA and Perfluorohexane sulfonic acid (PFHxS) exposure significantly increased T4 (p<0.01) and T3 (p=0.03), respectively, while perfluorononanoic acid (PFNA) decreased TSH (p=0.04) concentration in newborn girls. Thus, prenatal PFC exposure may disrupt thyroid hormone homeostasis. Thyroid hormones play a crucial role in fetal development and may have gender specific action. Hence, these results are of utmost importance in high-risk groups, such as pregnant women and children.

2,4,6-Tribromophenol Interferes with the Thyroid Hormone System by Regulating Thyroid Hormones and the Responsible Genes in Mice.

2,4,6-Tribromophenol (TBP) is a brominated flame retardant (BFR). Based on its affinity for transthyretin, TBP could compete with endogenous thyroid hormone. In this study, the effects of TBP on the thyroid hormone system were assessed in mice. Briefly, animals were exposed to 40 and 250 mg/kg TBP. Thyroid hormones were also administered with or without TBP. When mice were treated with TBP, deiodinase 1 (Dio1) and thyroid hormone receptor β isoform 2 (Thrβ2) decreased in the pituitary gland. The levels of deiodinase 2 (Dio2) and growth hormone (Gh) mRNA increased in response to 250 mg/kg of TBP, and the relative mRNA level of thyroid stimulating hormone β (Tshβ) increased in the pituitary gland. Dio1 and Thrβ1 expression in the liver were not altered, while Dio1 decreased in response to co-treatment with thyroid hormones. The thyroid gland activity decreased in response to TBP, as did the levels of free triiodothyronine and free thyroxine in serum. Taken together, these findings indicate that TBP can disrupt thyroid hormone homeostasis and the presence of TBP influenced thyroid actions as regulators of gene expression. These data suggest that TBP interferes with thyroid hormone systems