Reduced Thyroid Hormone Levels Research Articles

Thyrotoxicosis in Partial Mola Hidatidosa

Thyrotoxicosis is a clinical condition associated with excessive thyroid hormone levels. Symptoms can range from asymptomatic to life-threatening due to thyroid storm. Thyrotoxicosis in hydatidiform moles is a rare condition but has a high mortality rate, so etiological studies are still needed for optimal management. Case Report: Patient Mrs. T, 25 years old Hindu, Balinese, 12 weeks pregnant (Gravida 1 Para 0 abortion 0), came to the obstetrics ER on September 24, 2023 with complaints of discharge from the birth canal since the morning, nausea (+), often shaking, easily tired and often sweaty. physical examination obtained blood pressure 100/60mmHg, pulse 78x/min, respiratory rate 20x/min, axillary temperature 36.80C oxygen saturation 99%. From obstetric examination, fundus uteri height ½ center, vaginal toucher vulva vagina within normal limits, portiono (-) fluxus (+), laboratory examination obtained HCG 387,392.8 mIU/m, FT4 31.05 pmol/L (N: 9-22), TSH <0.01 uIU/mL (N: 0.4-4.2) ultrasound results describe honey comb appearance and histopathology results describe partial mola. Evacuation by curettage was performed, resulting in reduced serum ?-hCG levels and reduced thyroid hormone levels. Discussion: The patient was diagnosed with partial hydatidiform mole and thyrotoxicosis. Hydatidiform moles can cause thyrotoxicosis. This condition is caused by the structure of ?- hCG which resembles TSH so that it can activate TSH receptors. After evacuation of hydatidiform moles, normal TSH and FT4 levels will be obtained. Conclusion: The female patient with thyrotoxicosis due to hydatidiform moles had the moles evacuated, resulting in normal thyroid hormone levels.

Assessment of bidirectional relationships between hypothyroidism and endometrial cancer: a two-sample Mendelian randomization study.

Hypothyroidism, characterized by reduced thyroid hormone levels, and endometrial cancer, a prevalent gynecological malignancy, have been suggested to have a potential association in previous observational studies. However, the causal relationship between them remains uncertain. This study aimed to investigate the causal relationship between hypothyroidism and endometrial cancer using a bilateral Mendelian randomization approach. A bidirectional two-sample Mendelian randomization study was conducted using summary statistics from genome-wide association studies to identify genetic variants associated with hypothyroidism and endometrial cancer. The inverse variance weighting method was used as the main analysis, and sensitivity analyses were conducted to validate the MR results. The results of our analysis did not support a causal effect of hypothyroidism (OR: 0.93, p=0.08) or autoimmune hypothyroidism (OR: 0.98, p=0.39) on endometrial cancer risk. In the reverse MR analysis, we did not find a significant causal effect of endometrial cancer on hypothyroidism (OR: 0.96, p=0.75) or autoimmune hypothyroidism (OR: 0.92, p=0.50). Based on subgroup analysis by pathological subtypes of endometrial cancer, the above findings were further substantiated (all p-value >0.05). Our Mendelian randomization analysis suggests a lack of causal association between hypothyroidism and endometrial cancer. To gain a deeper understanding of this association, it is essential to conduct large-scale randomized controlled trials in the future to validate our findings.

Maternal and Neonatal Effects of Maternal Oral Exposure to Perfluoro-2-methoxyacetic Acid (PFMOAA) during Pregnancy and Early Lactation in the Sprague-Dawley Rat.

Perfluoro-2-methoxyacetic acid (PFMOAA) is a short-chain perfluoroalkyl ether carboxylic acid that has been detected at high concentrations (∼10 μg/L) in drinking water in eastern North Carolina, USA, and in human serum and breastmilk in China. Despite documented human exposure there are almost no toxicity data available to inform risk assessment of PFMOAA. Here we exposed pregnant Sprague-Dawley rats to a range of PFMOAA doses (10-450 mg/kg/d) via oral gavage from gestation day (GD) 8 to postnatal day (PND) 2 and compared results to those we previously reported for perfluorooctanoic acid (PFOA) and hexafluoropropylene oxide-dimer acid (HFPO-DA or GenX). Newborn pups displayed reduced birthweight (≥30 mg/kg), depleted liver glycogen concentrations (all doses), hypoglycemia (≥125 mg/kg), and numerous significantly altered genes in the liver associated with fatty acid and glucose metabolism similar to gene changes produced by HFPO-DA. Pup survival was significantly reduced at ≥125 mg/kg, and at necropsy on PND2 both maternal and neonatal animals displayed increased liver weights, increased serum aspartate aminotransferase (AST), and reduced serum thyroid hormones at all doses (≥10 mg/kg). Pups also displayed highly elevated serum cholesterol at all doses. PFMOAA concentrations in serum and liver increased with maternal oral dose in both maternal and F1 animals and were similar to those we reported for PFOA but considerably higher than HFPO-DA. We calculated 10% effect levels (ED10 or EC10) and relative potency factors (RPF; PFOA = index chemical) among the three compounds based on maternal oral dose and maternal serum concentration (μM). Reduced pup liver glycogen, increased liver weights and reduced thyroid hormone levels (maternal and pup) were the most sensitive end points modeled. PFMOAA was ∼3-7-fold less potent than PFOA for most end points based on maternal serum RPFs, but slightly more potent for increased maternal and pup liver weights. PFMOAA is a maternal and developmental toxicant in the rat producing a constellation of adverse effects similar to PFOA and HFPO-DA.

Cellular Iron Deficiency Disrupts Thyroid Hormone Regulated Gene Expression in Developing Hippocampal Neurons

BackgroundDeveloping neurons have high thyroid hormone and iron requirements to support their metabolically demanding growth. Early-life iron and thyroid-hormone deficiencies are prevalent and often coexist, and each independently increases risk of permanently impaired neurobehavioral function in children. Early-life dietary iron deficiency reduces thyroid-hormone concentrations and impairs thyroid hormone-responsive gene expression in the neonatal rat brain, but it is unclear whether the effect is cell-intrinsic. ObjectivesThis study determined whether neuronal-specific iron deficiency alters thyroid hormone-regulated gene expression in developing neurons. MethodsIron deficiency was induced in primary mouse embryonic hippocampal neuron cultures with the iron chelator deferoxamine (DFO) beginning at 3 d in vitro (DIV). At 11DIV and 18DIV, thyroid hormone-regulated gene messenger ribonucleic acid (mRNA)concentrations indexing thyroid hormone homeostasis (Hairless, mu-crystallin, Type II deiodinase, solute carrier family member 1c1, and solute carrier family member 16a2) and neurodevelopment (neurogranin, Parvalbumin, and Krüppel-like factor 9) were quantified. To assess the effect of iron repletion, DFO was removed at 14DIV from a subset of DFO-treated cultures, and gene expression and adenosine 5'-triphosphate (ATP) concentrations were quantified at 21DIV. ResultsAt 11DIV and 18DIV, neuronal iron deficiency decreased neurogranin, Parvalbumin, and mu-crystallin, and by 18DIV, solute carrier family member 16a2, solute carrier family member 1c1, Type II deiodinase, and Hairless were increased, suggesting cellular sensing of a functionally abnormal thyroid hormone state. Dimensionality reduction with Principal component analysis reveals that thyroid hormone homeostatic genes strongly correlate with and predict iron status. Iron repletion from 14–21DIV did not restore ATP concentration, and Principal component analysis suggests that, after iron repletion, cultures maintain a gene expression signature indicative of previous iron deficiency. ConclusionsThese novel findings suggest there is an intracellular mechanism coordinating cellular iron/thyroid hormone activities. We speculate this is a part of the homeostatic response to acutely match neuronal energy production and growth signaling. However, the adaptation to iron deficiency may cause permanent deficits in thyroid hormone-dependent neurodevelopmental processes even after recovery from iron deficiency.

THU659 Plasmapheresis As A Therapy For Amiodarone-induced Thyrotoxicosis: A Case Report And Literature Review

Abstract Disclosure: C.L. Loughner: None. P.L. Bononi: None. Introduction: Amiodarone-induced thyrotoxicosis (AIT) is a common cause of hyperthyroidism. Treatment consists of stabilizing the thyroid followed by thyroidectomy1. Plasmapheresis has been suggested as a temporary measure when illness severity precludes standard therapy. Here, we review current literature and provide a case of AIT treated with plasmapheresis. Clinical Case: A 71-year-old male was seen for progressive subclinical hyperthyroidism, diagnosed several years prior. Three years ago, he started taking amiodarone for paroxysmal ventricular tachycardia. One month prior to admission, he was admitted for decompensated heart failure and had TSH 0.02 mcU/mL (n 0.4-4.4 mcU/mL), free T4 4.48 ng/dL (n 0.7-1.9 ng/dL), and free T3 2.58 pg/mL (n 2.0-4.4 pg/mL). Amiodarone was halved after being diagnosed with AIT. Methimazole and prednisone were started. He was readmitted one month later. TSH was undetectable at admission and free T4 was 4.04 ng/dL. Amiodarone was discontinued. His hepatic enzymes were elevated, necessitating the discontinuation of methimazole. His heart failure precluded thyroidectomy. Due to the limitation of treatment options, the patient was given three rounds of plasmapheresis to reduce thyroid hormone levels. His free T4 dropped to 2.81 ng/dL. The patient underwent total thyroidectomy once stable. His free T4 was 1.73 after and was started on levothyroxine. Clinical Lesson: When patients are unable to have standard treatment of AIT, other options must be considered. While there are some case reports3,4, there are currently no RCTs for plasmapheresis for AIT. In the case of this patient with cardiac complications from AIT and concurrent hepatic impairment, plasmapheresis provided stability of thyroid hormones until surgical correction could be achieved.

Local modulation of thyroid hormone signaling in the retina affects the development of diabetic retinopathy

Thyroid hormone (TH) dyshomeostasis is associated with poor prognosis in acute and prolonged illness, but its role in diabetic retinopathy (DR) has never been investigated. Here, we characterized the TH system in the retinas of db/db mice and highlighted regulatory processes in MIO-M1 cells. In the db/db retinas, typical functional traits and molecular signatures of DR were paralleled by a tissue-restricted reduction of TH levels. A local condition of low T3 (LT3S) was also demonstrated, which was likely to be induced by deiodinase 3 (DIO3) upregulation, and by decreased expression of DIO2 and of TH receptors. Concurrently, T3-responsive genes, including mitochondrial markers and microRNAs (miR-133-3p, 338-3p and 29c-3p), were downregulated. In MIO-M1 cells, a feedback regulatory circuit was evidenced whereby miR-133-3p triggered the post-transcriptional repression of DIO3 in a T3-dependent manner, while high glucose (HG) led to DIO3 upregulation through a nuclear factor erythroid 2-related factor 2–hypoxia-inducible factor-1 pathway. Finally, an in vitro simulated condition of early LT3S and hyperglycemia correlated with reduced markers of both mitochondrial function and stress response, which was reverted by T3 replacement. Together, the data suggest that, in the early phases of DR, a DIO3-driven LT3S may be protective against retinal stress, while, in the chronic phase, it not only fails to limit HG-induced damage, but also increases cell vulnerability likely due to persistent mitochondrial dysfunction.

Thyroid storm and hypercalcemic crisis as a result of unconventional treatment of Graves’ disease

We present a case of severe thyroid storm with simultaneous hypercalcemic crisis resulting from excessive intake of 5% Lugol’s iodine solution (5% iodine, 15% potassium iodide, 85% water; 10 drops/day) and vitamin D3 (10000 IU/day) during 2 months of unconventional treatment in a 78-year-old female with a history of hyperthyroidism in course of Graves’ disease. Supplements were prescribed by herbalist/healer before admission to the hospital. At the clinic, we started therapy with antithyroid drugs, inorganic iodide and corticosteroids but without positive effect. Patient’s condition kept deteriorating with loss of consciousness. Plasmapheresis (4 procedures) was required to successfully reduce thyroid hormone levels and finally total thyroidectomy was performed resulting in postoperative hypothyroidism and transient hypoparathyroidism. Additionally, patient suffered from serious complications such as Takotsubo cardiomyopathy and sepsis requiring intensive care unit. Treatment with corticosteroids led to secondary adrenal insufficiency. Following 2-month hospitalization, patient was discharged in stable condition.

Early life stressful experiences escalate aggressive behavior in adulthood via changes in transthyretin expression and function

Escalated and inappropriate levels of aggressive behavior referred to as pathological in psychiatry can lead to violent outcomes with detrimental impact on health and society. Early life stressful experiences might increase the risk of developing pathological aggressive behavior in adulthood, though molecular mechanisms remain elusive. Here, we provide prefrontal cortex and hypothalamus specific transcriptome profiles of peripubertal stress (PPS) exposed Balb/c adult male mice exhibiting escalated aggression and adult female mice resilient to such aberrant behavioral responses. We identify transthyretin (TTR), a well known thyroid hormone transporter, as a key regulator of PPS induced escalated aggressive behavior in males. Brain-region-specific long-term changes in Ttr gene expression and thyroid hormone (TH) availability were evident in PPS induced escalated aggressive male mice, circulating TH being unaltered. Ttr promoter methylation marks were also altered being hypermethylated in hypothalamus and hypomethylated in prefrontal cortex corroborating with its expression pattern. Further, Ttr knockdown in hypothalamus resulted in escalated aggressive behavior in males without PPS and also reduced TH levels and expression of TH-responsive genes (Nrgn, Trh, and Hr). Escalated aggressive behavior along with reduced Ttr gene expression and TH levels in hypothalamus was also evident in next generation F1 male progenies. Our findings reveal that stressful experiences during puberty might trigger lasting escalated aggression by modulating TTR expression in brain. TTR can serve as a potential target in reversal of escalated aggression and related psychopathologies.

Assessment of Thyroid Endocrine Disruption Effects of Parabens Using In Vivo, In Vitro, and In Silico Approaches.

The extensive applications of parabens in foods, drugs, and cosmetics cause inevitable exposure to humans. Revealing the developmental toxicity of parabens is of utmost importance regarding their safety evaluation. In this study, the effects of four commonly used parabens, including methyl paraben (20 ∼ 200 μM), ethyl paraben (20 ∼ 100 μM), propyl paraben (5 ∼ 20 μM), and butyl paraben (BuP, 2 ∼ 10 μM), were investigated on the early development of zebrafish embryos and larvae. The underlying mechanisms were explored from the aspect of their disturbance in the thyroid endocrine system using in vivo, in vitro, and in silico assays. Paraben exposure caused deleterious effects on the early development of zebrafish, with BuP displaying the highest toxicity among all, resulting in the exposure concentration-related mortality, decreased hatching rate, reduced body length, lowered heart rate, and the incidence of malformation. Further investigation showed that paraben exposure reduced thyroid hormone levels and disturbed the transcriptional expressions of the target genes in the hypothalamic-pituitary-thyroid axis. Molecular docking analysis combined with in vitro GH3 cell proliferation assay testified that all test parabens exhibited thyroid receptor agonistic activities. The findings confirmed the developmental toxicity of the test parabens and their thyroid endocrine disruption effects, providing substantial evidence on the safety control of paraben-based preservatives.

How to do it: Plasmapheresis via venoarterial extracorporeal membrane oxygenation circuit for thyroid storm

Thyrotoxicosis-induced cardiomyopathy is a rare complication occurring in <1% of the population, which can require mechanical circulatory support (VA-ECMO) as a bridge to anti-thyroid therapies. Therapeutic plasma exchange (TPE) is an alternative treatment used to rapidly reduce thyroid hormone levels in refractory cases of thyrotoxic crisis without clinical improvement from other therapies. We describe a novel technique of facilitating plasmapheresis via a VA-ECMO circuit in a 26-year-old man with thyroid storm and subsequent circulatory collapse.

Challenges With Hormonal Contraception in Women Receiving Antiseizure Drugs

Epilepsy and antiseizure drug (ASD) use poses several issues and complications for women. Seizure frequency may be affected by hormonal variations during the menstrual cycle and pregnancy. ASDs use can reduce libido, reduce thyroid hormone levels, lead to spontaneous abortion and birth defects, and can be transferred via breast milk to infants. 1 Stephen L.J. Harden C. Tomson T. et al. Management of epilepsy in women. Lancet Neurol. 2019; 18: 481-491https://doi.org/10.1016/S1474-4422(18)30495-2 Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Preconception counseling is essential for women of childbearing potential due to the concerns of the teratogenic effects of many ASDs, particularly valproate. Francesco Ciummo, PharmD, BCCCP, is an assistant professor of pharmacy practice, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University (LIU Pharmacy), Brooklyn, New York. He can be reached at: [email protected] . Department Editor Timothy Nguyen, PharmD, BCPS, CCP, FASCP, who would like to hear your ideas for future columns, can be reached at [email protected] .

Inadequate control of thyroid hormones sensitizes to hepatocarcinogenesis and unhealthy aging.

An inverse correlation between thyroid hormone levels and longevity has been reported in several species and reduced thyroid hormone levels have been proposed as a biomarker for healthy aging and metabolic fitness. However, hypothyroidism is a medical condition associated with compromised health and reduced life expectancy. Herein, we show, using wild-type and the Pax8 ablated model of hypothyroidism in mice, that hyperthyroidism and severe hypothyroidism are associated with an overall unhealthy status and shorter lifespan. Mild hypothyroid Pax8 +/- mice were heavier and displayed insulin resistance, hepatic steatosis and increased prevalence of liver cancer yet had normal lifespan. These pathophysiological conditions were precipitated by hepatic mitochondrial dysfunction and oxidative damage accumulation. These findings indicate that individuals carrying mutations on PAX8 may be susceptible to develop liver cancer and/or diabetes and raise concerns regarding the development of interventions aiming to modulate thyroid hormones to promote healthy aging or lifespan in mammals.

Chronic exposure to microcystin-LR reduces thyroid hormone levels by activating p38/MAPK and MEK/ERK signal pathway

Microcystin-LR (MC-LR) is the most toxic and abundant microcystin that produced by cyanobacteria. Previous studies have shown MC-LR had acute toxic to thyroid, however, the mechanism is still unclear, and the effect of long-term, low-dose MC-LR on thyroid remains uncertain. In this study, we investigated the chronic, low-dose effect of MC-LR on mouse thyroid tissues and thyroid hormone metabolism. MC-LR was orally administered to mice at 0, 1, 10, 20 and 40 μg/L for 6 consecutive months for histopathological and immunoblot analysis. Nthy-ori 3–1 cells were cultured in various concentrations of MC-LR (0, 0.5, 5, 50, 500 nmol/L) for indicated time, meanwhile the cell viability and proteins change were tested. From our study, the chronic, low-dose MC-LR exposure can disturb thyroid hormone synthesis and metabolism through activating the p38/MAPK and MEK/ERK signaling pathways, then up-regulating the expression of type 3 deiodinase. These data support the potential toxic effects of MC-LR on thyroid tissue and thyroid hormone metabolism.

Role of irisin in Chinese patients with hypothyroidism: an interventional study.

ObjectiveIrisin is a myokine that greatly affects energy expenditure and systemic metabolism. While thyroid hormone is likely associated with irisin, a direct relationship remains to be fully elucidated. This study aimed to investigate plasma irisin levels in Chinese patients with hypothyroidism.MethodsA total of 155 subjects were divided into the hypothyroidism group or the control group. Fifty-seven patients in the hypothyroidism group received levothyroxine treatment. Baseline irisin levels were measured in the two groups and post-treatment levels were measured in the hypothyroidism group.ResultsIrisin levels were significantly lower in the hypothyroidism group than in the control group. In the hypothyroidism group, irisin levels were positively associated with free triiodothyronine and free thyroxine levels, and negatively associated with thyrotropin levels. In the hypothyroidism group, irisin levels were significantly increased after levothyroxine treatment. Multiple linear regression models showed that total cholesterol and free thyroxine levels were the only significant predictors of serum irisin levels.ConclusionsIrisin levels are decreased in patients with hypothyroidism. Our results suggest that decreased irisin levels are directly associated with reduced thyroid hormone levels. These values may be restored after levothyroxine treatment in Chinese patients with hypothyroidism.

Hypothyroidism in Clinical Practice

Hypothyroidism in Clinical Practice

Prenatal urinary triclosan concentrations and child neurobehavior

BackgroundExposure to triclosan, an antimicrobial chemical, is ubiquitous among pregnant women and may reduce thyroid hormone levels that are important for fetal neurodevelopment. Few studies have examined the association between prenatal triclosan exposure and children's neurobehavior. ObjectiveWe investigated the relationship of prenatal urinary triclosan concentrations with children's behavior and cognitive abilities at age three years in a prospective pregnancy and birth cohort in Canada. MethodsWe measured triclosan in urine samples collected at ~12 weeks of gestation in 794 Canadian women enrolled in a prospective pregnancy and birth cohort study (MIREC) from 2008 to 2011. Around age 3 years, we assessed children's cognitive abilities using the Wechsler Primary and Preschool Scale of Intelligence-III (WPPSI-III), and two scales of the Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P). Parents reported children's problem and reciprocal social behaviors using the Behavior Assessment System for Children-2 (BASC-2) and Social Responsiveness Scale-2 (SRS-2), respectively. ResultsAfter adjusting for confounders using multivariable linear regression, triclosan was not associated with most of the 30 examined neurobehavioral scales. Each 10-fold increase in triclosan was associated with better WPPSI-III picture completion scores (β: 0.2; 95% CI: 0,0.5) and BASC-2 externalizing (β: −0.5; 95% CI: −1.1, 0) and hyperactivity (β: −0.6; 95% CI: −1.2, −0.1) scores, suggesting less externalizing and hyperactive behaviors. Child sex did not modify these associations. ConclusionsIn this cohort, urinary triclosan concentrations measured once in early pregnancy were not associated with most assessed aspects of neurobehavior and weakly associated with a few others, but not in the hypothesized direction.

Thyroidectomy for the treatment of Graves' thyrotoxicosis in thioamide-induced agranulocytosis and sepsis.

A 51 year old man presented with sepsis in the setting of thioamide-induced agranulocytosis. Empiric broad-spectrum antibiotics was followed by directed narrow-spectrum antibiotics, and his neutrophil count recovered with support from granulocyte-colony stimulating factor (G-CSF) analogue transfusions. After a brief period of multi-modal therapy for nine days including potassium iodide (Lugol’s iodine), cholestyramine, propanolol and lithium to temper his persisting hyperthyroidism, a total thyroidectomy was performed while thyroid hormone levels remained at thyrotoxic levels. Postoperative recovery was uncomplicated and he was discharged home on thyroxine. There is limited available evidence to guide treatment in this unique cohort of patients who require prompt management to avert impending clinical deterioration. This case report summarises the successful emergent control of thyrotoxicosis in the setting of thioamide-induced agranulocytosis complicated by sepsis, and demonstrates the safe use of multi-modal pharmacological therapies in preparation for total thyroidectomy.Learning points:Thioamide-induced agranulocytosis is an uncommon but potentially life-threatening complication of which all prescribers and patients need to be aware.A multi-modal preoperative pharmacological approach can be successful, even when thioamides are contraindicated, when needing to prepare a thyrotoxic patient for semi-urgent total thyroidectomy.There is not enough evidence to confidently predict the safe timing when considering total thyroidectomy in this patient cohort, and therefore it should be undertaken when attempts have first been made to safely reduce thyroid hormone levels.Thyroid storm is frequently cited as a potentially severe complication of thyroid surgery undertaken in thyrotoxic patients, although the evidence does not demonstrate this as a common occurrence.

Parental exposure to microcystin-LR induced thyroid endocrine disruption in zebrafish offspring, a transgenerational toxicity

Microcystin-LR is the most poisonous and commonly encountered hepatotoxin produced by cyanobacteria in an aquatic ecosystem, and it may cause thyroid dysfunction in fish. The present study aimed to reveal the effects of transgenerational toxicity of MCLR on the thyroid endocrine system under sub-chronic exposure conditions. Adult zebrafish (F0) were exposed to environmentally relevant concentrations (1, 5 and 25 μg/L) of MCLR for 45 days. The produced F1 embryos were then tested without further MCLR treatment. In the F0 generation, exposure to 25 μg/L MCLR reduced thyroxine (T4) but not 3, 5, 3′-triiodothyronine (T3) levels in females, while the T4 and T3 levels were unchanged in males. After parental exposure to MCLR, we observed a decreased hatching and growth retardation correlated with reduced thyroid hormone levels in the F1 offspring. The gene transcription and protein expression along the hypothalamic-pituitary-thyroid axis were detected to further investigate the possible mechanisms of MCLR-induced thyroid disruption. Our results indicated MCLR could disturb the thyroid endocrine system under environmentally relevant concentrations and the disrupting effects could be remarkably transmitted to its F1 offspring. We regard these adverse effects as a parental transgenerational toxicity of MCLR.

Endocrine-disrupting activity of per- and polyfluoroalkyl substances: Exploring combined approaches of ligand and structure based modeling

Exposure to perfluorinated and polyfluoroalkyl substances (PFCs/PFASs), endocrine disrupting halogenated pollutants, has been linked to various diseases including thyroid toxicity in human populations across the globe. PFASs can compete with thyroxine (T4) for binding to the human thyroid hormone transport protein transthyretin (TTR) which may lead to reduce thyroid hormone levels leading to endocrine disrupting adverse effects. Environmental fate and endocrine-disrupting activity of PFASs has initiated several research projects, but the amount of experimental data available for these pollutants is limited. In this study, experimental data for T4-TTR competing potency of 24 PFASs obtained in a radioligand-binding assay were modeled using classification- and regression-based quantitative structure-activity relationship (QSAR) tools with simple molecular descriptors obtained from chemical structure of these compounds in order to identify the responsible structural features and fragments of the studied PFASs for endocrine disruption activity. Additionally, docking studies were performed employing the crystal structure complex of TTR with bound 2′, 6′-difluorobiphenyl-4-carboxylic acid (PDB: 2F7I) in order to constitute the receptor model for human TTR. The results corroborate evidence for these binding interactions and indicate multiple high-affinity modes of binding. The developed in silico models therefore advance our understanding of important structural attributes of these chemicals and may provide important information for the design of future synthesis of PFASs as well as may serve as an efficient query tool for virtual screening of large PFAS databases to check their endocrine toxicity profile.

Overexpression of Interleukin-4 in the Thyroid of Transgenic Mice Upregulates the Expression of Duox1 and the Anion Transporter Pendrin.

The dual oxidases (Duox) are involved in hydrogen peroxide generation, which is essential for thyroid hormone synthesis, and therefore they are markers of thyroid function. During inflammation, cytokines upregulate DUOX gene expression in the airway and the intestine, suggesting a role for these proteins in innate immunity. It was previously demonstrated that interleukin-4 (IL-4) upregulates DUOX gene expression in thyrocytes. Although the role of IL-4 in autoimmune thyroid diseases has been studied extensively, the effects of IL-4 on thyroid physiology remain largely unknown. Therefore, a new animal model was generated to study the impact of IL-4 on thyroid function. Transgenic (Thyr-IL-4) mice with thyroid-targeted expression of murine IL-4 were generated. Transgene expression was verified at the mRNA and protein level in thyroid tissues and primary cultures. The phenotype of the Thyr-IL-4 animals was characterized by measuring serum thyroxine (T4) and thyrotropin levels and performing thyroid morphometric analysis, immunohistochemistry, whole transcriptome sequencing, quantitative reverse transcription polymerase chain reaction, and ex vivo thyroid function assays. Thyrocytes from two Thyr-IL-4 mouse lines (#30 and #52) expressed IL-4, which was secreted into the extracellular space. Although 10-month-old transgenic animals had T4 and thyrotropin serum levels in the normal range, they had altered thyroid follicular structure with enlarged follicles composed of elongated thyrocytes containing numerous endocytic vesicles. These follicles were positive for T4 staining the colloid, indicating their capacity to produce thyroid hormones. RNA profiling of Thyr-IL-4 thyroid samples revealed modulation of multiple genes involved in inflammation, while no major leukocyte infiltration could be detected. Upregulated expression of Duox1, Duoxa1, and the pendrin anion exchanger gene (Slc26a4) was detected. In contrast, the iodide symporter gene Slc5a5 was markedly downregulated resulting in impaired iodide uptake and reduced thyroid hormone levels in transgenic thyroid tissue. Hydrogen peroxide production was increased in Thyr-IL-4 thyroid tissue compared with wild-type animals, but no significant oxidative stress could be detected. This is the first study to show that ectopic expression of IL-4 in thyroid tissue upregulates Duox1/Duoxa1 and Slc26a4 expression in the thyroid. The present data demonstrate that IL-4 could affect thyroid morphology and function, mainly by downregulating Slc5a5 expression, while maintaining a normal euthyroid phenotype.