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Environmental Pollution (Barking, Essex... Jan 2024Mice were exposed to a low dose of the model thyroid hormone disruptor, propylthiouracil. Although this had only a modest effect on maternal thyroid hormones production,...
Mice were exposed to a low dose of the model thyroid hormone disruptor, propylthiouracil. Although this had only a modest effect on maternal thyroid hormones production, postnatal analysis of the pups' plasma by mass spectrometry and the brain striatum by RNA sequencing gave evidence of low lasting changes that could reflect an adverse effect on neurodevelopment. Overall, these methods proved to be sensitive enough to detect minor disruptions of thyroid hormone signalling in vivo.
Topics: Animals; Mice; Transcriptome; Thyroid Hormones; Thyroid Gland; Propylthiouracil; Brain
PubMed: 37866749
DOI: 10.1016/j.envpol.2023.122783 -
Bioorganic Chemistry Dec 2023Lactoperoxidase was previously used as a model enzyme to test the inhibitory activity of selenium analogs of anti-thyroid drugs with...
Lactoperoxidase was previously used as a model enzyme to test the inhibitory activity of selenium analogs of anti-thyroid drugs with 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) as a substrate. Peroxidases oxidize ABTS to a metastable radical ABTS, which is readily reduced by many antioxidants, including thiol-containing compounds, and it has been used for decades to measure antioxidant activity in biological samples. We showed that anti-thyroid drugs 6-n-propyl-2-thiouracil, methimazole, and selenium analogs of methimazole also reduced it rapidly. This reaction may explain the anti-thyroid action of many other compounds, particularly natural antioxidants, which may reduce the oxidized form of iodine and/or tyrosyl radicals generated by thyroid peroxidase thus decreasing the production of thyroid hormones. However, influence of selenium analogs of methimazole on the rate of hydrogen peroxide consumption during oxidation of ABTS by lactoperoxidase was moderate. Direct hydrogen peroxide reduction, proposed before as their mechanism of action, cannot therefore account for the observed inhibitory effects. 1-Methylimidazole-2-selone and its diselenide were oxidized by ABTS to relatively stable seleninic acid, which decomposed slowly to selenite and 1-methylimidazole. In contrast, oxidation of 1,3-dimethylimidazole-2-selone gave selenite and 1,3-dimethylimidazolium cation. Accumulation of the corresponding seleninic acid was not observed.
Topics: Antioxidants; Cations; Hydrogen Peroxide; Lactoperoxidase; Methimazole; Oxidation-Reduction; Selenious Acid; Selenium; Propylthiouracil
PubMed: 37788560
DOI: 10.1016/j.bioorg.2023.106891 -
The Journal of Reproduction and... Dec 2023The adenohypophysis is comprised of the anterior and intermediate lobes (AL and IL, respectively). Cluster of differentiation 9 (CD9)- and sex-determining region Y-box 2...
The adenohypophysis is comprised of the anterior and intermediate lobes (AL and IL, respectively). Cluster of differentiation 9 (CD9)- and sex-determining region Y-box 2 (SOX2)-positive cells are stem/progenitor hormone-producing cells in the AL. They are located in the marginal cell layer (MCL) facing Rathke's cleft between the AL and IL (primary niche) and the parenchyma of the AL (secondary niche). We previously showed that, in rats, CD9/SOX2-positive cells in the IL side of the MCL (IL-side MCL) migrate to the AL side (AL-side MCL) and differentiate into prolactin-producing cells (PRL cells) in the AL parenchyma during pregnancy, lactation, and diethylstilbestrol treatment, all of which increase PRL cell turnover. This study examined the changes in CD9/SOX2-positive stem/progenitor cell niches and their proportions by manipulating the turnover of growth hormone (GH)- and thyroid-stimulating hormone (TSH)-producing cells (GH and TSH cells, respectively), which are Pit1 lineage cells, as well as PRL cells. After induction, the isolated CD9/SOX2-positive cells from the IL-side MCL formed spheres and differentiated into GH and TSH cells. We also observed an increased GH cell proportion upon treatment with GH-releasing hormone and recovery from continuous stress and an increased TSH cell proportion upon propylthiouracil treatment, concomitant with alterations in the proportion of CD9/SOX2-positive cells in the primary and secondary niches. These findings suggest that CD9/SOX2-positive cells have the potential to supply GH and TSH when an increase in GH and TSH cell populations is required in the adult pituitary gland.
Topics: Animals; Female; Rats; Growth Hormone; Pituitary Gland; Pituitary Gland, Anterior; Prolactin; Thyrotropin; Tetraspanin 29; SOXB1 Transcription Factors
PubMed: 37778977
DOI: 10.1262/jrd.2023-023 -
Neurotoxicology and Teratology 2023Identifying xenobiotics that interrupt the thyroid axis has significant public health implications, given that thyroid hormones are required for brain development. As...
Identifying xenobiotics that interrupt the thyroid axis has significant public health implications, given that thyroid hormones are required for brain development. As such, some developmental and reproductive toxicology (DART) studies now require or recommend serum total thyroxine (T4) measurements in pregnant, lactating, and developing rats. However, serum T4 concentrations are normally low in the fetus and pup which makes quantification difficult. These challenges can be circumvented by technologies like mass spectrometry, but these approaches are expensive and not always widely available. To demonstrate the feasibility of measuring T4 using a commercially available assay, we examine technical replicates of rat serum samples measured both by liquid chromatography mass spectrometry (LC/MS/MS) and radioimmunoassay (RIA). These samples were obtained from rats on gestational day 20 (dams and fetuses) or postnatal day 5 (pups), following maternal exposure to the goitrogen propylthiouracil (0-3 ppm) to incrementally decrease T4. We show that with assay modification, it is possible to measure serum T4 using low sample volumes (25-50 μL) by an RIA, including in the GD20 fetus exposed to propylthiouracil. This proof-of-concept study demonstrates the technical feasibility of measuring serum T4 in DART studies.
Topics: Pregnancy; Female; Rats; Animals; Thyroxine; Triiodothyronine; Propylthiouracil; Radioimmunoassay; Tandem Mass Spectrometry; Lactation; Fetus
PubMed: 37777095
DOI: 10.1016/j.ntt.2023.107303 -
Folia Histochemica Et Cytobiologica 2023Among the plant ingredients, some compounds interfere with the functions of the thyroid gland. However, there is limited research on the effect of curcumin (CMN) on the...
INTRODUCTION
Among the plant ingredients, some compounds interfere with the functions of the thyroid gland. However, there is limited research on the effect of curcumin (CMN) on the functions of this gland. The aim of this study was to analyze the effect of CMN on morphology, histochemical reactivity of cytochrome c oxidase (CCO) and secretion functions of the thyroid gland under conditions of hypothyroidism induced by propylthiouracil (PTU).
MATERIAL AND METHODS
The rats were treated for 30 days by gavage with CMN (100 mg/kg b.w.) and/or PTU (1 mg/kg b.w.). Control rats received vehicle only. Histomorphometric tests were performed on the thyroid glands, cytochrome c oxidase activity was visualized using the histochemical method, and the levels of thyroid hormones were measured using the radioimmunoassay method.
RESULTS
Rats receiving PTU showed compensatory changes in their thyroid glands, including a significant increase in thyroid epithelium height, a decrease in colloid volumen density, a decrease in the percentage of small follicles, an increase in medium-sized follicles compared to the control group, as well as a significant increase in CCO histochemical reactivity in the columnar epithelium and a decrease in FT4 serum level compared to the control group. The administration of CMN reversed these adverse changes caused by PTU. The PTU + CMN group exhibited a significant decrease in the height of the thyroid follicle epithelium compared to the PTU group. The percentage of small and medium-size follicles in the CMN + PTU group did not differ from the control group. Furthermore, CCO reactivity in the cubic epithelium and serum FT4 levels increased compared to the PTU group. Administration of CMN alone resulted in a significant increase in FT4 levels compared to the control group.
CONCLUSIONS
The administration of CMN to rats with induced hypothyroidism resulted in a reduction of hyperplasia, hypertrophy, and increase in secretory activity of the thyroid gland. These findings suggest the protective effect of CMN against induced hypothyroidism.
Topics: Rats; Animals; Propylthiouracil; Curcumin; Electron Transport Complex IV; Hypothyroidism
PubMed: 37724034
DOI: 10.5603/fhc.96497 -
International Medical Case Reports... 2023Agranulocytosis is a rare but fatal side effect of antithyroid drugs (ATDs) with incidence reported at 0.1%-1%. Agranulocytosis is defined as a granulocyte count...
BACKGROUND
Agranulocytosis is a rare but fatal side effect of antithyroid drugs (ATDs) with incidence reported at 0.1%-1%. Agranulocytosis is defined as a granulocyte count <500 cells/μL following the use of ATDs and is an absolute contraindication to the use of these drugs; in this case, radioactive iodine (RAI) or surgery are therapeutic options.
CASE PRESENTATION
A 28-year-old female patient was on follow-up at our clinic after she presented with anterior neck swelling of 4 years. The patient was started on propylthiouracil (PTU) and propranolol based on clinical symptoms of hyperthyroidism and low thyroid stimulating hormone (TSH) levels. After taking the ATDs for 7 months, she came to the clinic for her regular follow-up. At this point, she was declared euthyroid and booked for surgery. Investigations were sent and the complete blood count (CBC) result showed leucopenia with agranulocytosis, even though she was completely asymptomatic. The offending ATD was immediately discontinued. The patient was kept inpatient for monitoring, and lugol's iodine and propranolol were initiated. Eight days after discontinuing the ATD, the CBC profile was determined once again, showing normalized total leukocyte, as well as, absolute neutrophil count. Eventually, the multinodular goiter (MNG) was managed with subtotal thyroidectomy.
CONCLUSION
Despite the fact that agranulocytosis is an extremely rare side effect of ATDs, most often PTU; it is a potentially fatal complication when it occurs. Patient education at the time of prescription should not be overlooked, and systematic programs should be put in place. The baseline granulocyte count should be determined and monitored on a regular basis.
PubMed: 37701536
DOI: 10.2147/IMCRJ.S424053 -
Reproductive Toxicology (Elmsford, N.Y.) Oct 2023Thyroid disruption is an increasingly recognized issue in the use and development of chemicals and new drugs, especially to help toxicologist to complement the...
Thyroid disruption is an increasingly recognized issue in the use and development of chemicals and new drugs, especially to help toxicologist to complement the reproductive and developmental toxicology information of chemicals. Still, adequate assessment methods are scarce and often suffer a trade-off between physiological relevance and labor- and cost-intensive assays. Here, we present a tiered approach for a medium-throughput screening of chemicals to identify their thyroid disrupting potential in zebrafish embryos as a New Approach Methodology (NAM). After identifying the maximum tolerated concentrations, we exposed zebrafish larvae to sub-adverse effect levels of the reference compounds benzophenone-2, bisphenol A, phenylthiourea, potassium perchlorate, propylthiouracil, and phloroglucinol to exclude any systemic toxicity. Applying the transgenic zebrafish line that carries a gene for the red fluorescence protein (Tg(tg:mCherry)) under the thyroglobulin promoter, we could identify the thyroid disrupting effects of the chemicals by a time and cost-effective image analysis measuring the fluorescence levels in the thyroid glands. Our observations could be confirmed by altered expression patterns of genes involved in the hypothalamus-pituitary-thyroid (HPT) axis. Finally, to anchor the observed thyroid disruption, we determined some changes in the Thyroid hormone levels of triiodothyronine (T3) and Thyroxine (T4) using a newly developed liquid chromatography mass spectrometric (LCMS) method. The presented approach carries the potential to extend the toolbox for legislative authorities and chemical producers for the assessment of thyroid-specific endocrine disruption and to overcome current challenges in the evaluation of endocrine disruptors.
PubMed: 37619763
DOI: 10.1016/j.reprotox.2023.108463 -
Proceedings (Baylor University. Medical... 2023Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune condition characterized by necrotizing inflammation of small vessels throughout the...
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune condition characterized by necrotizing inflammation of small vessels throughout the body. Pharmaceutical agents have been noted as an emerging etiology. This case presents a 41-year-old woman with a longstanding history of Graves' disease who previously failed other interventions and was started on propylthiouracil (PTU) nearly 2 years prior to symptom onset. The patient presented with severely pruritic purpuric lesions on her lower extremities that transformed into large bullae and became extremely painful. A thorough workup revealed only slightly elevated perinuclear ANCA and a mild protein S deficiency. Tissue biopsy was consistent with thrombotic vasculitis. A presumptive clinical diagnosis of PTU-induced vasculitis was made. Because the condition is relatively uncommon, the best course of treatment has not clearly been defined. Though PTU was immediately discontinued, the patient also required corticosteroids and referral for tissue debridement. While some cases have had symptom resolution after cessation of PTU, this case adds to a growing body of evidence for the timely use of corticosteroids in controlling PTU-induced vasculitis.
PubMed: 37614859
DOI: 10.1080/08998280.2023.2230830 -
Thyroid : Official Journal of the... Dec 2023When the antithyroid drugs were discovered in the early 1940s, they were immediately recognized as a revolutionary new treatment for hyperthyroidism. Although much has...
When the antithyroid drugs were discovered in the early 1940s, they were immediately recognized as a revolutionary new treatment for hyperthyroidism. Although much has been learned about their mechanism of action and clinical utility, they continue to be used today in much the same way as they have been since their introduction. In 1995, Dr. Clark Sawin gave an address on the history of antithyroid drug development at the 11th International Thyroid Congress in Toronto, Ontario, Canada. In his review, Dr. Sawin recounted the original observations by Drs. Julia and Cosmo Mackenzie and Curt Richter at the Johns Hopkins University School of Medicine, and how their work ultimately led to Dr. Edwin (Ted) B. Astwood's seminal 1943 report on the use of thiourea and thiouracil in the Journal of the American Medical Association. He also described the development of propylthiouracil and methimazole as less toxic alternatives. He concluded his remarks by noting the often-serendipitous pathway of drug development and the role of pharmaceutical companies in the process. Antithyroid drugs remain a cornerstone of thyroid therapeutics. It is informative to review the process by which they came into use, as this is a seminal part of the history of thyroid disease in the 20th century. This knowledge may also spark additional research leading to new pharmacotherapies for patients with hyperthyroidism.
Topics: Male; Humans; Antithyroid Agents; Graves Disease; Methimazole; Propylthiouracil; Hyperthyroidism; Ontario
PubMed: 37594736
DOI: 10.1089/thy.2022.0410 -
International Journal of Developmental... Nov 2023The present study aimed to analyse both neurobehavioural and biochemical results of neonates born of mothers exposed to different doses of lithium along with the groups...
INTRODUCTION
The present study aimed to analyse both neurobehavioural and biochemical results of neonates born of mothers exposed to different doses of lithium along with the groups that received lithium at the highest dose with folic acid as a preventive treatment.
MATERIALS AND METHODS
Male and female rats were mated in separate cages, and pregnant rats were divided into eight first group as (1) vehicle; (2) propylthiouracil (PTU)-induced hypothyroidism; (3-4) received two different doses of lithium carbonate (15 and 30 mg/kg); (5-7) the highest doses of lithium (30 mg/kg) plus three different doses of folic acid (5, 10 and 15 mg/kg); and (8) received just folic acid (15 mg/kg). All treatments were dissolved in drinking water and continued until delivery, followed by returning to a regular diet without treatment.
RESULTS
Lithium (30 mg/kg) disrupts both behavioural and biochemical markers, including TSH, T3 and T4 as measuring indicators to assess thyroid function, IL-10 and TNF-α as anti-inflammatory and inflammatory agents, respectively, malondialdehyde as an oxidative stress marker, alongside SOD, and catalase activity as antioxidant indicators. Besides, folic acid, almost at the highest dose (15 mg/kg), attenuated memory impairement and anxiety-like behaviour caused by lithium. Moreover, the groups treated with folic acid alone in comparison with vehicles demonstrated higher levels of antioxidant and anti-inflammatory indicators.
CONCLUSION
According to the results, prenatal exposure to a high dose of lithium (30 mg/kg) leads to foetal neurodevelopmental disorder and growth restriction through various mechanisms more likely attributed to hypothyroidism, which means it should be either prohibited or prescribed cautiously during pregnancy.
Topics: Pregnancy; Rats; Animals; Female; Male; Antioxidants; Lithium; Rats, Wistar; Hypothyroidism; Propylthiouracil; Folic Acid; Dietary Supplements; Anti-Inflammatory Agents; Cognition
PubMed: 37582655
DOI: 10.1002/jdn.10289