Maternal hypothyroxinemia disrupts neurotransmitter metabolic enzymes in developing brain. (25/3269)

Maternal thyroid status influences early brain development and, consequently, cognitive and motor function in humans and rats. The biochemical targets of maternal thyroid hormone (TH) action in fetal brain remain poorly defined. A partially thyroidectomized rat dam model was therefore used to investigate the influence of maternal hypothyroxinemia on the specific activities of cholinergic and monoaminergic neurotransmitter metabolic enzymes in the developing brain. Maternal hypothyroxinemia was associated with reduced monoamine oxidase (MAO) activity in fetal whole brain at 16 and 19 days gestation (dg). A similar trend was observed for choline acetyltransferase (ChAT) activity. In contrast, DOPA decarboxylase (DDC) activity was markedly elevated at 21 dg. Further study of these enzymes at 14 dg showed no differences between normal and experimental progeny - suggesting they become TH sensitive after this age. Tyrosine hydroxylase (TyrH) and acetylcholinesterase (AChE) activities were unaffected prenatally. During postnatal development, the activities of TyrH, MAO, DDC and, to a lesser extent, AChE were increased in a brain region- and age-specific manner in experimental progeny. The prenatal disturbances noted in this study may have wide-ranging consequences since they occur when neurotransmitters have putative neurotropic roles in brain development. Furthermore, the chronic disturbances in enzyme activity observed during postnatal life may affect neurotransmission, thereby contributing to the behavioural dysfunction seen in adult progeny of hypothyroxinemic dams.  (+info)

Thyroid hormone induces activation of mitogen-activated protein kinase in cultured cells. (26/3269)

Thyroid hormone [L-thyroxine (T4)] rapidly induced phosphorylation and nuclear translocation (activation) of mitogen-activated protein kinase (MAPK) in HeLa and CV-1 cells in the absence of cytokine or growth factor. A pertussis toxin-sensitive and guanosine 5'-O-(3-thiotriphosphate)-sensitive cell surface mechanism responsive to T4 and agarose-T4, suggesting a G protein-coupled receptor, was implicated. Cells depleted of MAPK or treated with MAPK pathway inhibitors showed reduced activation of MAPK and of the signal transducer and activator of transcription STAT1alpha by T4; they also showed reduced T4 potentiation of the antiviral action of interferon-gamma (IFN-gamma). T4 treatment caused tyrosine-phosphorylated MAPK-STAT1alpha nuclear complex formation and enhanced Ser-727 phosphorylation of STAT1alpha, in the presence or absence of IFN-gamma. STAT1alpha-deficient cells transfected with STAT1alpha containing an alanine-for-serine substitution at residue 727 (STAT1alphaA727) showed minimal T4-stimulated STAT1alpha activation. IFN-gamma induced the antiviral state in cells containing wild-type STAT1alpha (STAT1alphawt) or STAT1alphaA727; T4 potentiated IFN-gamma action in STAT1alphawt cells but not in STAT1alphaA727 cells. T4-directed STAT1alpha Ser-727 phosphorylation is MAPK mediated and results in potentiated STAT1alpha activation and enhanced IFN-gamma activity.  (+info)

Reduction of thyroid hormone levels by methylsulfonyl metabolites of tetra- and pentachlorinated biphenyls in male Sprague-Dawley rats. (27/3269)

Male Sprague-Dawley rats received four consecutive intraperitoneal (i.p.) doses of five kinds of methylsulfonyl (MeSO2) metabolites of tetra- and pentachlorinated biphenyls (tetra- and pentaCBs) to determine their effects on thyroid hormone levels. The five MeSO2 metabolites, which were the major MeSO2-PCBs detected in human milk, liver and adipose tissue were 3-MeSO2-2,2',4',5-tetraCB (3-MeSO2-CB49),3-MeSO2-2,3',4',5-tetraCB (3-MeSO2-CB70), 3-MeSO2-2,2',3',4',5-pentaCB (3-MeSO2-CB87), 3-MeSO2-2,2',4',5,5'-pentaCB (3-MeSO2-CB101), and 4-MeSO2-2,2',4',5,5'-pentaCB (4-MeSO2-CB101). All five tested MeSO2 metabolites (20 mumol/kg once daily for 4 days) reduced serum total thyroxine levels 16-40% on days 2, 3, 4, and 7 (after the last dosage). The total triiodothyronine level was reduced 37% by treatment with 3-MeSO2-CB49 at day 7, but was increased 35% and 38% by 3-MeSO2-CB70 and 4-MeSO2-CB101 at days 3 and 4, respectively. The reductions in thyroid hormone levels led to an increase in thyroid stimulating hormone (TSH) levels by 3-MeSO2-CB49, 3-MeSO2-CB87 and 3-MeSO2-CB101. A 30% increase in thyroid weight was produced by 3-MeSO2-CB101 treatment. Thus, it is likely that all five tested MeSO2 metabolites could influence thyroid hormone metabolism. The results show that the tested 3- and 4-MeSO2 metabolites of tetra- and pentaCBs reduce thyroid hormone levels in rats, suggesting that the metabolites may act as endocrine-disrupters.  (+info)

Enhancing or suppressive effects of antibodies on processing of a pathogenic T cell epitope in thyroglobulin. (28/3269)

Thyroglobulin (Tg)-specific Abs occur commonly in thyroid disease, but it is not clear to what extent they affect Tg processing and presentation to T cells. Here we show that generation of the nondominant pathogenic Tg epitope (2549-2560), containing thyroxine (T4) at position 2553 (T4(2553)), is augmented by Tg-specific IgG mAbs that facilitate FcR-mediated internalization of Tg. However, other mAbs of the same (IgG1) subclass enhanced Tg uptake by APC but had no effect on the generation of this peptide. Treatment of APC with chloroquine or glutaraldehyde abrogated enhanced generation of T4(2553). The boosting effect was selective, since the enhancing mAbs did not facilitate generation of the neighboring cryptic (2495-2511) peptide, which is also pathogenic in mice. When Tg was simultaneously complexed to a mAb reactive with T4(2553) and to a mixture of boosting mAbs, the presentation of this epitope was totally suppressed. These results suggest that Tg-specific Abs alter Tg processing and may boost or suppress the presentation of nondominant pathogenic determinants during the course of disease.  (+info)

Thyroid nodular disease after radiotherapy to the neck for childhood Hodgkin's disease. (29/3269)

Patients who receive radiotherapy to the neck are at risk of developing thyroid dysfunction. This prospective study of patients whose treatment for Hodgkin's disease in childhood included radiotherapy to the neck aimed to investigate the incidence and natural history of thyroid dysfunction and the morphological changes of the gland demonstrated on ultrasound. Forty-seven patients were investigated by clinical examination, thyroid function tests and thyroid ultrasound. Only six patients had a clinically detectable abnormality, but 64% had abnormal thyroid function tests. All patients had an abnormal thyroid ultrasound scan and 42% had at least one focal abnormality. A significant association was found between the presence of a focal lesion on ultrasound and young age at radiotherapy, longer follow-up and the length of time that the thyroid-stimulating hormone (TSH) level had been elevated. During follow-up, 65% of patients not on thyroxine developed new focal abnormalities. The longest time interval between radiotherapy and an increase in TSH level was 94 months, and from radiotherapy to the appearance of a focal abnormality on thyroid ultrasound was over 18 years. Three patients were found to have a thyroid carcinoma. These findings indicate the importance of long-term follow-up for patients treated by neck irradiation for Hodgkin's disease in childhood.  (+info)

Short-term influence of prednisone and phenobarbital on thyroid function in euthyroid dogs. (30/3269)

The short-term effects of prednisone and phenobarbital on serum total thyroxine (tT4), free thyroxine (fT4), and thyroid stimulating hormone (TSH) were evaluated in euthyroid dogs. Twenty-six beagles were randomly divided into 3 groups receiving, respectively, a placebo, prednisone (1.2 to 2 mg/kg body weight, per os, every 12 hours for 3 weeks), or phenobarbital (1.8 to 3 mg/kg body weight for 1 week, then 2.7 to 4.5 mg/kg body weight, per os, every 12 hours for 2 weeks). Blood samples taken over a 6-week period were assayed for serum tT4, fT4, and TSH. Phenobarbital therapy in our study did not affect serum tT4, fT4, or TSH concentrations. Prednisone therapy, however, significantly decreased serum tT4 and fT4, but did not affect serum TSH concentrations.  (+info)

Effects of oral propylthiouracil treatment on nitric oxide production in rat aorta. (31/3269)

The effects of oral propylthiouracil (PTU) treatment on vascular nitric oxide (NO) production were studied in the rat aorta. Rats were fed a standard low fat diet with or without 0.1% PTU, for 2 or 4 weeks, or for 2 weeks with additional thyroxine injections. Concentration response curves were then constructed to phenylephrine (PE) in both endothelium-intact and denuded aortic rings from these animals and after incubation with 0.1 mM L-N(G)nitroarginine (L-NOARG). In addition, expression of nitric oxide synthase (NOS) was analysed in sections of aorta from PTU-treated and control rats using rabbit polyclonal antibodies to both inducible NOS (iNOS) and endothelial NOS (eNOS). Oral PTU treatment resulted in a significant reduction in both the maximum response (control, 0.53+/-0.02; 2 week PTU, 0.20+/-0.07; 4 week PTU, 0.07+/-0.02 g mg(-1)) and vessel sensitivity (EC50 values: control, 9.10x10(-8)+/-0.67; 2 week PTU, 7.45x10(-7)+/-1.15; 4 week PTU, 9.73x10(-7)+/-0.45 M) to PE in endothelium-intact vessel rings, as compared to controls (P<0.05). Both endothelial removal and incubation with L-NOARG restored the maximum response after 2, but not 4 weeks, although, in general, vessel sensitivity was not altered by either treatment. Vessels from PTU-treated rats given thyroxine injections showed no significant differences between any of the dose response curve parameters. Immunohistochemical analysis suggested that labelling for eNOS may be increased after PTU treatment as compared to control animals, whereas iNOS antibody immunoreactivity was not different between the two groups. These results suggest that the hyporesponsiveness to PE observed after oral PTU treatment is, in part, due to enhanced nitric oxide (NO) production by the endothelium, and demonstrate for the first time that thyroid hormones may play a role in the regulation of eNOS activity in the rat aorta.  (+info)

Early cellular abnormalities induced by RET/PTC1 oncogene in thyroid-targeted transgenic mice. (32/3269)

The RET/PTC1 oncogene, a rearranged form of the RET proto-oncogene, has been reported to be associated with human papillary thyroid carcinomas. We have shown that targeted expression of RET/PTC1 in the thyroid gland leads to the development of thyroid carcinomas in transgenic mice with histologic and cytologic similarities to human papillary thyroid carcinoma. To further investigate how RET/PTC1 expression contributes to the pathogenesis of papillary thyroid tumor, the time of tumor onset and the early phenotypic consequences of RET/PTC1 expression in thyrocytes were determined. All high copy transgenic mice developed bilateral thyroid tumors as early as 4 days of age. At embryological days 16-18, increased proliferation rate, distorted thyroid follicle formation and reduced radioiodide concentrating activity were identified in transgenic embryos. The reduced radioiodide concentrating activity was attributed to decreased expression of the sodium-iodide symporter. Our study showed that RET/PTC1 not only increased proliferation of thyrocytes, it also altered morphogenesis and differentiation. These findings provide a model for the role of RET/PTC1 in the formation of abnormal follicles with reduced iodide uptake ability observed in human papillary thyroid carcinoma.  (+info)