tretinoin and Hyperthyroidism

Previous studies have highlighted the connections between neural tube defects (NTDs) and both thyroid hormones (TH) and vitamin A. However, whether the two hormonal signaling pathways interact in NTDs has remained unclear. We measured the expression levels of TH signaling genes in human fetuses with spinal NTDs associated with maternal hyperthyroidism as well as levels of retinoic acid (RA) signaling genes in mouse fetuses exposed to an overdose of RA using NanoString or real-time PCR on spinal cord tissues. Interactions between the two signaling pathways were detected by ChIP assays. The data revealed attenuated DIO2/DIO3 switching in fetuses with NTDs born to hyperthyroid mothers. The promoters of the RA signaling genes CRABP1 and RARB were ectopically occupied by increased RXRG and RXRB but displayed decreased levels of inhibitory histone modifications, suggesting that elevated TH signaling abnormally stimulates RA signaling genes. Conversely, in the mouse model, the observed decrease in Dio3 expression could be explained by increased levels of inhibitory histone modifications in the Dio3 promoter region, suggesting that overactive RA signaling may ectopically derepress TH signaling. This study thus raises in vivo a possible abnormal cross-promotion between two different hormonal signals through their common RXRs and the subsequent recruitment of histone modifications, prompting further investigation into their involvement in the etiology of spinal NTDs.

Topics: Animals; Base Sequence; Cells, Cultured; Female; Gene Expression Regulation, Developmental; Histones; Humans; Hyperthyroidism; Iodide Peroxidase; Male; Mice; Mouse Embryonic Stem Cells; Neural Tube Defects; Pregnancy; Pregnancy Complications; Promoter Regions, Genetic; Protein Processing, Post-Translational; Thyroid Hormones; Tretinoin

Thyroid hormone negatively regulates the amyloid-beta precursor protein (APP) gene in thyroid hormone receptor (TR)-transfected neuroblastoma cells. A negative thyroid hormone response element (nTRE) that mediates this regulation has been identified in the first exon of the APP gene. We demonstrate in an in vivo system that expression of APP mRNA, APP protein, and APP secretase cleavage products in mouse brain is influenced by thyroid status. Adult female mice were made hyperthyroid or hypothyroid for 3 weeks and compared to euthyroid mice. APP gene product expression was increased in hypothyroid mouse brain and reduced in hyperthyroid mouse brain, when compared to euthyroid controls. We observed similar effects of thyroid hormone on endogenous APP gene expression in human neuroblastoma cells. The incidence of hypothyroidism increases with age, and localized hypothyroidism of central nervous system has been reported in some patients with Alzheimer's disease (AD). Reduced action of thyroid hormone on the APP gene may contribute to AD pathology by increasing APP expression and the levels of processed APP products. These findings may be an underlying mechanism contributing to the association of hypothyroidism with AD in the elderly, as well as identifying a potential therapeutic target. Pharmacologic supplementation of thyroid hormone, or its analogs, may reduce APP gene expression and beta amyloid peptide accumulation.

Topics: Amyloid beta-Protein Precursor; Animals; Cell Line, Tumor; Female; Gene Expression Regulation; Humans; Hyperthyroidism; Hypothyroidism; Mice; Neuroblastoma; Thyroxine; Tretinoin

Recent studies indicated that hormonal imbalances have a role in modulating the metabolism of methyl groups and homocysteine, interrelated pathways that when disrupted, are associated with a number of pathologies. Retinoic acid (RA) was shown to induce hepatic glycine N-methyltransferase (GNMT), a key regulatory protein in methyl group metabolism, and to reduce circulating homocysteine levels. Because thyroid status influences the hepatic folate-dependent one-carbon pool and retinoids can alter thyroid hormone levels, the aim of this study was to examine the interaction between retinoids and thyroid function. For hypothyroid studies, rats were administered 0.5 g/L propylthiouracil in the drinking water for 15 d, and RA [30 micromol/(kg . d)] for the final 5 d. For hyperthyroid studies, rats were treated with RA [30 micromol/(kg . d)] for 8 d and triiodothyronine [T(3); 50 microg/(100 g . d)] the last 4 d. T(3) treatment prevented the RA-mediated increase in GNMT activity. However, GNMT abundance remained elevated, indicating that GNMT regulation by T(3) in RA-treated rats may be, at least in part, at the post-translational level. In addition, T(3) treatment elevated plasma levels of homocysteine 177%, an elevation that was prevented by RA. T(3)-mediated hyperhomocysteinemia may be due to a 70% decrease in hepatic betaine-homocysteine S-methyltransferase, the enzyme that catalyzes folate-independent remethylation of homocysteine, whereas the RA-mediated stimulation of hepatic homocysteine remethylation by folate-dependent methionine synthase may contribute to lowering plasma homocysteine levels. These findings indicate that thyroid hormones, alone and in conjunction with RA, play an important role in the regulation of methyl group and homocysteine metabolism.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Animals; Betaine-Homocysteine S-Methyltransferase; Enzyme Induction; Glycine N-Methyltransferase; Homocysteine; Hyperthyroidism; Hypothyroidism; Liver; Male; Methyltransferases; Rats; Rats, Sprague-Dawley; Tretinoin; Triiodothyronine

Triiodothyronine (T3) receptors (TRs) and retinoic acid (RA) receptors (RARs) exert their effects on growth, differentiation and cellular homeostasis by acting as transcription factors. The binding characteristics of these receptors have been studied in liver of hypothyroid and hyperthyroid rats, with or without treatment with T3, RA or T3 + RA together. The changes in binding induced by RA treatment depended on the hormonal status of the rat. In hypothyroid rats the T3 binding capacity was unaltered by administration of T3 or RA alone but increased by 48% after treatment with T3 and RA together. In these rats administration of RA, T3 or T3 + RA increased the RAR binding capacity by 45, 79 and 112%, respectively. In hyperthyroid rats the administration of RA reduced the TR and RAR binding capacities by 22 and 37%, respectively. We found also that the affinity constants of TRs and RARs were reduced in hypothyroid rats after treatment with T3 or T3 + RA. It is suggested that this change of the properties of receptors is related to a ligand-dependent conformational change in these receptors.

Topics: Animals; Homeostasis; Hyperthyroidism; Hypothyroidism; Liver; Male; Rats; Rats, Wistar; Receptors, Retinoic Acid; Receptors, Thyroid Hormone; Thyroid Gland; Tretinoin; Triiodothyronine

Retinoic acid (RA) and triiodothyronine (T3) exert many of their actions by binding to specific nuclear receptors (respectively, RA receptor (RAR) and T3) receptor (TR) belonging to a 'superfamily' of receptors. Some heterologous regulation of these receptors has been shown, and in particular regulation of the maximum binding capacity of TR by either retinol or RA. Now, using hyperthyroidic rats as a model, the effect of RA on binding capacity and on the mRNA levels of TR and RAR was investigated. The results show that the benefit of vitamin A treatment for the hyperthyroidic state, which has been described for a long time, could be the result of a down-heteroregulation of TR by RA, the active metabolite of retinol.

Topics: Animals; Autoradiography; Base Sequence; Carrier Proteins; Chromatography, Gel; DNA; Hyperthyroidism; Kinetics; Male; Molecular Sequence Data; Rats; Rats, Wistar; Receptors, Retinoic Acid; Receptors, Thyroid Hormone; RNA, Messenger; Tretinoin

Topics: Alcohol Dehydrogenase; Animals; Hyperthyroidism; Hypothyroidism; Liver; Male; Oxidation-Reduction; Rats; Retinaldehyde; Retinoids; Thyroid Diseases; Thyroxine; Tretinoin

Topics: Adult; Humans; Hyperthyroidism; Isotretinoin; Male; Tretinoin

Topics: Animals; Brain; Hyperthyroidism; Hypothyroidism; Male; Rats; Tretinoin