tretinoin and Hypothyroidism

Topics: Adult; Aged; Alitretinoin; Female; Humans; Hypothyroidism; Ichthyosis, Lamellar; Keratin-10; Keratolytic Agents; Male; Middle Aged; Mutation; Pilot Projects; Transglutaminases; Tretinoin

Mounting evidence suggests a potential link between cocaine abuse, disruptions in hypothalamic-pituitary-thyroid axis signaling, and neuroplasticity, but molecular mechanisms remain unknown. Neurogranin (Ng) is a gene containing a thyroid hormone-responsive element within its first intron that is involved in synaptic plasticity. Transcriptional activation requires heterodimerization of thyroid hormone receptor (TR) and retinoid X receptor (RXR) bound by their respective ligands, tri-iodothryonine and 9-cis-retinoic acid (9-cis-RA), and subsequent binding of this complex to the thyroid hormone-responsive element of the Ng gene. In this study, the effects of chronic cocaine abuse on Ng expression in euthyroid and hypothyroid mice were assessed. In cocaine-treated mice, decreased Ng expression was observed in the absence of changes in levels of thyroid hormones or other hypothalamic-pituitary-thyroid signaling factors. Therefore, we hypothesized that cocaine decreases Ng expression via alterations in 9-cis-RA availability and TR/RXR signaling. In support of this hypothesis, RXR-γ was significantly decreased in brains of cocaine-treated mice while CYP26A1, the main enzyme responsible for neuronal RA degradation, was significantly increased. Results from this study provide the first evidence for a direct effect of cocaine abuse on TR/RXR signaling, RA metabolism, and transcriptional regulation of Ng, a gene essential for adult neuroplasticity.

Topics: Animals; Antithyroid Agents; Blotting, Western; Cocaine; Cytochrome P-450 Enzyme System; Depression, Chemical; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Hypothyroidism; Iodide Peroxidase; Male; Mice; Mice, Inbred C57BL; Neurogranin; Propylthiouracil; Real-Time Polymerase Chain Reaction; Receptors, Thyroid Hormone; Retinoic Acid 4-Hydroxylase; Retinoid X Receptors; RNA; Signal Transduction; Stereotyped Behavior; Thyroid Hormones; Tretinoin

Retinoids play an important role in skin homeostasis and when administered topically cause skin hyperplasia, abnormal epidermal differentiation and inflammation. Thyroidal status in humans also influences skin morphology and function and we have recently shown that the thyroid hormone receptors (TRs) are required for a normal proliferative response to 12-O-tetradecanolyphorbol-13-acetate (TPA) in mice.. We have compared the epidermal response of mice lacking the thyroid hormone receptor binding isoforms TRα1 and TRβ to retinoids and TPA. Reduced hyperplasia and a decreased number of proliferating cells in the basal layer in response to 9-cis-RA and TPA were found in the epidermis of TR-deficient mice. Nuclear levels of proteins important for cell proliferation were altered, and expression of keratins 5 and 6 was also reduced, concomitantly with the decreased number of epidermal cell layers. In control mice the retinoid (but not TPA) induced parakeratosis and diminished expression of keratin 10 and loricrin, markers of early and terminal epidermal differentiation, respectively. This reduction was more accentuated in the TR deficient animals, whereas they did not present parakeratosis. Therefore, TRs modulate both the proliferative response to retinoids and their inhibitory effects on skin differentiation. Reduced proliferation, which was reversed upon thyroxine treatment, was also found in hypothyroid mice, demonstrating that thyroid hormone binding to TRs is required for the normal response to retinoids. In addition, the mRNA levels of the pro-inflammatory cytokines TNFα and IL-6 and the chemotactic proteins S1008A and S1008B were significantly elevated in the skin of TR knock-out mice after TPA or 9-cis-RA treatment and immune cell infiltration was also enhanced.. Since retinoids are commonly used for the treatment of skin disorders, these results demonstrating that TRs regulate skin proliferation, differentiation and inflammation in response to these compounds could have not only physiological but also therapeutic implications.

Topics: Alitretinoin; Animals; Blotting, Western; Cell Differentiation; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Epidermis; Female; Hyperplasia; Hypothyroidism; Interleukin-6; Keratins; Lymphocytes; Macrophages; Male; Mice; Mice, Knockout; Retinoids; Reverse Transcriptase Polymerase Chain Reaction; Skin; Tetradecanoylphorbol Acetate; Thyroid Hormone Receptors alpha; Thyroid Hormone Receptors beta; Tretinoin; Tumor Necrosis Factor-alpha

The effect of hypothyroidism, induced by 6-n-propyl-2-thiouracil (PTU) administration to rats, on the retinoylation reaction and oxidative status was investigated in rat-testes mitochondria. In hypothyroid mitochondria, when compared to euthyroid controls, we found a noticeable increase in the amount of all-trans-retinoic acid (atRA) bound to mitochondrial proteins by an acylation process (34.2 +/- 1.9 pmoles atRA/mg protein/360 min and 22.2 +/- 1.7 pmoles atRA/mg protein/360 min, respectively). This increase, which was time- and temperature-dependent, was accompanied by a strong reduction in the cardiolipin (CL) amount in the mitochondrial membranes of hypothyroid (2.6 +/- 0.2%) as compared to euthyroid rats (4.5 +/- 0.5%) Conversely, a decreased retinoylation reaction was observed when CL liposomes were added to mitochondria or mitoplasts from both euthyroid and hypothyroid rats, thus confirming a role of CL in the retinoylation process. In mitochondria from the latter animals an increase of the level of oxidized CL occurred. The ATP level, which was reduced in hypothyroid mitochondria (27.3 +/- 4.1 pmoles ATP/mg protein versus 67.1 +/- 8.3 pmoles ATP/mg protein of euthyroid animals), was surprisingly increased in mitochondria by the retinoylation reaction in the presence of 100 nM atRA (481.5 +/- 19.3 pmoles ATP/mg protein of hypothyroid animals versus 84.7 +/- 7.7 pmoles ATP/mg protein of euthyroid animals). Overall, in hypothyroid rat-testes mitochondria the increase in retinoylation activity correlates with a significant depletion of the CL level, due to a peroxidation of this lipid. In addition, an enhanced production of reactive oxygen species was observed.

Topics: Animals; Cardiolipins; Humans; Hypothyroidism; Male; Mitochondria; Rats; Rats, Wistar; Reactive Oxygen Species; Testis; 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

Recent data have shown that fine regulation of retinoid mediated gene expression is fundamentally important for optimal brain functioning in aged mice. Nevertheless, alteration of the thyroid hormone signalling pathway may be a limiting factor, which impedes retinoic acid (RA) from exerting its modulating effect. Mild hypothyroidism is often described in the elderly. Thus, in the present study, it was of interest to determine if RA exerts its neurological modulating effect in mild hypothyroidism. To obtain further insight into this question, mice were submitted to a low propylthiouracyl (PTU) drink (0.05%) in order to slightly reduce the serum level of triiodothyronine (T3). A quantitative evaluation of RA nuclear receptors (RAR, RXR), T3 nuclear receptor (TR) and of neurogranin (RC3, a RA target gene which codes for a protein considered as a good marker of synaptic plasticity) in PTU treated mice injected with vehicle or RA or T3 was carried out. The PTU-related decrease in expression of RAR, RXR and RC3 was restored following RA or T3 administration, as observed in aged mice. The amount of TR mRNA, which was not affected in PTU treated mice, was increased only after T3 treatment as observed in overt hypothyroidism. These results suggest that neurobiological alterations observed in aged mice are probably related to RA and T3 signalling pathway modifications associated, in part, with mild changes in thyroid function.

Topics: Animals; Calmodulin-Binding Proteins; Hypothyroidism; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Neurogranin; Propylthiouracil; Receptors, Retinoic Acid; Retinoid X Receptors; RNA, Messenger; Tretinoin; Triiodothyronine

Topics: Antineoplastic Agents; Autoantibodies; Autoimmune Diseases; Humans; Hypothyroidism; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Peroxidase; Tretinoin

The prohormone convertases (PCs) PC1 and PC2 are key enzymes capable of processing a variety of prohormones to their bioactive forms. In this study, we demonstrated that 6-n-propyl-2-thiouracil (PTU)-induced hypothyroidism stimulated, whereas triido-L-thyronine (T(3))-induced hyperthyroidism suppressed, PC1 mRNA levels in the rat anterior pituitary. Using 5' deletions of the human PC1 (hPC1) promoter transiently transfected into GH3 (a somatotroph cell line) cells, we found that T(3) negatively regulated hPC1 promoter activity and that this regulation required the region from -82 to +19 bp relative to the transcription start site. Electrophoretic mobility shift assays (EMSAs) using purified thyroid hormone receptor-alpha1 (TR alpha 1) and retinoid X receptor-beta (RXRbeta) proteins and GH3 nuclear extracts demonstrated that the region from -10 to +19 bp of the hPC1 promoter bound TR alpha 1 as both a monomer and a homodimer and bound TR alpha 1/RXR beta as a heterodimer and multimer. EMSAs with oligonucleotides containing point mutations of the putative negative thyroid response elements (TREs) exhibited diminished homodimer and loss of multimer binding. We conclude that there are multiple novel TRE-like sequences in the hPC1 promoter located from -10 to +19 bp.

Topics: Alitretinoin; Animals; Antineoplastic Agents; Aspartic Acid Endopeptidases; Cells, Cultured; Gene Deletion; Gene Expression Regulation, Enzymologic; Genes, Reporter; Hypothyroidism; Luciferases; Male; Mutagenesis, Insertional; Oligonucleotides; Peptide Fragments; Pituitary Gland, Anterior; Promoter Regions, Genetic; Proprotein Convertases; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley; Receptors, Retinoic Acid; Retinoid X Receptors; RNA, Messenger; Transcription Factors; Tretinoin; Triiodothyronine; Uracil

Pit-1 is a pituitary-specific transcription factor responsible for pituitary development and hormone expression in mammals. Pit-1 contains two protein domains, termed POU-specific and POU-homeo, which are both necessary for DNA binding and activation of the GH and PRL genes and regulation of the PRL, TSH-beta subunit (TSH-beta), and Pit-1 genes. Pit-1 is also necessary for retinoic acid induction of its own gene during development through a Pit-1-dependent enhancer. Combined pituitary hormone deficiency is caused by defective transactivation of target genes in the anterior pituitary. In the present report, we provide in vivo evidence that retinoic acid induction of the Pit-1 gene can be impaired by a Pit-1 gene mutation, suggesting a new molecular mechanism for combined pituitary hormone deficiency in man.

Topics: Animals; Child, Preschool; DNA; DNA-Binding Proteins; Enhancer Elements, Genetic; Gene Expression Regulation; Human Growth Hormone; Humans; Hypothyroidism; Male; Mutation; Pituitary Hormones; Prolactin; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; RNA, Messenger; Signal Transduction; Transcription Factor Pit-1; Transcription Factors; Tretinoin

Thyroid hormone exerts profound effects on the insulin-like growth factors (IGFs)/IGF factor I receptor (IGF-IR) system through its action on the production of IGF-I peptide and IGF-binding proteins. Most of these actions are mediated by the direct control of pituitary GH gene by thyroid hormone. In this work, we have analyzed the possible effect of hypothyroidism on the expression of IGF-IR gene, both in adult and developing animals. Our results show that in the lung and heart, thyroid hormone exerts a negative effect on IGF-IR gene expression in the adult animals and during perinatal life (from day 15 onwards). This negative effect is exerted at different levels. In the heart, this regulation occurs at a pretranslational level, indicated by the fact that parallel changes in the number of membrane IGF-I receptors and IGF-IR transcripts were observed, whereas in lung, no effect of thyroid hormone was noted in the amount of IGF-IR transcripts, suggesting a translational or posttranslational control. GH does not seem to mediate T3 effects on this gene. In contrast, retinoic acid increases the expression of IGF-IR gene at a transcriptional or posttranscriptional level in adult lung and heart. Because the IGFE/ IGF-IR system is depressed in hypothyroid animals, the specific increase in the number of IGF-IRs in the lung and heart of these animals could represent a mechanism to ameliorate the negative effects of hypothyroidism on these important organs.

Topics: Aging; Animals; Animals, Newborn; Female; Gene Expression Regulation; Heart; Human Growth Hormone; Hypothyroidism; Insulin-Like Growth Factor I; Lung; Myocardium; Rats; Rats, Wistar; Receptors, Somatomedin; RNA, Messenger; Tretinoin; Triiodothyronine

Retinoids are needed for normal growth and development. Retinoic acid (RA), an active metabolite of vitamin A, acts through nuclear receptors that belongs to the superfamily which also includes the T3 receptors and 1-25-dihydroxyvitamin D receptor. In order to assess whether RA is a regulator of in vivo thyroid-stimulating hormone (TSH) secretion, we studied the effect of RA administration on spontaneous basal TSH secretion and TSH responses to TRH in either euthyroid or hypothyroid rats. We found that rats treated with RA showed a decrease in spontaneous basal TSH levels and TSH responses to TRH. Similarly, RA administration to hypothyroid rats led to a decrease on TSH responses to TRH. Our data suggests that RA plays an important inhibitory role on in vivo secretion and this effect is unrelated to the thyroid status of the animals.

Topics: Animals; Euthyroid Sick Syndromes; Hypothyroidism; Male; Rats; Rats, Sprague-Dawley; Thyrotropin; Thyrotropin-Releasing Hormone; Tretinoin

The purposes of this study were to determine whether expression of the gene encoding ornithine aminotransferase (OAT) in the rat liver and kidney is regulated by retinoic acid (RA) and to characterize further the role of thyroid hormone in regulating the expression of this gene. The level of OAT messenger RNA (mRNA) was reduced 70% in the liver of animals fed a vitamin A-deficient diet relative to that in animals fed a vitamin A-sufficient diet. RA, administered at a dose of 20 micrograms/rat to A-deficient rats for 1 or 3 days, restored OAT mRNA to near the level observed in animals fed the A-sufficient diet. Retinol was also effective in this regard. T3, when injected alone at a dose of 10 micrograms/100 g BW, had no effect on the level of OAT mRNA in the liver. However, when injected concurrently with RA, T3 blocked the ability of RA to induce OAT mRNA in the liver of rats fed the vitamin A-deficient diet. Animals made both vitamin A deficient and hypothyroid responded to RA in a manner similar to vitamin A-deficient animals. The vitamin A-deficient, hypothyroid rats responded somewhat differently to T3, however. T3 was unable to block the induction of OAT mRNA in the liver of vitamin A-deficient, hypothyroid rats when injected concurrently with RA for 1 day, but did block the induction of OAT mRNA by RA when these two hormones were injected concurrently for 3 days. These data indicate that RA and T3 exert opposing effects on the level of OAT mRNA in the liver. The effects of RA and T3 on OAT mRNA were markedly different in the kidney. Neither vitamin A deficiency nor RA had any apparent affect on the level of OAT mRNA in the kidney. T3, however, increased the level of OAT mRNA in the kidney of vitamin A-deficient rats. In the kidney of vitamin A-deficient, hypothyroid rats, T3 was unable to increase OAT mRNA when injected for 1 day, but did increase this mRNA when injected for 3 days. Together, these data indicate cell-type specific effects of both RA and T3 on the OAT gene.

Topics: Animals; Animals, Newborn; Female; Gene Expression Regulation, Enzymologic; Hypothyroidism; Kidney; Lactation; Liver; Male; Organ Specificity; Ornithine-Oxo-Acid Transaminase; Propylthiouracil; Rats; Rats, Inbred Lew; RNA, Messenger; Thyroxine; Tretinoin; Triiodothyronine; Vitamin A; Vitamin A Deficiency

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

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

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