tretinoin and triphenyltin

An attempt has been made to delineate the role of natural and synthetic retinoid receptor ligands on vimentin expression in the human triple-negative breast cancer cells. The effects of currently synthesized triorganotin derivatives of the general formula R

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Down-Regulation; Electrophoresis, Gel, Two-Dimensional; Epithelial-Mesenchymal Transition; Female; Humans; Organotin Compounds; Proteomics; Retinoid X Receptors; Signal Transduction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tandem Mass Spectrometry; Tretinoin; Trialkyltin Compounds; Vimentin

Complement component 8 γ (C8γ) is a subunit of complement protein 8 (C8), which itself is a subunit of the complement cytolytic membrane attack complex. However, C8γ is also suggested to be a carrier protein for the general clearance of endogenous and exogenous compounds because it belongs to the lipocalin family of small secreted proteins that have the common ability to bind small hydrophobic ligands. Although retinoic acid, a metabolite of vitamin A, has been suggested as a potential ligand of C8γ, it remains unclear which other substances are able to bind to C8γ as ligands. Here, we evaluated the binding affinity of several organotin compounds that are ligands of a receptor of retinoic acid, retinoid X receptor, by using radioligand binding assays. The amount of [

Topics: Binding, Competitive; Carrier Proteins; Complement C8; Complement Membrane Attack Complex; Ligands; Organotin Compounds; Protein Binding; Retinoid X Receptors; Tretinoin; Trialkyltin Compounds

Ampullariidae are unique among gastropods in that females normally show a primordium of the copulatory apparatus (CApp). The aims of this study were (a) to quantitatively evaluate the development and growth of the female CApp with age; (b) to compare the effects of RXR and PPARγ agonists in adult females of known age and (c) to explore the effect of masculinizing RXR agonists on the expression of RXR in the CApp. It was found that the CApp grows and develops with age. A significant increase in penile sheath length (PsL) and also in a developmental index (DI) was observed in 7-8 months old females, as compared with 4-5 months old ones. A reported endogenous agonist of RXR, 9-cis retinoic acid (9cis-RA), as well as two organotin compounds, tributyltin (TBT) and triphenyltin (TPT) which have been also reported to bind to RXR, were injected and its masculinizing effects were measured. Also, the effect of a PPARγ agonist, rosiglitazone, was studied. All studied RXR agonists, but not the PPARγ agonist, were effective in increasing PsL, penile length (PL) and DI. Finally, the expression of the RXR in the CApp was studied (Western blot) in control, TBT, TPT, and 9cis-RA treated females. A significantly increased expression of RXR was only observed after 9cis-RA treatment. It is concluded that (a) development and growth of the CApp is significantly affected by female age; (b) reported RXR agonists, but not a PPARγ agonist, cause female masculinization of young females. An appraisal of previous studies of female masculinization in the Ampullariidae has also been made and it is emphasized that the masculinizing effect of aging should be considered, particularly when interpreting field data.

Topics: Aging; Animals; Endocrine Disruptors; Female; Gastropoda; Male; Organotin Compounds; Penis; Retinoid X Receptors; Sex Characteristics; Tretinoin; Trialkyltin Compounds

Organotins, such as tributyltin (TBT) and triphenyltin (TPT), may disrupt endocrine activity in mammals arising from their ability to act as ligands for the retinoid X receptor (RXR) and the peroxisome proliferator-activated receptor γ (PPARγ). The structure of TBT is completely different from that of 9-cis retinoic acid (9cRA), an endogenous RXR ligand; and X-ray crystallographic studies have revealed that TBT and 9cRA have distinct binding interactions with human RXRα. Therefore, organotins and rexinoids likely activate RXR by different mechanisms. Here, we used human RXRα mutants to investigate which amino acid residues of the receptor are critical for transactivation induced by rexinoids and organotins. We found that 9cRA and a synthetic RXR agonist (LG100268) failed to activate R316A and L326A RXRα mutants. In contrast, all the tested organotins activated the R316A mutant, the L326A mutant, or both but failed to activate a C432A mutant. These results suggest that the importance of L326, which is located in the β-strand, for rexinoid-induced transactivation of RXRα is comparable to that of R316; in contrast, C432 is critical for organotin-induced transactivation, whereas R316 and L326 are not required. We used a PPARγ/RXRα C432A heterodimer to determine whether TBT and TPT could activate the heterodimer by binding to PPARγ. We found that TBT and TPT activated the PPARγ/RXRα C432A heterodimer, which suggests that both compounds can activate the heterodimer through PPARγ. These findings indicate that the amino acid residues that are critical for organotin-induced transactivation of RXRα are distinct from those required for rexinoid-induced transactivation.

Topics: Alitretinoin; Cell Line, Tumor; Humans; Organotin Compounds; Point Mutation; Retinoid X Receptor alpha; Transcriptional Activation; Tretinoin; Trialkyltin Compounds

Xenopus tropicalis embryos were exposed for 48 hr to the mixtures of 5 μg Sn/L triphenyltin (TPT), which is a well-known endocrine disruptor, and 0.25-5 μg/L 9-cis retinoic acid (9c-RA), which is the natural ligand of retinoid X receptor. The phenotypes induced by combined exposure were more variable than those resulting from single exposure to either TPT or 9c-RA. The prominent phenotypes included underdeveloped head structures, abnormal eyes, narrow fins, enlarged proctodaeum, etc. Especially, combined exposure induced unexpected notochord malformations, which ranged from small swellings of the surface of the tails to the extension and extrusion of notochord out of the posterior tails. Compared with the 5 μg Sn/L TPT-treated group, the index of fin deficiency was not affected, and the index of axis deficiency was significantly increased with increasing RA concentrations in the mixtures. Our results suggest that combined exposure to TPT and 9c-RA induced not only more variable phenotypes of malformations than exposure to single compound but also some new and unexpected phenotypes.

Topics: Abnormalities, Drug-Induced; Alitretinoin; Animals; Drug Interactions; Embryo, Nonmammalian; Embryonic Development; Female; Male; Organotin Compounds; Phenotype; Retinoid X Receptors; Teratogenesis; Tretinoin; Xenopus

Retinoic acid (RA) enhances TGF-β-dependent differentiation of Foxp3(+) inducible regulatory T cells (iTregs) and inhibits Th17 differentiation by binding to the RA receptor (RAR)/retinoid X receptor (RXR) heterodimer. The major physiologic RA, all-trans-RA, binds to RAR but not to RXR at physiological concentrations. It remained unclear whether RXR-mediated stimulation affected the iTregs and Th17 differentiation. We found in this study that the RXR agonists, PA024 and tributyltin, augmented the ability of all-trans-RA or the RAR agonist Am80 to enhance CD4(+)CD25(-) T cells to acquire Foxp3 expression and suppressive function. However, they failed to enhance Foxp3 expression in the presence of the RAR antagonist LE540, suggesting that the effect depends on RAR-mediated signals. They exerted the effect largely by augmenting the ability of all-trans-RA to suppress the production of IL-4, IL-21, and IFN-γ that inhibited Foxp3 expression. Agonists of peroxisome proliferator-activated receptors and liver X receptors (LXRs), permissive partners of RXR, failed to enhance Foxp3 expression. In contrast, RXR agonists and LXR agonists suppressed IL-17 expression. The RXR-mediated suppression was not canceled by blocking RAR stimulation but was likely to involve permissive activation of LXRs. All-trans-RA and an agonist of RXR or LXR additively suppressed IL-17 expression when the all-trans-RA concentration was low. RXR agonists also suppressed Ccr6 expression that is essential for Th17 cells to enter the CNS. Accordingly, tributyltin treatment of mice ameliorated experimental autoimmune encephalomyelitis through regulating Th17 cell activities. These results suggest that RXR stimulation modulates Foxp3(+) iTreg and Th17 differentiation with differential dependence on RAR-mediated stimulation.

Topics: Animals; CD4-Positive T-Lymphocytes; Cell Differentiation; Cytokines; Forkhead Transcription Factors; Liver X Receptors; Mice; Organotin Compounds; Orphan Nuclear Receptors; Peroxisome Proliferator-Activated Receptors; Receptors, Retinoic Acid; Retinoid X Receptors; Signal Transduction; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta; Tretinoin; Trialkyltin Compounds

Zebrafish (Danio rerio) embryos were comparably exposed to seven known agonists of retinoid X receptors (RXRs) including two endogenous compounds (9-cis-retinoic acid and docosahexaenoic acid), four man-made selective ligands (LGD1069, SR11237, fluorobexarotene and CD3254), and a biocide (triphenyltin). The dominant phenotypes of malformation were sharp mouths and small caudal fins in 1 mg/L SR11237-treated group after 5 days exposure. 9-cis-retinoic acid and LGD1069 induced multiple malformations including small eyes, bent notochords, reduced brain, enlarged proctodaems, absence of fins, short tails and edema after 5 days exposure. Fluorobexarotene and CD3254 induced similar phenotypes of malformations after 5 days exposure at low concentration (20 μg/L) to those after the 1st d exposure at high concentrations (50 and 100 μg/L). Triphenlytin induced multiple malformations including deformed eyes, bent notochords, bent tails, and edema in hearts after 5 days exposure at concentrations of 1-10 μg Sn/L. In contrast, no discernible malformations were observed in triphenlytin-treated groups after each separate day exposure. These agonists not only showed different ability of teratogenicity but also induced different phenotypes of malformation in zebrafish embryos. In addition, the sensitive stages of zebrafish embryos were different in response to these agonists. Therefore, our results suggest that the agonists of RXRs had divergent teratogenicity in zebrafish embryos.

Topics: Animals; Embryo, Nonmammalian; Environmental Exposure; Female; Male; Organotin Compounds; Phenotype; Retinoid X Receptors; Teratogens; Tretinoin; Water Pollutants, Chemical; Zebrafish

To clarify how tributyltin (TBT) and triphenyltin (TPT) interact with the retinoid X receptor (RXR) to induce growth of male sex organs in female gastropods, we treated female rock shells (Thais clavigera) with three different concentrations (0.1, 1, or 5 microg/g wet wt) of 9-cis-retinoic acid (9CRA) or with a single concentration (1 microg/g wet wt) of TBT, TPT, or fetal bovine serum (as a control). The effects of each treatment were measured as the incidence of imposex, the length of the penis-like structure, and the vas deferens sequence (VDS) index. 9CRA induced imposex in a dose-dependent manner; imposex incidence was significantly higher in the rock shells that received 1 (P < 0.05) or 5 microg (P < 0.001) 9CRA than in the controls. After 1 month, the rock shells treated with 5 microg 9CRA exhibited substantial growth of the penis-like structure that was not as evident in the other treated shells. The length of the structure differed between the 0.1- and 5-microg 9CRA treatment groups (P < 0.05) but not between the 1- and 5-microg 9CRA treatment groups (P > 0.05). Compared with the control, the VDS index increased significantly in the 1- (P < 0.05) and 5-microg (P < 0.001) 9CRA groups. The penis-like structures behind the right tentacle in female rock shells treated with 5 microg 9CRA were essentially the same as the penises and vasa deferentia of normal males and of TBT-treated or TPT-treated imposexed females. These results further support the hypothesis that imposex in gastropods could be mediated by RXR.

Topics: Alitretinoin; Animals; Disorders of Sex Development; Environmental Exposure; Female; Gastropoda; Male; Organotin Compounds; Penis; Tretinoin; Trialkyltin Compounds; Vas Deferens