alitretinoin and triphenyltin

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

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