RESUMEN
The widely used surfactant nonylphenol ethoxylate (NPEO) and its raw material 4-n-nonylphenol (4-n-NP), as well as its degradation products, are recognized as endocrine disrupting chemicals. The USA Environmental Protection Agency (EPA) released an assessment that looked for safe alternatives to NPEO. Vanillin ethoxylate (VAEO) is a novel substitute for NPEO and is quite similar to NPEO in structure; there is a risk that it has similar endocrine disrupting effects to NPEO. However, their effects on various nuclear hormone receptors have not been thoroughly examined. In this study, the effects of NPEO, VAEO, 4-n-NP and Vanillin on the estrogen receptor α (ERα), androgen receptor (AR), thyroid hormone receptor (TR), retinoic X receptor ß (RXRß) and estrogen-related receptor γ (ERRγ) were determined and compared using a battery of recombined yeast strains expressing ß-galactosidase. The results showed that NPEO and 4-n-NP acted as significant antagonists of ER, AR, TR and ERRγ. In addition, 4-n-NP also had antagonistic activity toward RXRß. Moreover, VAEO was shown to be a very weak antagonist of TR and ERRγ, and Vanillin had no interaction with any nuclear receptors. For the first time, it was found that NPEO had AR, TR and ERRγ antagonistic effects and that 4-n-NP was an antagonist of RXRß. The in vitro data indicated that NPEO, 4-n-NP and VAEO have the potential to act as endocrine disruptors involving more than one nuclear hormone receptor, but VAEO has much lower endocrine disrupting potential than NPEO. Thus, it is critical to find safe substitutes for NPEO and a substitute of NPEO with structural analogues should be carried out with caution. Furthermore, to look for preferable alternatives for NPEO, more in vivo and in vitro studies of the alternatives concerning endocrine disruption are needed, especially in vitro studies need to involve various target points, not only focus on their effects on ER but also take other nuclear hormone receptor pathways into consideration.
Asunto(s)
Benzaldehídos/toxicidad , Disruptores Endocrinos/toxicidad , Glicoles de Etileno/toxicidad , Fenoles/toxicidad , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Benzaldehídos/química , Relación Dosis-Respuesta a Droga , Disruptores Endocrinos/química , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor alfa de Estrógeno/genética , Glicoles de Etileno/química , Estructura Molecular , Fenoles/química , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Receptores de Hormona Tiroidea/antagonistas & inhibidores , Receptores de Hormona Tiroidea/genética , Receptor beta X Retinoide/antagonistas & inhibidores , Receptor beta X Retinoide/genética , Técnicas del Sistema de Dos HíbridosRESUMEN
Brown adipose tissue (BAT) has attracted considerable research interest because of its therapeutic potential to treat obesity and associated metabolic diseases. Augmentation of brown fat mass and/or its function may represent an attractive strategy to enhance energy expenditure. Using high-throughput phenotypic screening to induce brown adipocyte reprogramming in committed myoblasts, we identified a retinoid X receptor (RXR) agonist, bexarotene (Bex), that efficiently converted myoblasts into brown adipocyte-like cells. Bex-treated mice exhibited enlarged BAT mass, enhanced BAT function, and a modest browning effect in subcutaneous white adipose tissue (WAT). Expression analysis showed that Bex initiated several "browning" pathways at an early stage during brown adipocyte reprogramming. Our findings suggest RXRs as new master regulators that control brown and beige fat development and activation, unlike the common adipogenic regulator PPARγ. Moreover, we demonstrated that selective RXR activation may potentially offer a therapeutic approach to manipulate brown/beige fat function in vivo.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Reprogramación Celular/genética , Adipogénesis/efectos de los fármacos , Tejido Adiposo Pardo/citología , Tejido Adiposo Blanco/metabolismo , Animales , Bexaroteno , Peso Corporal/efectos de los fármacos , Células Cultivadas , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Ratones , Ratones Endogámicos C57BL , Mioblastos/citología , Mioblastos/efectos de los fármacos , Mioblastos/metabolismo , Consumo de Oxígeno/efectos de los fármacos , PPAR gamma/metabolismo , Interferencia de ARN , Receptor alfa X Retinoide/antagonistas & inhibidores , Receptor alfa X Retinoide/genética , Receptor alfa X Retinoide/metabolismo , Receptor beta X Retinoide/antagonistas & inhibidores , Receptor beta X Retinoide/genética , Receptor beta X Retinoide/metabolismo , Receptor gamma X Retinoide/antagonistas & inhibidores , Receptor gamma X Retinoide/genética , Receptor gamma X Retinoide/metabolismo , Tetrahidronaftalenos/farmacología , Termogénesis/efectos de los fármacos , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína Desacopladora 1/metabolismoRESUMEN
There is increasing evidence of activities of chlorinated by-products of bisphenol A (BPA) on retinoic acid system. Their agonistic and antagonistic activities to human retinoid X receptor (RXR) were assessed by a two-hybrid yeast assay. Aqueous solutions of 1mg/L BPA were chlorinated by sodium hypochlorite (NaClO). It showed that chlorination of BPA increased RXRß antagonistic activity, while no agonistic activity was detected, showing chlorine might act as a toxic potentiator rather than a toxic deactivator in RXRß disrupting effects. BPA and its byproducts including 2,2',6,6'-tetrachlorobisphenol A (TCBPA) and 2,4,6-trichlorophenol (TCP) were quantitatively determined by gas chromatography/mass spectrometry (GC/MS). BPA rapidly degraded. With the increasing of ICC and reaction time, concentration of formed TCBPA increased initially then decreased, while concentration of formed TCP increased stably. Using the toxic equivalent (TEQ) approach, the main contributors should be mono-, di- and tri- chlorobisphenol A at initial chlorine concentration (ICC) of 1mg/L. At ICC of 2 and 5mg/L, the main contributors were TCBPA and TCP, being 57.7%-70.7% and 45.3%-59.4%. Molecular docking showed BPA chlorination by-products might have the same mode of action with BPA, forming hydrogen bond and pi-pi interaction with their OH group or hydrophobic ring.
Asunto(s)
Compuestos de Bencidrilo/química , Disruptores Endocrinos/química , Halogenación , Fenoles/química , Receptor beta X Retinoide/agonistas , Receptor beta X Retinoide/antagonistas & inhibidores , Desinfección , Humanos , Simulación del Acoplamiento Molecular , Hipoclorito de Sodio , Técnicas del Sistema de Dos HíbridosRESUMEN
The present study aimed to investigate the role of a retinoic acid receptor-ß (RARß) inhibitor LE135 on TGF-ß induced chondrogenesis of human bone marrow mesenchymal stem cells (hMSCs). Pellet culture with exogenous transforming growth factor-ß (TGF-ß), and a mechanically loaded scaffold system were used to provide two culture models. All samples were cultured for 8 days and changes in early gene expression were determined. Glycosaminoglycan and mRNA expression data showed that LE135 itself did not induce any chondrogenic response in either pellet culture or scaffold culture of hMSCs. LE135 actually inhibited the chondrogenic response caused by exogenous TGF-ß, or endogenous TGF-ß induced by mechanical load, while the expression of genes normally associated with osteogenesis was not affected. This suggests that the inhibitor LE135 affects the osteochondral differentiation pathway at a different stage, inhibiting chondrogenic gene expression while having no effect on genes normally associated with the osteogenic phenotype. Alternatively, it might be that different cells were proceeding down different lineages. Some cells were undergoing chondrogenesis and this was affected by LE135, while other cells underwent osteogenic differentiation and were not affected by LE135.