Dibutyltin Compounds Effects on PPARγ/RXRα Activity, Adipogenesis, and Inflammation in Mammalians Cells

Abstract

Organotins are a group of chemical compounds that have a tin atom covalently bound to one or more organic groups. The best-studied organotin is tributyltin chloride, which is an environmental pollutant and an endocrine disruptor. Tributyltin chloride has been shown to bind to PPARγ/RXRα and induces adipogenesis in different mammalian cells. However, there are few studies with other organotin compounds, such as dibutyltins. The aim of this study was to investigate the effect of dibutyltins diacetate, dichloride, dilaurate, and maleate on the transcriptional activity of the nuclear PPARγ and RXRα receptors, and on adipogenesis and inflammation. Analogous to tributyltin chloride, in reporter gene assay using HeLa cells, we observed that dibutyltins diacetate, dichloride, dilaurate, and maleate are partial agonists of PPARγ. Unlike tributyltin chloride, which is a full agonist of RXRα, dibutyltins dichloride and dilaurate are partial RXRα agonists. Additionally, the introduction of the C285S mutation, which disrupts tributyltin chloride binding to PPARγ, abrogated the dibutyltin agonistic activity. In 3T3-L1 preadipocytes, all dibutyltin induced adipogenesis, although the effect was less pronounced than that of rosiglitazone and tributyltin chloride. This adipogenic effect was confirmed by the expression of adipogenic markers Fabp4, Adipoq, and Glut4. Exposure of 3T3-L1 cells with dibutyltin in the presence of T0070907, a specific PPARγ antagonist, reduced fat accumulation, suggesting that adipogenic effect occurs through PPARγ. Furthermore, dibutyltins dichloride, dilaurate, and maleate inhibited the expression of proinflammatory genes in 3T3-L1 cells, such as Vcam1, Dcn, Fn1, S100a8, and Lgals9. Additionally, in RAW 264.7 macrophages, tributyltin chloride and dibutyltin dilaurate reduced LPS-stimulated TNFα expression. Our findings indicate that dibutyltins diacetate, dichloride, dilaurate, and maleate are PPARγ partial agonists and that dibutyltins dichloride and dilaurate are also partial RXRα agonists. Furthermore, dibutyltins induce adipogenesis in a PPARγ-dependent manner and repress inflammatory genes in 3T3-L1 and RAW 264.7 cells. Although dibutyltins display some partial PPARγ/RXRα agonistic effects, the translation of cell-based results assays into in vivo effects on inflammation and insulin resistance is not entirely known. Nevertheless, further studies are necessary to address their effects in different periods of life and to elucidate the actions of organostanic compounds in whole-body context.

Transgenerational effects of obesogens

“…TBT binds directly to the “master regulator” of adipogenesis, peroxisome proliferator‐activated receptor gamma (PPARγ) and its heterodimeric partner, 9‐cis retinoic acid receptor (RXR) at nanomolar (parts per billion) levels . Several studies have shown that pre‐adipocytes as well as mouse and human multipotent mesenchymal stromal cells (aka mesenchymal stem cells, MSCs) can be induced to differentiate into adipocytes by organotins such as TBT and TPT as well as the highly prevalent DBT . These results are largely dependent on the ability of these chemicals to activate PPARγ .…”

“…70,74,75 Several studies have shown that pre-adipocytes as well as mouse and human multipotent mesenchymal stromal cells (aka mesenchymal stem cells, MSCs) can be induced to differentiate into adipocytes by organotins such as TBT and TPT 70,75 as well as the highly prevalent DBT. 76,77 These results are largely dependent on the ability of these chemicals to activate PPARγ. 78,79 Adult mice exposed to TBT in utero displayed increased lipid accumulation in adipose depots, livers and testis 70,81 and treatment of adolescent or adult mice, rats, goldfish and zebrafish led to increased fat deposition and hepatic steatosis.…”

Effects of Perinatal Exposure to Dibutyltin Chloride on Fat and Glucose Metabolism in Mice, and Molecular Mechanisms, in Vitro

“…2006 ). More recently, transfection assays performed in HeLa cells showed that DBT activated ( Milton et al. 2017 ); however, the species from whom the gene was cloned was not specified.…”

“…2017 ); however, the species from whom the gene was cloned was not specified. Studies performed using the murine preadipocyte cell line 3T3-L1 and the MSC-like mouse cell line BMS2 showed that DBT induced lipid accumulation when the cells were induced to differentiate into adipocytes ( Milton et al. 2017 ; Yanik et al.…”

Mediators of Impaired Adipogenesis in Obesity-Associated Insulin Resistance and T2DM

“…Another evidence suggests that uremic toxin-treated 3T3-L1 cells and MSC-derived adipocytes exhibit impaired adipogenesis and apoptosis through activation of the Na/K-ATPase/ROS amplification cycle [194]. Other types of environmental pollutants include organotins, widely used antifouling biocides for ships and fishing nets, play a role as endocrine disruptors as they bind to PPARγ/ RXRα, induce adipogenesis, and repress inflammatory genes in different mammalian cells [195].…”