The Endocrine Disruptor Tributyltin Commits Mesenchymal Stem Cells to the Adipose Lineage Via the Retinoid X Receptor

Presentation Number: OR15-4
Date of Presentation: April 1st, 2017

Bassem M. Shoucri*1, Timothy J. Abreo1, Victor T. Hung1, Eric S. Martinez1, Toshi Shioda2 and Bruce Blumberg1
1University of California, Irvine, Irvine, CA, 2MGH Cancer Ctr, Charlestown, MA

Abstract

Accumulating evidence links developmental exposure to endocrine disrupting chemicals (EDCs) to the obesity epidemic. These "obesogens" can promote adiposity by stimulating fat cell development, thus increasing total fat cell number, a strong predictor of obesity in adults. We previously showed that tributyltin (TBT) is such an obesogen, acting through the peroxisome proliferator-activated receptor γ (PPARγ) and the retinoid X receptor (RXR) to bias mesenchymal stem cells (MSCs) towards the formation of fat at the expense of bone (1, 2). Mice treated prenatally with environmentally-relevant levels of TBT display increased adipose depot weights, hepatic steatosis, and MSCs reprogrammed to favor the adipose lineage, effects that persist in the F1, F2, and F3 progeny of exposed F0 mothers (2, 3). Importantly, undifferentiated MSCs from these mice already have a pro-adipogenic gene expression profile, suggesting that TBT can act early in MSC fate specification.

Current in vitro approaches to studying EDCs mechanistically during adipogenesis are limited in that they combine chemical exposures with an adipogenic induction cocktail, creating difficulties in distinguishing obesogens that act early during MSC lineage commitment from those that might promote terminal differentiation. To overcome this limitation, we developed an in vitro assay to screen for obesogens that act during the commitment step whereby MSCs are pretreated with chemical ligands prior to being differentiated with a standard cocktail. Using this new approach, we found that TBT commits MSCs to the adipose lineage in a PPARγ-independent, RXR-dependent manner. Transcriptomic profiling of MSCs treated with TBT revealed genome-wide changes in gene expression that were replicated by an RXR agonist, but not a PPARγ agonist. Pathway analysis of altered transcripts indicated an enrichment of gene targets of the repressive histone modifier Enhancer of Zeste 2 (EZH2), which led us to explore how TBT acts through RXR to reshape the epigenome of unspecified MSCs. Taken together, our data show a critical and unreported role for RXR in early MSC specification. Furthermore, we have shown for the first time that TBT induces adipogenesis in two distinct phases: first during lineage commitment through RXR, and subsequently during differentiation through PPARγ and RXR.

 

Nothing to Disclose: BMS, TJA, VTH, ESM, TS, BB