Developmental exposure to environmental factors has been linked to obesity risk later in life. Nuclear receptors are molecular sensors that play critical roles during development and, as such, are prime candidates to explain the developmental programming of disease risk by environmental chemicals. We have previously characterized the obesogen tributyltin (TBT), which activates the nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and retinoid X receptor (RXR) to increase adiposity in mice exposed in utero. Mesenchymal stem cells (MSCs) from these mice are biased toward the adipose lineage at the expense of the osteoblast lineage, and MSCs exposed to TBT in vitro are shunted toward the adipose fate in a PPARγ-dependent fashion. To address where in the adipogenic cascade TBT acts, we developed an in vitro commitment assay that permitted us to distinguish early commitment to the adipose lineage from subsequent differentiation. TBT and RXR activators (rexinoids) had potent effects in committing MSCs to the adipose lineage, whereas the strong PPARγ activator rosiglitazone was inactive. We show that activation of RXR is sufficient for adipogenic commitment and that rexinoids act through RXR to alter the transcriptome in a manner favoring adipogenic commitment. RXR activation alters expression of enhancer of zeste homolog 2 (EZH2) and modifies genome-wide histone 3 lysine 27 trimethylation (H3K27me3) in promoting adipose commitment and programming subsequent differentiation. These data offer insights into the roles of RXR and EZH2 in MSC lineage specification and shed light on how endocrine-disrupting chemicals such as TBT can reprogram stem cell fate.

Department of Developmental and Cell Biology University of California Irvine Irvine California 92697 2300

Department of Developmental and Cell Biology University of California Irvine Irvine California 92697 2300 Department of Pharmaceutical Sciences University of California Irvine Irvine California 92697

Department of Developmental and Cell Biology University of California Irvine Irvine California 92697 2300 Masaryk University Faculty of Science RECETOX 625 00 Brno Czech Republic

Department of Developmental and Cell Biology University of California Irvine Irvine California 92697 2300 Medical Scientist Training Program University of California Irvine Irvine California 92697

Massachusetts General Hospital Center for Cancer Research and Harvard Medical School Charlestown Massachusetts 02129

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