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Endocrine-Disrupting Organotin Compounds Are Potent Inducers of Adipogenesis in Vertebrates

Department of Developmental and Cell Biology (F.G., Z.Z., L.M., K.A., R.C., D.M.G., B.B.), University of California Irvine, Irvine California 92697-2300; National Institutes of Natural Sciences (H.W., T.I.), National Institute for Basic Biology, Okazaki Institute for Integrative Bioscience, Okazaki 444-8787, Japan; and Division of Cellular & Molecular Toxicology (J.K.), Biological Safety Research Center, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan

Address all correspondence and requests for reprints to: Bruce Blumberg, Department of Developmental and Cell Biology, University of California Irvine, 2113 McGaugh Hall, Irvine, California 92697-2300. E-mail: blumberg{at}uci.edu.

Dietary and xenobiotic compounds can disrupt endocrine signaling, particularly of steroid receptors and sexual differentiation. Evidence is also mounting that implicates environmental agents in the growing epidemic of obesity. Despite a long-standing interest in such compounds, their identity has remained elusive. Here we show that the persistent and ubiquitous environmental contaminant, tributyltin chloride (TBT), induces the differentiation of adipocytes in vitro and increases adipose mass in vivo. TBT is a dual, nanomolar affinity ligand for both the retinoid X receptor (RXR) and the peroxisome proliferator-activated receptor (PPAR). TBT promotes adipogenesis in the murine 3T3-L1 cell model and perturbs key regulators of adipogenesis and lipogenic pathways in vivo. Moreover, in utero exposure to TBT leads to strikingly elevated lipid accumulation in adipose depots, liver, and testis of neonate mice and results in increased epididymal adipose mass in adults. In the amphibian Xenopus laevis, ectopic adipocytes form in and around gonadal tissues after organotin, RXR, or PPAR ligand exposure. TBT represents, to our knowledge, the first example of an environmental endocrine disrupter that promotes adipogenesis through RXR and PPAR activation. Developmental or chronic lifetime exposure to organotins may therefore act as a chemical stressor for obesity and related disorders.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ  |  RARα  |  PPARα  |  PPARδ  |  PPARγ  |  LXRα  |  PXR  |  RXRα  |  RXRγ  |  NURR1

Ligands:   LGD 100268  |  17β-Estradiol  |  Pirinixic acid  |  9-cis-Retinoic acid  |  Arotinoid acid  |  Rosiglitazone

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