Endocrine-disrupting organotin compounds are potent inducers of adipogenesis in vertebrates.
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 gamma (PPARgamma). 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 PPARgamma ligand exposure. TBT represents, to our knowledge, the first example of an environmental endocrine disrupter that promotes adipogenesis through RXR and PPARgamma activation. Developmental or chronic lifetime exposure to organotins may therefore act as a chemical stressor for obesity and related disorders.
Grün
Felix
F
Department of Developmental and Cell Biology, University of California Irvine, 2113 McGaugh Hall, Irvine, California 92697-2300, USA.
Watanabe
Hajime
H
Zamanian
Zamaneh
Z
Maeda
Lauren
L
Arima
Kayo
K
Cubacha
Ryan
R
Gardiner
David M
DM
Kanno
Jun
J
Iguchi
Taisen
T
Blumberg
Bruce
B
D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D015415:Biomarkers; D002460:Cell Line; D019281:Dimerization; D052244:Endocrine Disruptors / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008024:Ligands; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D009947:Organotin Compounds / Q000494:pharmacology*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D015415:Biomarkers; D052244:Endocrine Disruptors; D008024:Ligands; D009947:Organotin Compounds; D047495:PPAR gamma; D047490:Retinoid X Receptor alpha