title: The unexpected teratogenicity of RXR antagonist UVI3003 via activation of PPARγ in Xenopus tropicalis.
abstract: The RXR agonist (triphenyltin, TPT) and the RXR antagonist (UVI3003) both show teratogenicity and, unexpectedly, induce similar malformations in Xenopus tropicalis embryos. In the present study, we exposed X. tropicalis embryos to UVI3003 in seven specific developmental windows and identified changes in gene expression. We further measured the ability of UVI3003 to activate Xenopus RXRα (xRXRα) and PPARγ (xPPARγ) in vitro and in vivo. We found that UVI3003 activated xPPARγ either in Cos7 cells (in vitro) or Xenopus embryos (in vivo). UVI3003 did not significantly activate human or mouse PPARγ in vitro; therefore, the activation of Xenopus PPARγ by UVI3003 is novel. The ability of UVI3003 to activate xPPARγ explains why UVI3003 and TPT yield similar phenotypes in Xenopus embryos. Our results indicate that activating PPARγ leads to teratogenic effects in Xenopus embryos. More generally, we infer that chemicals known to specifically modulate mammalian nuclear hormone receptors cannot be assumed to have the same activity in non-mammalian species, such as Xenopus. Rather they must be tested for activity and specificity on receptors of the species in question to avoid making inappropriate conclusions.
authors.affiliation: State Key Laboratory of Estuarine and Coastal Research, East China Normal University, Shanghai 200062, China.
authors.forename: Jingmin
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, California 92697-2300, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Janesick
authors.affiliation: State Key Laboratory of Estuarine and Coastal Research, East China Normal University, Shanghai 200062, China.
authors.forename: Lijiao
authors.initials: L
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Estuarine and Coastal Research, East China Normal University, Shanghai 200062, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Hu
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, California 92697-2300, USA.
authors.forename: Weiyi
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, California 92697-2300, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Blumberg
authors.affiliation: State Key Laboratory of Estuarine and Coastal Research, East China Normal University, Shanghai 200062, China. Electronic address: hhshi@des.ecnu.edu.cn.
authors.forename: Huahong
authors.initials: H
authors.lastname: Shi
mesh_terms: D000014:Abnormalities, Drug-Induced; D000818:Animals; D003373:Coumaric Acids / Q000633:toxicity*; D047495:PPAR gamma / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000037:antagonists & inhibitors*; D013723:Teratogens / Q000633:toxicity*; D013764:Tetrahydronaphthalenes / Q000633:toxicity*; D014981:Xenopus / Q000196:embryology / Q000378:metabolism*
chemical_list: D003373:Coumaric Acids; D047495:PPAR gamma; D047488:Retinoid X Receptors; D013723:Teratogens; D013764:Tetrahydronaphthalenes; C525131:UVI 3003
keywords: Peroxisome proliferator activated receptor γ; Retinoid X receptor; TPT; Teratogenicity; UVI3003; Xenopus