The unexpected teratogenicity of RXR antagonist UVI3003 via activation of PPAR? 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 RXR? (xRXR?) and PPAR? (xPPAR?) in vitro and in vivo. We found that UVI3003 activated xPPAR? either in Cos7 cells (in vitro) or Xenopus embryos (in vivo). UVI3003 did not significantly activate human or mouse PPAR? in vitro; therefore, the activation of Xenopus PPAR? by UVI3003 is novel. The ability of UVI3003 to activate xPPAR? explains why UVI3003 and TPT yield similar phenotypes in Xenopus embryos. Our results indicate that activating PPAR? 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.

SUBMITTER: Zhu J 

PROVIDER: S-EPMC5183475 | biostudies-other | 2017 Jan

REPOSITORIES: biostudies-other