The unexpected teratogenicity of RXR antagonist UVI3003 via activation of PPARγ in Xenopus tropicalis.
The unexpected teratogenicity of RXR antagonist UVI3003 via activation of PPARγ in Xenopus tropicalis.
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DOI：
10.1016/j.taap.2016.11.014
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发表时间：
2017-01-01
影响因子：
3.8
通讯作者：
Shi, Huahong
中科院分区：
文献类型：
--
作者：
Zhu, Jingmin;Janesick, Amanda;Wu, Lijiao;Hu, Lingling;Tang, Weiyi;Blumberg, Bruce;Shi, Huahong
关键词：
RXR激动剂（三苯基锡，TPT）和RXR拮抗剂（UVI3003）均显示致畸性，并且意外地在热带爪蟾胚胎中诱导类似的畸形。在本研究中，我们在七个特定的发育窗口中暴露于UVI3003，并鉴定了基因表达的变化。我们进一步测定了UVI3003在体外和体内激活爪蟾RXRα (xRXRα)和PPARγ (xPPARγ)的能力。我们发现UVI3003在Cos7细胞（体外）和爪蟾胚胎（体内）中都能激活xPPARγ。UVI3003在体外对人或小鼠PPARγ无显著激活作用；因此，UVI3003对爪蟾PPARγ的激活是新颖的。UVI3003激活xPPARγ的能力解释了为什么UVI3003和TPT在爪蟾胚胎中产生相似的表型。我们的研究结果表明，激活PPARγ会导致爪蟾胚胎的致畸作用。更一般地说，我们推断，已知的专门调节哺乳动物核激素受体的化学物质不能假设在非哺乳动物物种（如非洲爪蟾）中具有相同的活性。相反，它们必须在有关物种的受体上进行活性和特异性测试，以避免得出不适当的结论。
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.
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影响因子：
6.9
作者：
Inoue, Daisuke;Nakama, Koki;Ike, Michihiko
通讯作者：
Ike, Michihiko
影响因子：
4.8
作者：
Grun, Felix;Blumberg, Bruce
通讯作者：
Blumberg, Bruce
影响因子：
3.3
作者：
Fort, DJ;Paul, RR
通讯作者：
Paul, RR
DOI：
10.1073/pnas.89.6.2321
发表时间：
1992-03-15
影响因子：
11.1
作者：
BLUMBERG, B;MANGELSDORF, DJ;DEROBERTIS, EM
通讯作者：
DEROBERTIS, EM
影响因子：
16
作者：
Barak, Y;Nelson, MC;Evans, RM
通讯作者：
Evans, RM