Common nature in the effects of thalidomide on embryo‐fetal development in <scp>Kbl</scp>:<scp>JW</scp> and <scp>Kbl</scp>:<scp>NZW</scp> rabbits

Kawamura, Yuta; Shirotsuka, Yasuki; Awatsuji, Hirofumi; Matsumoto, Kiyoshi; Sato, Keiichiro

doi:10.1111/cga.12037

Cited by 6 publications

(22 citation statements)

References 26 publications

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“…We have confirmed that Kbl:JW rabbits have same sensitivity as Kbl:NZW rabbits to the TM‐induced malformations (Kawamura et al. , ). Estrous virgin females were mated with males on a one‐to‐one basis in the morning.…”

Section: Methodssupporting

confidence: 84%

“…Short or absent radius was induced by TM treatment in our in vivo study using Kbl:JW rabbits as well as Kbl:NZW rabbits (Kawamura et al. ). However, expression of the limb development‐related genes has not been vigorously characterized in TM‐treated rabbit embryos (TM embryos) and only one report has revealed expression of Fgf8, Fgf10 and twist (Hansen et al.…”

Section: Introductionmentioning

confidence: 78%

“…However, the sensitive periods of the limb malformation in the TM single dose study for the embryo‐fetal development in JW‐NIBS rabbits were GD 8 or 9 (Matsubara and Mikami ) and the sensitive period of the limb malformation in Kbl:JW rabbits was GDs 9 and 10 and the limb malformation was not observed in the fetuses treated on GDs 7 and 8 (Kawamura et al. ). Therefore, the single dose of TM on GD 9 was considered to induce the limb malformation in Kbl:JW rabbit fetuses.…”

Section: Methodsmentioning

confidence: 99%

“…Absent or short radius was observed in TM‐treated rabbit fetuses (Kawamura et al. ). Hoxa11 is a one of the homeobox genes and the deletion of Hoxa11 induces misshapen ulna and radius in mice (Small and Potter ).…”

Section: Introductionmentioning

confidence: 98%

“…The expression at the autopod was considered to be related to the development of the digits and digit malformations were observed in the TM‐treated rabbit fetuses (Kawamura et al. ). Therefore, Hoxd11 was not selected to avoid the confusion in the interpretation of the expression changes in the limb bud.…”

Section: Introductionmentioning

confidence: 99%

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Effects of thalidomide on Fgf8, Bmp4 and Hoxa11 expression in the limb bud in Kbl:JW rabbit embryos

Kawamura

Yamashita

Yamauchi

et al. 2014

Congenital Anomalies

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Thalidomide (TM) induces limb defects inhumans and some animal species including rabbits. Although the mechanism of TM-induced limb defects has been investigated for a long period, the limb development-related genes expressions have not been vigorously characterized in rabbits. In this study, we investigated the Fgf8, Bmp4 and Hoxa11 expressions in TM-treated JW rabbit embryos on gestation days (GDs) 10, 11 and 12 by whole mount in situ hybridization. On GDs 10 and 11, growth retardation of the embryo was induced by TM treatment. The Fgf8 expression lengths on GDs 10 and 11 in the forelimb bud were significantly or tended to be decreased in the TM-treated embryos, which was correlated to the growth retardation and was not considered to be directly relevant to the teratogenic effect of TM in the forelimb. The TM-induced characteristic changes in the expression pattern of Hoxa11 and Bmp4 on GDs 10 and/or 11 were not noted. On GD 12, TM-induced growth retardation was not noted and the Fgf8 and Bmp4 expressions were not changed. On the contrary, Hoxa11 expression was narrowed at the anterior region, which was located on the radial side, and was not changed at the middle and posterior regions in the forelimb bud and in all regions in the hindlimb bud. Because the radius malformations were induced by TM treatment, we concluded the decrease in the Hoxa11 expression was related to the TM-induced limb defects and can be a good marker for early prediction of the teratogenic effect of TM.

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Section: Methodssupporting

confidence: 84%

Section: Introductionmentioning

confidence: 78%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Effects of thalidomide on Fgf8, Bmp4 and Hoxa11 expression in the limb bud in Kbl:JW rabbit embryos

Kawamura

Yamashita

Yamauchi

et al. 2014

Congenital Anomalies

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Establishment of an in vitro method of rabbit embryo toxicity with toxicokinetics study

Zhu

Jia

Guo

et al. 2021

J of Applied Toxicology

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This report introduces a novel method, rabbit whole embryo culture (WEC) combined with toxicokinetics (TK), for toxicity testing. Rodent WEC has been extensively used for in vitro screening of developmental toxicity. To improve the reliability of in vitro data, it is important to consider TK and species specificity. To test the utility and effectiveness of this method, we investigated the toxic effect of thalidomide on rabbit embryos and its behavior in test systems both in vitro and in vivo under the same experimental condition. The data showed that thalidomide induced embryo malformations such as embryonic brain hypoplasia, short limb buds, and declined embryonic growth both in vitro and in vivo. The toxic effect increased with the increasing exposure of the embryo to thalidomide. In addition, we observed similar toxic effects and exposure-effect relationships in vivo and in vitro. Therefore, we preliminarily conclude that this new method can effectively predict and explain thalidomide toxicity. Furthermore, we investigated the behavior of test compounds in the WEC system for the first time, and this method is expected to be an important technique for in vitro toxicity study after extensive verification.

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Thalidomide and Its Analogs Differentially Target Fibroblast Growth Factor Receptors: Thalidomide Suppresses FGFR Gene Expression while Pomalidomide Dampens FGFR2 Activity

Sundaresan

Kumar

Manivannan

et al. 2019

Chem. Res. Toxicol.

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Thalidomide is an infamous teratogen and it is continuously being explored for its anticancer properties. Fibroblast growth factor receptors (FGFRs) are implicated in embryo development and cancer pathophysiology. With striking similarities observed between FGFR implicated conditions and thalidomide embryopathy, we hypothesized thalidomide targets FGFRs. We utilized three different cell lines and chicken embryo model to investigate the effects of thalidomide and analogs on FGFR expression. We performed molecular docking, KINOMEscan analysis, and kinase activity assays to study the drug−protein interactions. The expression of FGFR1 and FGFR2 was differentially regulated by all the three drugs in cells as well as in developing organs. Transcriptome analysis of thalidomide-treated chick embryo strongly suggests the modulation of FGFR signaling and key transcription factors. Corroboration with previous studies suggests that thalidomide might affect FGFR expression through the transcription factor, E2F1. At the protein level, molecular docking predicted all three analogs to interact with lysine residue at 517th and 508th positions of FGFR2 and FGFR3, respectively. This lysine coordinates the ATP binding site of FGFR, thus hinting at the possible perturbation of FGFR activity by thalidomide. Kinome analysis revealed that kinase activities of FGFR2 and FGFR3 (G697C) reduced by 31% and 65%, respectively, in the presence of 10 μM thalidomide. Further, we checked and confirmed that the analogs inhibited the FGFR2 kinase activity in a dose-dependent manner. This study suggests that FGFRs could be potential targets of thalidomide and the two analogs, and also endorses the link between the teratogenicity and antitumor activities of the drugs.

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Common nature in the effects of thalidomide on embryo‐fetal development in Kbl:JW and Kbl:NZW rabbits

Cited by 6 publications

References 26 publications

Effects of thalidomide on Fgf8, Bmp4 and Hoxa11 expression in the limb bud in Kbl:JW rabbit embryos

Effects of thalidomide on Fgf8, Bmp4 and Hoxa11 expression in the limb bud in Kbl:JW rabbit embryos

Establishment of an in vitro method of rabbit embryo toxicity with toxicokinetics study

Thalidomide and Its Analogs Differentially Target Fibroblast Growth Factor Receptors: Thalidomide Suppresses FGFR Gene Expression while Pomalidomide Dampens FGFR2 Activity

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