Thalidomide induced early gene expression perturbations indicative of human embryopathy in mouse embryonic stem cells

Gao, Xiugong; Sprando, Robert L.; Yourick, Jeffrey J.

doi:10.1016/j.taap.2015.05.009

Cited by 10 publications

(12 citation statements)

References 41 publications

(62 reference statements)

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“…Taking the osteoblast mEST as an example, the traditional test requires 14 days of culture, while the transcriptomics analysis requires only 6 days to detect alterations in gene expression. In support of our results, Piersma et al was able to identify developmental toxicants 96 h after exposure in the mEST [1], while Gao et al was able to detect thalidomide-induced effects within 24h after exposure using transcriptomics [5]. In conclusion, this study suggests that transcriptomics is a promising tool that can be a valuable addition to the drug safety evaluations toolbox.…”

Section: Discussionsupporting

confidence: 87%

“…Compounds which caused significant deviations from the differentiation track were predicted as potential developmental toxicants. Teratogenicity of thalidomide was evaluated by using human [4] and mouse [5] ESCs. In addition to the expected perturbation of limb and embryonic development, other biological processes dysregulated by thalidomide included heart and neural development.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptomics analysis of early embryonic stem cell differentiation under osteoblast culture conditions: Applications for detection of developmental toxicity

Chen

Han

Fisher

et al. 2017

Reproductive Toxicology

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The mouse embryonic stem cell test (mEST) is a promising in vitro assay for predicting developmental toxicity. In the current study, early differentiation of D3 mouse embryonic stem cells (mESCs) under osteoblast culture conditions and embryotoxicity of cadmium sulfate were examined. D3 mESCs were exposed to cadmium sulfate for 24, 48 or 72 h, and whole genome transcriptional profiles were determined. The results indicate a track of differentiation was identified as mESCs differentiate. Biological processes that were associated with differentiation related genes included embryonic development and, specifically, skeletal system development. Cadmium sulfate inhibited mESC differentiation at all three time points. Functional pathway analysis indicated biological pathways affected included those related to skeletal development, renal and reproductive function. In summary, our results suggest that transcriptional profiles are a sensitive indicator of early mESC differentiation. Transcriptomics may improve the predictivity of the mEST by suggesting possible modes of action for tested chemicals.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Transcriptomics analysis of early embryonic stem cell differentiation under osteoblast culture conditions: Applications for detection of developmental toxicity

Chen

Han

Fisher

et al. 2017

Reproductive Toxicology

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“…Furthermore, studies looking at differential gene expression after direct thalidomide exposure have been carried out using microarray techniques in monkey embryos limb and heart development and the immune response (Gao et al, 2014;Gao et al, 2015;Ema et al, 2010, Meganathan et al, 2012. Some of these changes may be primary, secondary or even tertiary.…”

Section: Genetic Studiesmentioning

confidence: 99%

Thalidomide and Birth Defects

Fraga¹,

Diamond²,

Vargesson³

2016

Encyclopedia of Life Sciences

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Thalidomide is a teratogenic drug that caused horrific birth defects when prescribed as an antiemetic to pregnant women in the 1960's. The most stereotypical defect is symmetrical limb malformations such as phocomelia, though ear, eye and internal organ defects are also observed. Thalidomide was consequently withdrawn from the market. However, Thalidomide has since been shown to have many beneficial anti-inflammatory and immunomodulatory effects and is therefore used in a regulated manner in the treatment against cancers and inflammatory disorders. Sadly, new cases of babies affected by thalidomide are being born in Brazil, likely due to medicine sharing. The mechanisms of how thalidomide causes a wide range of embryonic malformations are becoming clearer; thalidomide is thought to act through molecules such as cereblon and tubulin and also affect blood vessel development and cell death, resulting in teratogenesis. Fully understanding the molecular events induced by thalidomide is essential if we are to develop a safe but clinically relevant form of the drug.

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“…Meta-analyses of non-, weak, and strong embryotoxicants have characterized the accuracy of the mEST as between 53-79% for predicting in vivo embryotoxicity 16,17 . However, the mEST is notably insensitive to the effects of thalidomide and only exhibits nonspecific toxicity to thalidomide exposure above 400 µM 18 , which is orders of magnitude higher than the Cmax of thalidomide in humans 7 . The insensitivity of the mEST to thalidomide is a concordant result as thalidomide exhibits species-specific teratogenicity and does not elicit limb malformations in mice.…”

mentioning

confidence: 95%

Thalidomide Inhibits Human iPSC Mesendoderm Differentiation by Modulating CRBN-dependent Degradation of SALL4

Belair¹,

Lü²,

Waller³

et al. 2020

Sci Rep

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exposure to thalidomide during a critical window of development results in limb defects in humans and non-human primates while mice and rats are refractory to these effects. Thalidomide-induced teratogenicity is dependent on its binding to cereblon (CRBN), the substrate receptor of the Cul4A-DDB1-CRBN-RBX1 E3 ubiquitin ligase complex. Thalidomide binding to CRBN elicits subsequent ubiquitination and proteasomal degradation of CRBN neosubstrates including SALL4, a transcription factor of which polymorphisms phenocopy thalidomide-induced limb defects in humans. Herein, thalidomide-induced degradation of SALL4 was examined in human induced pluripotent stem cells (hiPSCs) that were differentiated either to lateral plate mesoderm (LPM)-like cells, the developmental ontology of the limb bud, or definitive endoderm. Thalidomide and its immunomodulatory drug (iMiD) analogs, lenalidomide, and pomalidomide, dose-dependently inhibited hipSc mesendoderm differentiation. Thalidomide-and IMiD-induced SALL4 degradation can be abrogated by CRBN V388I mutation or SALL4 G416A mutation in hiPSCs. Genetically modified hiPSCs expressing CRBN E377V/ V388I mutant or SALL4 G416A mutant were insensitive to the inhibitory effects of thalidomide, lenalidomide, and pomalidomide on LPM differentiation while retaining sensitivity to another known limb teratogen, all-trans retinoic acid (atRA). Finally, disruption of LPM differentiation by atRA or thalidomide perturbed subsequent chondrogenic differentiation in vitro. the data here show that thalidomide, lenalidomide, and pomalidomide affect stem cell mesendoderm differentiation through CRBN-mediated degradation of SALL4 and highlight the utility of the LPM differentiation model for studying the teratogenicity of new cRBn modulating agents.

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Thalidomide induced early gene expression perturbations indicative of human embryopathy in mouse embryonic stem cells

Cited by 10 publications

References 41 publications

Transcriptomics analysis of early embryonic stem cell differentiation under osteoblast culture conditions: Applications for detection of developmental toxicity

Transcriptomics analysis of early embryonic stem cell differentiation under osteoblast culture conditions: Applications for detection of developmental toxicity

Thalidomide and Birth Defects

Thalidomide Inhibits Human iPSC Mesendoderm Differentiation by Modulating CRBN-dependent Degradation of SALL4

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