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

Abstract

Developmental toxicity testing has traditionally relied on animal models which are costly, time consuming, and require the sacrifice of large numbers of animals. In addition, there are significant disparities between human beings and animals in their responses to chemicals. Thalidomide is a species-specific developmental toxicant that causes severe limb malformations in humans but not in mice. Here, we used microarrays to study transcriptomic changes induced by thalidomide in an in vitro model based on differentiation of mouse embryonic stem cells (mESCs). C57BL/6 mESCs were allowed to differentiate spontaneously and RNA was collected at 24, 48, and 72 h after exposure to 0.25 mM thalidomide. Global gene expression analysis using microarrays revealed hundreds of differentially expressed genes upon thalidomide exposure that were enriched in gene ontology (GO) terms and canonical pathways associated with embryonic development and differentiation. In addition, many genes were found to be involved in small GTPases-mediated signal transduction, heart development, and inflammatory responses, which coincide with clinical evidences and may represent critical embryotoxicities of thalidomide. These results demonstrate that transcriptomics in combination with mouse embryonic stem cell differentiation is a promising alternative model for developmental toxicity assessment. - Highlights: • Studied genomic changes in mouse embryonic stem cellsmore » upon thalidomide exposure • Identified gene expression changes that may represent thalidomide embryotoxicity • The toxicogenomic changes coincide well with known thalidomide clinical outcomes. • The mouse embryonic stem cell model is suitable for developmental toxicity testing. • The model has the potential for high-throughput screening of a multitude of compounds.« less

Authors:
; ;
Publication Date:
OSTI Identifier:
22465804
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 287; Journal Issue: 1; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; DEOXYURIDINE; DMSO; DNA; EMBRYOS; GENES; GLYCOGEN; HEART; HUMAN POPULATIONS; IN VITRO; INFLAMMATION; LEUKEMIA; LIMBS; MALFORMATIONS; MICE; ONTOGENESIS; RNA; SCREENING; STEM CELLS; TOXICITY

Citation Formats

Gao, Xiugong, E-mail: xiugong.gao@fda.hhs.gov, Sprando, Robert L., and Yourick, Jeffrey J. Thalidomide induced early gene expression perturbations indicative of human embryopathy in mouse embryonic stem cells. United States: N. p., 2015. Web. doi:10.1016/J.TAAP.2015.05.009.
Gao, Xiugong, E-mail: xiugong.gao@fda.hhs.gov, Sprando, Robert L., & Yourick, Jeffrey J. Thalidomide induced early gene expression perturbations indicative of human embryopathy in mouse embryonic stem cells. United States. doi:10.1016/J.TAAP.2015.05.009.
Gao, Xiugong, E-mail: xiugong.gao@fda.hhs.gov, Sprando, Robert L., and Yourick, Jeffrey J. Sat . "Thalidomide induced early gene expression perturbations indicative of human embryopathy in mouse embryonic stem cells". United States. doi:10.1016/J.TAAP.2015.05.009.
@article{osti_22465804,
title = {Thalidomide induced early gene expression perturbations indicative of human embryopathy in mouse embryonic stem cells},
author = {Gao, Xiugong, E-mail: xiugong.gao@fda.hhs.gov and Sprando, Robert L. and Yourick, Jeffrey J.},
abstractNote = {Developmental toxicity testing has traditionally relied on animal models which are costly, time consuming, and require the sacrifice of large numbers of animals. In addition, there are significant disparities between human beings and animals in their responses to chemicals. Thalidomide is a species-specific developmental toxicant that causes severe limb malformations in humans but not in mice. Here, we used microarrays to study transcriptomic changes induced by thalidomide in an in vitro model based on differentiation of mouse embryonic stem cells (mESCs). C57BL/6 mESCs were allowed to differentiate spontaneously and RNA was collected at 24, 48, and 72 h after exposure to 0.25 mM thalidomide. Global gene expression analysis using microarrays revealed hundreds of differentially expressed genes upon thalidomide exposure that were enriched in gene ontology (GO) terms and canonical pathways associated with embryonic development and differentiation. In addition, many genes were found to be involved in small GTPases-mediated signal transduction, heart development, and inflammatory responses, which coincide with clinical evidences and may represent critical embryotoxicities of thalidomide. These results demonstrate that transcriptomics in combination with mouse embryonic stem cell differentiation is a promising alternative model for developmental toxicity assessment. - Highlights: • Studied genomic changes in mouse embryonic stem cells upon thalidomide exposure • Identified gene expression changes that may represent thalidomide embryotoxicity • The toxicogenomic changes coincide well with known thalidomide clinical outcomes. • The mouse embryonic stem cell model is suitable for developmental toxicity testing. • The model has the potential for high-throughput screening of a multitude of compounds.},
doi = {10.1016/J.TAAP.2015.05.009},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 287,
place = {United States},
year = {Sat Aug 15 00:00:00 EDT 2015},
month = {Sat Aug 15 00:00:00 EDT 2015}
}
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