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 72h after exposure to 0.25mM 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.
authors.affiliation: Division of Toxicology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, MD, United States. Electronic address: xiugong.gao@fda.hhs.gov.
authors.forename: Xiugong
authors.initials: X
authors.lastname: Gao
authors.affiliation: Division of Toxicology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, MD, United States.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sprando
authors.affiliation: Division of Toxicology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, MD, United States.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Yourick
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D039904:Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D013045:Species Specificity; D013792:Thalidomide / Q000633:toxicity*; D013997:Time Factors; D018675:Toxicity Tests / Q000379:methods; D043922:Toxicogenetics / Q000379:methods; D059467:Transcriptome / Q000187:drug effects
chemical_list: D013792:Thalidomide
keywords: Developmental toxicity; Differentiation; Embryonic stem cell; Microarray; Mouse; Thalidomide; Transcriptomics