title: Dynamic changes in energy metabolism upon embryonic stem cell differentiation support developmental toxicant identification.
abstract: Embryonic stem cells (ESC) are widely used to study embryonic development and to identify developmental toxicants. Particularly, the embryonic stem cell test (EST) is well known as in vitro model to identify developmental toxicants. Although it is clear that energy metabolism plays a crucial role in embryonic development, the modulation of energy metabolism in in vitro models, such as the EST, is not yet described. The present study is among the first studies that analyses whole genome expression data to specifically characterize metabolic changes upon ESC early differentiation. Our transcriptomic analyses showed activation of glycolysis, truncated activation of the tricarboxylic acid (TCA) cycle, activation of lipid synthesis, as well as activation of glutaminolysis during the early phase of ESC differentiation. Taken together, this energy metabolism profile points towards energy metabolism reprogramming in the provision of metabolites for biosynthesis of cellular constituents. Next, we defined a gene set that describes this energy metabolism profile. We showed that this gene set could be successfully applied in the EST to identify developmental toxicants known to modulate cellular biosynthesis (5-fluorouracil and methoxyacetic acid), while other developmental toxicants or the negative control did not modulate the expression of this gene set. Our description of dynamic changes in energy metabolism during early ESC differentiation, as well as specific identification of developmental toxicants modulating energy metabolism, is an important step forward in the definition of the applicability domain of the EST.
authors.affiliation: Human and Animal Physiology, Wageningen University, P.O. Box 338, 6700 AH Wageningen, The Netherlands. Electronic address: dorien.vandartel@wur.nl.
authors.forename: Dorien A M
authors.initials: DA
authors.lastname: van Dartel
authors.affiliation: Laboratory for Health Protection Research, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands; Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80.163, 3508 TD Utrecht, The Netherlands.
authors.forename: Sjors H
authors.initials: SH
authors.lastname: Schulpen
authors.affiliation: Laboratory for Health Protection Research, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Theunissen
authors.affiliation: Human and Animal Physiology, Wageningen University, P.O. Box 338, 6700 AH Wageningen, The Netherlands.
authors.forename: Annelies
authors.initials: A
authors.lastname: Bunschoten
authors.affiliation: Laboratory for Health Protection Research, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands; Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80.163, 3508 TD Utrecht, The Netherlands.
authors.forename: Aldert H
authors.initials: AH
authors.lastname: Piersma
authors.affiliation: Human and Animal Physiology, Wageningen University, P.O. Box 338, 6700 AH Wageningen, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Keijer
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D016000:Cluster Analysis; D030541:Databases, Genetic; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004734:Energy Metabolism / Q000187:drug effects* / Q000235:genetics; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D023281:Genomics; D006801:Humans; D051379:Mice; D018570:Risk Assessment; D013997:Time Factors; D014116:Toxicology / Q000379:methods
keywords: Embryonic stem cell test (EST); Embryonic stem cells; Energy metabolism; Toxicology; Transcriptomics