title: Comparison of MeHg-induced toxicogenomic responses across in vivo and in vitro models used in developmental toxicology.
abstract: Toxicogenomic evaluations may improve toxicity prediction of in vitro-based developmental models, such as whole embryo culture (WEC) and embryonic stem cells (ESC), by providing a robust mechanistic marker which can be linked with responses associated with developmental toxicity in vivo. While promising in theory, toxicogenomic comparisons between in vivo and in vitro models are complex due to inherent differences in model characteristics and experimental design. Determining factors which influence these global comparisons are critical in the identification of reliable mechanistic-based markers of developmental toxicity. In this study, we compared available toxicogenomic data assessing the impact of the known teratogen, methylmercury (MeHg) across a diverse set of in vitro and in vivo models to investigate the impact of experimental variables (i.e. model, dose, time) on our comparative assessments. We evaluated common and unique aspects at both the functional (Gene Ontology) and gene level of MeHg-induced response. At the functional level, we observed stronger similarity in MeHg-response between mouse embryos exposed in utero (2 studies), ESC, and WEC as compared to liver, brain and mouse embryonic fibroblast MeHg studies. These findings were strongly correlated to the presence of a MeHg-induced developmentally related gene signature. In addition, we identified specific MeHg-induced gene expression alterations associated with developmental signaling and heart development across WEC, ESC and in vivo systems. However, the significance of overlap between studies was highly dependent on traditional experimental variables (i.e. dose, time). In summary, we identify promising examples of unique gene expression responses which show in vitro-in vivo similarities supporting the relevance of in vitro developmental models for predicting in vivo developmental toxicity.
authors.affiliation: National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. joshua.robinson@rivm.nl
authors.forename: Joshua F
authors.initials: JF
authors.lastname: Robinson
authors.forename: Peter T
authors.initials: PT
authors.lastname: Theunissen
authors.forename: Dorien A M
authors.initials: DA
authors.lastname: van Dartel
authors.forename: Jeroen L
authors.initials: JL
authors.lastname: Pennings
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Faustman
authors.forename: Aldert H
authors.initials: AH
authors.lastname: Piersma
mesh_terms: D000818:Animals; D047108:Embryonic Development / Q000187:drug effects / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008767:Methylmercury Compounds / Q000633:toxicity*; D008954:Models, Biological; D013723:Teratogens / Q000633:toxicity*; D043922:Toxicogenetics / Q000379:methods* / Q000706:statistics & numerical data
chemical_list: D008767:Methylmercury Compounds; D013723:Teratogens