A statistical approach towards the derivation of predictive gene sets for potency ranking of chemicals in the mouse embryonic stem cell test.
The embryonic stem cell test (EST) is applied as a model system for detection of embryotoxicants. The application of transcriptomics allows a more detailed effect assessment compared to the morphological endpoint. Genes involved in cell differentiation, modulated by chemical exposures, may be useful as biomarkers of developmental toxicity. We describe a statistical approach to obtain a predictive gene set for toxicity potency ranking of compounds within one class. This resulted in a gene set based on differential gene expression across concentration-response series of phthalatic monoesters. We determined the concentration at which gene expression was changed at least 1.5-fold. Genes responding with the same potency ranking in vitro and in vivo embryotoxicity were selected. A leave-one-out cross-validation showed that the relative potency of each phthalate was always predicted correctly. The classical morphological 50% effect level (ID50) in EST was similar to the predicted concentration using gene set expression responses. A general down-regulation of development-related genes and up-regulation of cell-cycle related genes was observed, reminiscent of the differentiation inhibition in EST. This study illustrates the feasibility of applying dedicated gene set selections as biomarkers for developmental toxicity potency ranking on the basis of in vitro testing in the EST.
Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands; Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, The Netherlands. Electronic address: sjors.schulpen@rivm.nl.
Sjors H W
SH
Schulpen
Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
Jeroen L A
JL
Pennings
Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands; Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands.
Elisa C M
EC
Tonk
Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands; Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, The Netherlands.
Aldert H
AH
Piersma
D000014:Abnormalities, Drug-Induced / Q000209:etiology / Q000235:genetics; D000465:Algorithms; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D020869:Gene Expression Profiling / Q000379:methods*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D051379:Mice; D010795:Phthalic Acids / Q000633:toxicity*; D011237:Predictive Value of Tests; D011897:Random Allocation; D013723:Teratogens / Q000633:toxicity; D018675:Toxicity Tests / Q000379:methods*
D010795:Phthalic Acids; D013723:Teratogens
Concentration response analysis; Developmental toxicity; Embryonic stem cell test; Gene set; Phthalate monoesters; Potency ranking