Dose-response analysis of phthalate effects on gene expression in rat whole embryo culture

Joshua F. Robinson, Aart Verhoef, Vincent A. van Beelen, Jeroen L. A. Pennings, Aldert H. Piersma*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Web of Science)

Abstract

The rat postimplantation whole embryo culture (WEC) model serves as a potential screening tool for developmental toxicity. In this model, cultured rat embryos are exposed during early embryogenesis and evaluated for morphological effects. The integration of molecular-based markers may lead to improved objectivity, sensitivity and predictability of WEC in assessing developmental toxic properties of compounds. In this study, we investigated the concentration-dependent effects of two phthalates differing in potency, mono(2-ethylhexyl) phthalate (MEHP) and monomethyl phthalate (MMP, less toxic), on the transcriptome in WEC to examine gene expression in relation with dysmorphogenesis. MEHP was more potent than MMP in inducing gene expression changes as well as changes on morphology. MEHP induced significant enrichment of cholesterol/lipid/steroid (CLS) metabolism and apoptosis pathways which was associated with developmental toxicity. Regulation of genes within CLS metabolism pathways represented the most sensitive markers of MEHP exposure, more sensitive than classical morphological endpoints. As shown in direct comparisons with toxicogenomic in vivo studies, alterations in the regulation of CLS metabolism pathways has been previously identified to be associated with developmental toxicity due to phthalate exposure in utero. Our results support the application of WEC as a model to examine relative phthalate potency through gene expression and morphological responses. Additionally, our results further define the applicability domain of the WEC model for developmental toxicological investigations.
Original languageEnglish
Pages (from-to)32-41
JournalToxicology and Applied Pharmacology
Volume264
Issue number1
DOIs
Publication statusPublished - 1 Oct 2012

Keywords

  • Toxicogenomics
  • Gene expression
  • Whole embryo culture
  • Embryo
  • Phthalate
  • Neurulation
  • Potency
  • Cholesterol
  • Steroid

Cite this