C9: Mining the developmental toxicity genome in the zebrafish embryo test to develop a spatio-temporal map on morphogenesis and associated biomarker.

Description

The LRI C9 project “zet-o-map” aims to develop better tools for the identification of teratogenic compounds. One of the most promising assays is the zebrafish embryo teratogenicity assay (ZETA).

The main objective of the project is to build a knowledge map, which allows to identify key molecular biomarkers (e.g. families of genes) of developmental toxicity and to prove that they can be used in a predictive manner in human hazard assessment. In this mechanism driven approach, zet-o-map will identify principal molecular drivers of (dys)morphogenesis, by analysing time resolved ZETA transcriptome data (termed spatio-temporal maps) and link these to adverse outcomes e.g. induced by certain teratogenic compounds. The following seven objectives are defined, which are covered by the work packages (WPs) and described in detail, in the next section “work content”:

Obj.1: Mine existing literature and public/in house databases for ZETA data and integrate all relevant ZETA data (e.g. teratogenic changes, adverse outcomes, transcriptomics, knock-outs data etc.) into a knowledge map (KM, WP1).

Obj.2: Develop a quantitative spatio-temporal map of the major vertebrate morpho-genetic and developmental gene families in the zebrafish embryo model, based on the data from WP1 (WP2).

Obj.3: Develop quantitative spatio-temporal maps for perturbation of ZF gene expression after exposure to teratogenic compounds and link perturbation of the zebrafish genome/gene families from Obj. 2 to adverse teratogenic outcomes, based on the data from WP1 (WP3).

Obj.4: Fill knowledge gaps in the spatio-temporal map identified within Obj. 2 and 3 by performing dedicated zebrafish embryo tests (WP4).

Obj.5: Update the KM (WP1) to include the quantitative spatio-temporal maps/gene expression networks from Obj. 2, 3 & 4 to show how chemical exposure perturbs the spatio-temporal map of ZF development as the overarching concept for monitoring vertebrate developmental toxicity after compound exposure in ZETA (WP5).

Obj.6: Identify a shortlist of candidate genes that when monitored adequately cover this embryotoxicity gene expression network in the zebrafish embryo model. Validate the effect biomarkers in zebrafish embryos, and recommend strategies for translatability to mammals (WP6).

Obj.7: The gene expression pathway network should ultimately form the basis for a predictive in silico tool for developmental toxicity, that can be fed by data from the zebrafish embryo test and other dedicated in vitro assays (WP7)