ZET-O-MAP

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

Paradigm Shift Moving Towards Mechanistic Risk Assessment

© Fraunhofer ITEM, Sylvia Escher
The project is organised into seven R&D Work Packages (WPs 1-7).

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).

In human risk assessment the evaluation of developmental toxicity or teratogenicity requires the testing of rodents (preferably rats) and non-rodents (preferably rabbits) as described in the OECD 414 guideline. Currently human safety assessment is undergoing a paradigm shift moving towards mechanistic risk assessment and there is a high demand to replace, reduce or refine animal tests where possible for ethical and economic reasons.  

 

Approach of ZET-O-MAP

To promote the acceptance of the ZETA for regulatory purposes, a better mechanistic understanding of the morphogenesis in zebrafish embryos is needed. In order to map developmental outcome pathways, early molecular changes and morphological changes need to be linked. To identify adverse outcome pathways (AOPs), causal links with chemical exposure should be investigated and mapped.

ZET-O-MAP will develop a knowledge map, covering the whole developmental process from fertilization to 120 hpf using an innovative data mining/network/approach which comprises a network of early molecular changes (MC) and adverse outcomes (AOs) scored as teratogenic changes (TC) in ZETA.

In order to build this knowledge map transcriptome data will be analysed and linked to the adverse outcomes (AOs), indicating the development over time. In this mechanism driven approach, zet-o-map will identify principal molecular drivers of (dys)morphogenesis, by analysing time resolved ZETA transcriptome data  and link these to adverse outcomes e.g. induced by certain teratogenic compounds.

Zet-o-Map – Objectives

Objective 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).

Objective 2

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

Objective 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.

Objective 4

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

Objective 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.

Objective 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.

Objective 7

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

Project partners

Fraunhofer ITEM

Dr. Sylvia Escher, human toxicologist, data scientist, project coordinator:

  • Human risk assessment
  • NGS-transcriptome analysis (EU-ToxRisk, ExITox)
  • AOP development

Fraunhofer SCAI

Dr. Marc Jacobs, cheminformatician:

  • Automated processes to extract biomedical knowledge from scientific literature
  • Develop medical knowledge in comprehensive knowledge maps
  • Develop computer-readable models map entire medical indication areas

VITO

Dr. Hilda Witters, toxicology, expert zebrafish embryo model:

  • VITO provides science and technology for policy makers and industry to take informed decisions on environmental health and safety
  • Expert knowledge on the zebrafish embryo models and their validation
  • Discovery of novel biomarkers that causally link exposure to adverse health effects for early prediction of (onset of) disease

Your contact for ZET-O-MAP

Sylvia Escher

Contact Press / Media

Dr. Sylvia Escher

Head of Department of In-silico Toxicology

Phone +49 511 5350-330