Fraunhofer Institute for Toxicology and Experimental Medicine
Fraunhofer Institute for Toxicology and Experimental Medicine

ZET-O-MAP

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

Paradigm shift moving towards mechanistic risk assessment

© Fraunhofer ITEM, Sylvia Escher
The project is organized 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 analyzed 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 analyzing 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 Objective 2 to adverse teratogenic outcomes, based on the data from WP1.

Objective 4

Fill knowledge gaps in the spatio-temporal map identified within Objectives 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 Objectives 2, 3 and 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 which, 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 with data from the zebrafish embryo test and other dedicated in-vitro assays.

Project partners

© Fraunhofer ITEM

Fraunhofer ITEM

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

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

© Fraunhofer SCAI

Fraunhofer SCAI

Dr. Marc Jacobs, cheminformatician:

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

© VITO

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

Division Director of Safety Assessment and Toxicology & Head of Department of In-silico Toxicology

Phone +49 511 5350-330