Cefic-lri Programme | European Chemical Industry Council

AIMT5: Bulding a Prenatal Developmental Toxicity Ontology, integrating existing biological, chemical, in silico models and in vitro methods and data, aiming at an alternative integrated AoP/MoA framework for mechanistic hazard and risk assessment in developmental toxicology

Principal Investigator

Prof Dr Aldert Piersma
RIVM, National Institute for Public Health and the Environment
Centre for Health Protection
Antonie van Leeuwenhoeklaan 9
3720 BA Bilthoven
The Netherlands
aldert.piersma@rivm.nl
Tel: +31 30 2742526/3485

Collaborators

George Daston Ph.D., with Karen Blackburn, Shengde Wu, Jorge Naciff, Toxicologist, Procter & Gamble Company, Cincinnati, OH, daston.gp@pg.com
Lyle Burgoon Ph.D., Leader, Computational Toxicology and Bioinformatics, US Army Engineer Research and Development Center, lyle.d.burgoon@usace.army.mil

Description

The primary objective of this project is to establish a novel Developmental Toxicity Ontology (DTO), organizing information about Modes of Action (MoA) and their relationships with Adverse developmental toxicity Outcomes (AO) through an understanding of normal embryology.

An ontology is a representation of a domain of knowledge consisting of concepts, generally referred to as classes, and relationships between classes. Ontologies integrate data from disparate sources and allow investigators to make complicated queries of the data encoded by the ontology. Currently available ontologies classify anatomical relationships of rudimentary structures during normal organ system formation (e.g., EMAP, http://obofoundry.org), or of fetal malformations at term pregnancy (e.g., DevTox, www.devtox.org); however, these existing ontologies do not integrate developmental processes and toxicities. The DTO proposed here will build a comprehensive system that can be used to compile relevant data and information into an integrative model that makes the information more understandable and that facilitates hypothesis generation and the mechanistic explanation of the developmental toxicity of chemical exposures. In particular, the DTO will allow the derivation of new critical AOPs that will inform the construction and interpretation of alternative testing strategies.

The construction of a developmental toxicity ontology will be undertaken by integrating MoA and AOP information from three different perspectives, the biological, the chemical and the toxicological perspective. Information from these three points of view will be integrated into a formal DTO.

The biological perspective will be addressed by compiling detailed information on key mechanisms of human embryonic development, spanning the molecular, cellular, tissue, organ and organism level in time and space.
The chemical perspective provides another rich information source for building a developmental toxicity ontology.
The toxicological perspective will be introduced by mining current knowledge on end points of chemical-mediated toxicity.
The integration of information within each of the three perspectives followed by their overall integration into a developmental ontology format will be the main aim and challenge of the project.

Related Publications

Publications: 

Yvonne C.M. Staal, Jeroen L.A. Pennings, Ellen V.S. Hessel, and Aldert H. Piersma. Advanced Toxicological Risk Assessment by Implementation of Ontologies Operationalized in Computational Models. Applied In Vitro Toxicology. Volume: 3 Issue 4: Dec 1, 2017.

Posters:

Yvonne C.M. Staal, Nancy Baker, Lyle D. Burgoon, George Daston, Thomas B. Knudsen, Aldert H. Piersma. Towards Building an AOP-based Prenatal Developmental Toxicity Ontology. Cefic-LRI 18th Annual Workshop, November 2016, Brussels, Belgium.

Yvonne C.M. Staal, Nancy Baker, Lyle D. Burgoon, George Daston, Thomas B. Knudsen, Aldert H. Piersma. An AOP-based Ontology for Neural Tube Closure Caused by Disturbance in Retinoic Acid Signaling. EUROTOX, September 2018, Brussels, Belgium.

Yvonne C.M. Staal, Nancy Baker, Lyle D. Burgoon, George Daston, Thomas B. Knudsen, Aldert H. Piersma. Developmental Ontology: Computational modeling of Retinoic Acid in Development of Spina Bifida. Society of Toxicology 56th Annual Meeting, Baltimore, Maryland, USA.

Timeline: April 2016 > April 2018

LRI funding: € 300 000

Cefic-Lri Programme Responsible Care

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