Retinoic Acid and Neural Tube Defects

A single AOP for neural tube defects from Tonk et al. (2015) was modelled in the AOPO. This AOP starts with an MIE of chemical binding to and activating of the retinoic acid receptor (RAR). This MIE is followed by RAR and retinoid X receptor (RXR) heterodimerisation, leading to upregulation of Hoxb1 gene expression, Hoxb1 protein translation, and finally neural tube defects.

This AOP was modelled in the AOPO by creating a class for the adverse outcome (AO-NeuralTubeDefect), and an individual derived from this class (neural_tube_defect). Note that individuals are actual instantiation of a class, meaning that an individual is tangible, whereas a class is a description of the traits that individuals within a class must have. In addition, we have defined the individual neural_tube_defect to also be an instantiation of the HPO class “Abnormality of Neural Tube Closure.” This allows us to more easily connect/link the AOPO to other ontologies that use definitions based on the HPO.

Because of the interconnectedness of the AOPO with the BAO, in vitro assay data and toxicogenomic data can be overlaid on the AOP for RA-mediated neural tube defects. When assays detect, or transcriptomic experiments suggest, activation of RAR and Hoxb1 protein translation, we can infer that these chemicals may cause neural tube defects through this MOA. A representation of the retinoic acid receptor-mediated neural tube defect AOP is shown in Figure 6 below.

Figure 6: A representation of the retinoic acid receptor-mediated neural tube defect AOP

The boxes represent individuals or instances of a class within the ontology. For example, neural_tube_defect is an individual of the AdverseOutcome class. The lines are semantic relationships connecting two boxes, as follows:

• green lines are “has_downstream_key_event” relationships;
• purple lines are “has_upstream_key_event” relationships;
• the brown line between aop_neural_tube_defect_hoxb1 and neural_tube_defect represents the “has_adverse_outcome” relationship;
• the darker brown line from aop_neural_tube_defect_hoxb1 represents the “has_mie_relationship”;
• the golden line represents the “has_activated_key_event” relationship.