Science Inventory

An AOP-based Ontology for Spina Bifida Caused by Disturbance in Retinoic Acid Signaling

Citation:

Piersma, A., N. Baker, L. Burgoon, G. Daston, T. Knudsen, AND Y. Staal. An AOP-based Ontology for Spina Bifida Caused by Disturbance in Retinoic Acid Signaling. Presented at European Teratology Society Annual Meeting, Berlin, N/A, GERMANY, September 10 - 13, 2018. https://doi.org/10.1016/j.reprotox.2018.08.001

Impact/Purpose:

The retinoic acid (RA) pathway includes elements in retinoid metabolism and nuclear receptor (RAR, RXR) activation and thus serves as an excellent prototype for adverse outcome pathway (AOP) elucidation associated with developmental defects. The prototype ontology describes an AOP network that incorporates feedback-loops for retinoid homeostasis and putative molecular initiating events in chemical teratogenesis.

Description:

Retinoid signaling plays an important role in embryo-fetal development and its disruption is teratogenic. The retinoic acid (RA) pathway includes elements in retinoid metabolism and nuclear receptor (RAR, RXR) activation and thus serves as an excellent prototype for adverse outcome pathway (AOP) elucidation associated with developmental defects. The biology of the RA pathway, leading to defects in neural tube closure was the basis for the construction of an ontology for developmental toxicity. The prototype ontology describes an AOP network that incorporates feedback-loops for retinoid homeostasis and putative molecular initiating events in chemical teratogenesis. Basic elements in the ontology are subjects (enzymes, receptors, cell types) and their quantitative relationships (response-response relationships), together forming a network of biological interactions that can be mapped to a vulnerable window for teratogen-induced neural tube defects, specifically spina bifida. We have used the available data in the literature, which was searched using text-mining tools that allowed rapid identification of relevant literature related to human developmental biology, to map known molecular interactions, genetic signals and responses that: (a) play a crucial role in cellular differentiation; (b) establish anterior-posterior gradients (FGF and RA signaling) and dorsal-ventral gradients (zinc factors (Zic) and BMP signaling) for regional specification. Molecular initiating events important for RA balance (like CYP26 enzymes and RALDH2) potentially affected by xenobiotic compounds (using high-through-put screening data), will be connected with toxicological data on the development of posterior neural tube defects. Ultimately, this network can be dynamically modeled in silico, providing an integrated computational systems model with which toxicity predictions can be made at the level of adverse outcomes in the intact individual. A battery of cell-based in vitro assays can be used to monitor the critical rate-determining steps in the network, providing a tiered testing strategy to collect data feeding into the systems model. Integrating the dynamic model with information from exposure and kinetic models allows quantitative hazard and risk assessment while avoiding animal testing. The views presented in this abstract do not necessarily reflect current or future opinion or policy of the U.S. Environmental Protection Agency and the U.S. Army Corps of Engineers.