Computational Model of Secondary Palate Fusion and Disruption
Citation:
Hutson, S., M. Leung, N. Baker, R. Spencer, AND T. Knudsen. Computational Model of Secondary Palate Fusion and Disruption. CHEMICAL RESEARCH IN TOXICOLOGY. American Chemical Society, Washington, DC, 30(4):965-979, (2017).
Impact/Purpose:
• Agency Research Drivers - Predicting toxicity to the developing embryo is a complex problem of critical importance for EPA. Chemical exposures to the pregnant mother may impact her baby during the prenatal period, leading to adverse outcomes such as birth defects, childhood developmental disorders, and adult disease. Research is needed to understand how chemicals may alter human development at critical windows of susceptibility. • Science Challenge - Current testing paradigms lack sufficient throughput for assessing all chemicals in use and the array of chemical-biological interactions for effects on early lifestages (e.g., prenatal, birth, neonatal, adolescent, puberty). A predictive model is needed to translate chemical effects data into a estimate of effects on human development. • Research Approach –A computer model was developed simulating “morphogenetic fusion.” Fusion of tissues and disrupting fusion during embryo development causes birth defects such as cleft palate, hypospadias, and spina bifida. Performance of the fusion model was assessed by comparing predicted effects of chemical exposure to observed effects. • Results – The computer model of fusion effectively simulated development. Predicted outcomes of the computer model predicted in vitro (ToxCastDB) and in vivo (ToxRefDB) chemical-target effects. • Anticipated Impact/Expected use – The computational fusion model enables a predictive approach to identify chemicals that affect human development.
Description:
Morphogenetic events are driven by cell-generated physical forces and complex cellular dynamics. To improve our capacity to predict developmental effects from cellular alterations, we built a multi-cellular agent-based model in CompuCell3D that recapitulates the cellular networks and collective cell behavior underlying growth and fusion of the mammalian secondary palate. The model incorporated multiple signaling pathways (TGF, BMP, FGF, EGF, SHH) in a heuristic computational intelligence framework to recapitulate morphogenetic events from palatal outgrowth through midline fusion. It effectively simulated higher-level phenotypes (e.g., midline contact, medial edge seam (MES) breakdown, mesenchymal confluence, fusion defects) in response to genetic or environmental perturbations. Perturbation analysis of various control features revealed model functionality with respect to cell signaling systems and feedback loops for growth and fusion, diverse individual cell behaviors and collective cellular behavior leading to physical contact and midline fusion, and quantitative analysis of the TGF/EGF switch that controls MES breakdown – a key event in morphogenetic fusion. The virtual palate model was then executed with chemical perturbation scenarios to simulate switch behavior leading to a disruption of fusion following chronic (e.g., dioxin) and acute (e.g., retinoic acid, hydrocortisone) toxicant exposures. This computer model adds to similar systems models toward a ‘virtual embryo’ for simulation and quantitative prediction of adverse developmental outcomes following genetic perturbation and/or environmental disruption.
