Hypospadias is a developmental defect of urethral tube closure that has a complex etiology involving genetic and environmental factors, including anti-androgenic and estrogenic disrupting chemicals; however, little is known about the morphoregulatory consequences of androgen/estrogen balance during genital tubercle (GT) development. Computer models that predictively model sexual dimorphism of the GT may provide a useful resource to translate chemical-target bipartite networks and their developmental consequences across the human-relevant chemical universe. Here, we describe a multicellular agent-based model of genital tubercle (GT) development that simulates urethrogenesis from the sexually-indifferent urethral plate stage to urethral tube closure. The prototype model, constructed in CompuCell3D, recapitulates key aspects of GT morphogenesis controlled by SHH, FGF10, and androgen pathways through modulation of stochastic cell behaviors, including differential adhesion, motility, proliferation, and apoptosis. Proper urethral tube closure in the model was shown to depend quantitatively on SHH- and FGF10-induced effects on mesenchymal proliferation and epithelial apoptosis—both ultimately linked to androgen signaling. In the absence of androgen, GT development was feminized and with partial androgen deficiency, the model resolved with incomplete urethral tube closure, thereby providing an in silico platform for probabilistic prediction of hypospadias risk across combinations of minor perturbations to the GT system at various stages of embryonic development.
|Number of pages||11|
|State||Published - Sep 1 2016|
Bibliographical noteFunding Information:
We thank Muhammad Ahsan, Dustin Kapraun, and Caroline Ring for technical advice; and Woodrow Setzer and Nisha Sipes for helpful comments on the manuscript. This research was funded by the U.S. EPA Chemical Safety for Sustainability research Program . M.S.H. was supported in part by U.S. EPA Science to Achieve Results (STAR) Program (#83573601) under a cooperative agreement.
© 2016 Elsevier Inc.
- Agent-based model
- Computational toxicology
- Genital tubercle
ASJC Scopus subject areas