TY - JOUR
T1 - Computational modeling and simulation of genital tubercle development
AU - Leung, Maxwell C.K.
AU - Hutson, M. Shane
AU - Seifert, Ashley W.
AU - Spencer, Richard M.
AU - Knudsen, Thomas B.
N1 - Funding 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.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
KW - Agent-based model
KW - Computational toxicology
KW - Genital tubercle
KW - Hypospadias
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U2 - 10.1016/j.reprotox.2016.05.005
DO - 10.1016/j.reprotox.2016.05.005
M3 - Article
C2 - 27180093
AN - SCOPUS:84971646057
SN - 0890-6238
VL - 64
SP - 151
EP - 161
JO - Reproductive Toxicology
JF - Reproductive Toxicology
ER -