title: Computational modeling and simulation of genital tubercle development.
abstract: 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.
authors.affiliation: National Center for Computational Toxicology, U.S. Environmental Protection Agency, Research Triangle Park, NC, 27711, United States; Oak Ridge Institute for Science and Education, Oak Ridge, TN, 37831, United States. Electronic address: leung.maxwell@epa.gov.
authors.forename: Maxwell C K
authors.initials: MC
authors.lastname: Leung
authors.affiliation: Oak Ridge Institute for Science and Education, Oak Ridge, TN, 37831, United States; Department of Physics & Astronomy, Vanderbilt Institute for Integrative Biosystems Research & Education, Vanderbilt University, Nashville, TN, 37235, United States.
authors.forename: M Shane
authors.initials: MS
authors.lastname: Hutson
authors.affiliation: Department of Biology, University of Kentucky, Lexington, KY, 40506, United States.
authors.forename: Ashley W
authors.initials: AW
authors.lastname: Seifert
authors.affiliation: Lockheed Martin, Research Triangle Park, NC, 27709, United States.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Spencer
authors.affiliation: National Center for Computational Toxicology, U.S. Environmental Protection Agency, Research Triangle Park, NC, 27711, United States. Electronic address: knudsen.thomas@epa.gov.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Knudsen
mesh_terms: D000726:Androgen Antagonists / Q000633:toxicity; D000818:Animals; D003198:Computer Simulation; D052244:Endocrine Disruptors / Q000633:toxicity; D005260:Female; D005865:Gestational Age; D006801:Humans; D007021:Hypospadias / Q000139:chemically induced / Q000196:embryology*; D008297:Male; D051379:Mice; D008954:Models, Biological; D012727:Sex Characteristics; D012984:Software; D014521:Urethra / Q000187:drug effects / Q000196:embryology*
chemical_list: D000726:Androgen Antagonists; D052244:Endocrine Disruptors
keywords: Agent-based model; Computational toxicology; Genital tubercle; Hypospadias