Computational modeling and simulation of genital tubercle development.

Area of Science:

• Developmental biology
• Computational modeling
• Endocrinology

Background:

• Hypospadias results from complex genetic and environmental factors, including endocrine disruptors.
• The role of androgen and estrogen balance in genital tubercle (GT) development remains poorly understood.
• Predictive computer models can elucidate chemical impacts on GT sexual dimorphism.

Purpose of the Study:

• To develop a multicellular agent-based model simulating urethral tube closure during GT development.
• To investigate the morphoregulatory roles of androgen signaling in GT morphogenesis.
• To establish an in silico platform for predicting hypospadias risk.

Main Methods:

• Constructed a CompuCell3D-based agent-based model of GT development from the urethral plate stage.
• Simulated urethrogenesis, incorporating SHH, FGF10, and androgen pathways.
• Modeled cell behaviors: differential adhesion, motility, proliferation, and apoptosis.

Main Results:

• The model successfully recapitulated key GT morphogenesis aspects, including urethral tube closure.
• SHH and FGF10 effects on mesenchymal proliferation and epithelial apoptosis, linked to androgen signaling, were critical for closure.
• Androgen deficiency led to feminized GT development and incomplete urethral tube closure.

Conclusions:

• Androgen signaling is quantitatively essential for proper urethral tube closure during GT development.
• The developed in silico model provides a tool for assessing hypospadias risk associated with chemical exposures.
• This computational approach aids in understanding the developmental consequences of endocrine disruption.