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Computational Modeling of Male Reproductive Tract Development for Use in Predictive Toxicology (ASCCT meeting)
Leung, Maxwell C.K. AND T. Knudsen. Computational Modeling of Male Reproductive Tract Development for Use in Predictive Toxicology (ASCCT meeting). Presented at Annual ASCCT Meeting, RTP, NC, October 01 - 02, 2015. https://doi.org/10.23645/epacomptox.5071318
Adverse trends in male reproductive health have been reported for increased rates of testicular germ cell tumor, low semen quality, cryptorchidism, and hypospadias. An association with prenatal environmental exposure has been inferred from human and animal studies underlying male reproductive tract defects. The present study established the links between environmental chemicals, molecular targets, and adverse outcomes using systems-based and multi-scale biological modeling approaches. The systems-based approach revealed a phenotypic hierarchy of testicular atrophy, sperm effects, and malformations across 281 chemicals in ToxRefDB, a guideline animal study database, resembling what might be expected in testicular dysgenesis syndrome (TDS) in humans; 54 chemicals had ToxCastDB high-throughput screening data, interacting with 156 molecular targets in a bipartite network. The results confirmed the known role of estrogen and androgen signaling pathways in TDS, and importantly, broadened the list of molecular targets to include a variety of nuclear receptors, GPCRs, vascular remodeling proteins, and cytochrome-P450s. We further built a multicellular computer simulation that described the pathogenesis of hypospadias, using a cellular agent-based model (CompuCell3D.org) by incorporating key signals (e.g., SHH, FGF10, and androgen) and cellular behaviors (e.g., selective adhesion, motility) to control urethral tubulogenesis. Overall, the systems model and computer simulation: 1) provide a platform for integrating available biological information to predictively model the complex pathogenesis of male reproductive tract defects; 2) enable the generation of new research hypotheses; and, 3) contribute to better mechanistic understanding of this adverse developmental outcome.
Mining ToxRefDB and PubMed identified 71 chemicals producing MRDT, of which 54 had been tested in the ToxCastDB HTS, providing a novel resource for exploring phenotypic linkages to potential mechanistic pathways. This study reveals a phenotypic hierarchy of male reproductive effects across animal studies that were consistent with human TDS. While a number of recent studies have demonstrated that both hormonal and non-hormonal signaling is involved in male reproductive developmental defects, the present study extends these findings, showing androgen and estrogen receptors to be only a subset of the potential landscape of molecular targets. Steroid homeostasis and xenobiotic metabolism, developmental regulation, vascularization and angiogenesis, inflammation, and neural activity are predicted modes of action based on the 156 MRDT molecular targets, suggesting several molecular initiating events in further explorations of AOPs on male reproductive effects.
Record Details:Record Type: DOCUMENT (PRESENTATION/SLIDE)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL CENTER FOR COMPUTATIONAL TOXICOLOGY