Citation:

Leung, M., N. Baker, AND T. Knudsen. Chapter 50 - Systems Toxicology and Predictive Modeling of Male Developmental Toxicity. Chapter 50, Reproductive and Developmental Toxicology. Elsevier Inc, Waltham, MA, , 975-985, (2017). https://doi.org/10.1016/B978-0-12-804239-7.00050-0

Impact/Purpose:

This chapter integrates recent studies on the systems toxicology of male reproductive development (Leung et al. 2016, Envir Hlth Persp) with cellular agent-based models of hypospadias (Leung et al. 2016, Reprod Toxicol) for a multiscale systems model that can be used for quantitative prediction.

Description:

The ToxCast paradigm for predictive toxicology utilizes in vitro data from automated high-throughput screening (HTS), coupled with in silico models for data mining and systems modeling. This chapter highlights recent progress with an HTS-driven approach for developmental toxicity, using male reproductive tract development as an example. A systems toxicology model built from ToxCast data revealed a phenotypic hierarchy reflecting human Testicular Dysgenesis Syndrome (TDS). Bioactivity profiling of 54 chemicals across assays identified 156 candidate molecular targets in a network of biological processes for steroidogenic and xenobiotic metabolism, developmental regulation, angiogenesis and inflammatory pathways, and neural activity. Cell agent-based modeling was applied to recapitulate key events during genital tubercle (GT) development and dysmorphogenesis (hypospadias). Capturing SHH, FGF10, and androgen signaling pathways, as well as cell-autonomous programming, cellular biomechanics, and micro-physiological influences underlying urethral closure in a simulated ‘virtual GT’ provided a means to translate the systems toxicology model into a spatially-scaled dynamical systems and a probabilistic prediction of toxicity.

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