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Development of a Computational (in silico) Model of Ocular Teratogenesis
Citation:
SIPES, N., M. ROUNTREE, N. KLEINSTREUER, D. J. DIX, R. JUDSON, R. J. KAVLOCK, M. SWAT, J. A. GLAZIER, R. DEWOSKIN, A. V. SINGH, R. SPENCER, AND T. B. KNUDSEN. Development of a Computational (in silico) Model of Ocular Teratogenesis. Presented at Teratology Society Annual Meeting, Louisville, KY, June 26 - 30, 2010.
Impact/Purpose:
Linkages between eye morphogenesis, cellular effects, and the identified pathways in a virtual embryo using CompuCell3D modeling software
Description:
EPA’s ToxCast™ project is profiling the in vitro bioactivity of chemical compounds to assess pathway-level and cell-based signatures that are highly correlated with observed in vivo toxicity. In silico models provide a framework for interpreting the in vitro results and for simulating the toxicity pathways. One such model is being developed to predict the potential of chemical compounds and classes to disrupt embryonic development. The embryonic eye was initially used as a prototype for embryonic target organ systems modeling. Early eye development is broadly susceptible to mechanistically diverse teratogens. We hypothesize that cell signaling pathways underlying eye development are primary targets for diverse environmental chemicals that disrupt ocular formation and have combinatorial effects on cellular functions. To test this hypothesis, we are building an integrative cell-based model of early eye development based on in-vitro¬ high-throughput screening (HTS) and high-content screening (HCS) data from EPA’s ToxCast project, and in vivo developmental toxicity data from ToxRefDB. Initial analysis of in vitro profiles for several microphthalmia-inducing teratogens revealed pathway disruption of microtubule stability, mitotic inhibition, mitochondrial dysfunction, and perturbation of pro-inflammatory/anti-angiogenic factors (VCAM1, HLA-DRA, CXCL10, MMP1, and uPAR). Optic cup development, for example, is known to be sensitive to mitochondrial dysfunction. Three of the six ToxRefDB ocular teratogens tested in vitro disrupted mitochondrial function and also induced microphthamia in vivo. Studies are underway to investigate the linkages between eye morphogenesis, cellular effects, and the identified pathways in a virtual embryo using CompuCell3D modeling software. [This work is approved by EPA but does not reflect official Agency policy].