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Building predictive models of developmental toxicity from ToxRefDB and ToxCast
Citation:
SIPES, N., N. KLEINSTREUER, R. JUDSON, M. ROUNTREE, A. V. SINGH, D. J. DIX, R. J. KAVLOCK, R. DEWOSKIN, AND T. B. KNUDSEN. Building predictive models of developmental toxicity from ToxRefDB and ToxCast. Presented at 5th Annual Duke Systems Biology Symposium, Durham, NC, October 07, 2010.
Impact/Purpose:
Bottom up approaches focusing on cellular mechanism revealed pesticidal mode of action can be used to find associations with a group of HTS data and furthermore to in vivo endpoints. This work has shown promise to using HTS assays for correlating pathway level signatures to developmental defects for chemical teratogenicity.
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. We hypothesize that cell signaling pathways underlying development are primary targets for diverse environmental chemicals that disrupt embryogenesis and have combinatorial effects on cellular functions. To test this hypothesis, we are building statistical associations based on in-vitro¬ high-throughput screening (HTS) data from EPA’s ToxCastTM project, and in vivo developmental toxicity data from ToxRefDB. Initial analysis revealed no coherent correlations for overall developmental defects between rat or rabbit species, although species bias was seen for different assay platforms. Top down approaches focusing on developmental endpoints revealed unique associations for mammalian cleft palate and zebrafish eye reduction defects. As an example, this specific target pathway signature included FOX gene family pathways and histone deacetylase signaling. These signaling pathways when perturbed have been shown to be involved in incidences of zebrafish craniofacial defects and mammalian and human cleft palate, indicating potential key signaling pathways important for inducing cleft palate may be targets for chemical teratogens. Bottom up approaches focusing on cellular mechanism revealed pesticidal mode of action can be used to find associations with a group of HTS data and furthermore to in vivo endpoints. This work has shown promise to using HTS assays for correlating pathway level signatures to developmental defects for chemical teratogenicity. [This abstract does not necessarily reflect U.S. EPA policy].