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Probing the ToxCast Chemical Library for Predictive Signatures of Developmental Toxicity
Citation:
SIPES, N., N. KLEINSTREUER, R. JUDSON, D. REIF, A. V. SINGH, K. J. CHANDLER, M. ROUNTREE, D. J. DIX, R. J. KAVLOCK, AND T. B. KNUDSEN. Probing the ToxCast Chemical Library for Predictive Signatures of Developmental Toxicity. Presented at Annual Meeting of the Society of Toxicology, Washington, DC, March 06 - 10, 2011.
Impact/Purpose:
This work demonstrates the utility of HTS assays for developing pathway level signatures correlating to developmental defects
Description:
EPA’s ToxCast™ project is profiling the in vitro bioactivity of chemical compounds to assess pathway-level and cell-based signatures that correlate with observed in vivo toxicity. We hypothesize that cell signaling pathways are primary targets for diverse environmental chemicals that disrupt embryogenesis via combinatorial effects on cellular functions. To test this hypothesis, we built statistical associations based on in vitro¬ high-throughput screening (HTS) data from ToxCastTM and in vivo developmental toxicity data from ToxRefDB. Univariate associations from 2x2 contingency tables were used to filter HTS assays based on statistical correlation with distinct in vivo endpoints. Machine learning algorithms then built predictive models using linear discriminant analysis with multivariate feature selection trained by univariate associations. Initial results gave 389 univariate associations with distinctly different patterns for rat (308 associations) and rabbit (81 associations). Aggregating the species endpoints into a generic model revealed strong correlations between in vitro pathways and in vivo effects for urogenital defects and cleft palate. As an example, a cleft palate signature emerged that included forkhead box (FOX) transcription factor pathways and chromatin remodeling through histone deacetylase (HDAC) signaling. Interestingly, a model built from developmental zebrafish data implied the same target pathway signature for eye reduction defects. Perturbations of these signaling pathways are known to be causally involved in zebrafish craniofacial defects and mammalian (including human) cleft palate. This indicates potential key signaling pathways involved in cleft palate induction may be targets for chemical teratogens, and zebrafish as a model system may reveal similar pathway disruption. This work demonstrates the utility of HTS assays for developing pathway level signatures correlating to developmental defects. This abstract does not necessarily reflect US EPA policy.