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Chemical and HTS Profiling of 63 Cleft Palate Teratogens from ToxCast (FutureTox III)
Baker, N., N. Sipes, C. Grulke, M. Leung, J. A, B. Abbott, R. Judson, AND T. Knudsen. Chemical and HTS Profiling of 63 Cleft Palate Teratogens from ToxCast (FutureTox III). Presented at FutureTox III, Arlington, VA, November 19 - 20, 2015. https://doi.org/10.23645/epacomptox.5189362
Using ToxCast for predicting and understanding cleft palate toxicants.
Cleft palate is a common human birth defect that has been linked to both genetic and environmental factors. To characterize the potential molecular targets and biological processes across mechanistically diverse teratogens that cause cleft palate, we mined the ToxCast high-throughput screening (HTS) database for chemical-assay relationships. The objective was to describe patterns and linkages in the data that may help predict or elucidate Adverse Outcome Pathways (AOPs) underlying the chemical induction of cleft palate during prenatal exposures. Using a combination of chemical structural descriptors called chemotypes and ToxCast assay results filtered for cytotoxicity and summarized by gene (gene scores), we employed informatics and machine-learning methods to find distinctive and descriptive patterns that discriminated between 63 cleft palate active chemicals and 437 chemicals not found to cause cleft palate in animal studies. The initial attempt to build a global predictive model for cleft palate was not successful; however, cluster analysis revealed local clusters of interest centered on cytochrome P450s, G protein-coupled receptors, the retinoic acid receptors, adenosine receptors, and the glucocorticoid receptor. The roles of the ToxCast assay targets in putative AOPs was supported by the literature. This work demonstrated an integrative approach for profiling HTS data combined with chemical structural data that can be applied to investigate the role of environmental chemicals in other developmental AOPs. (Disclaimer: this abstract does not reflect EPA policy.)