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Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays
Citation:
Sipes, N., M. Martin, P. Kothiya, D. Reif, R. Judson, A. Richard, K. Houck, D. Dix, R. Kavlock, AND T. Knudsen. Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. CHEMICAL RESEARCH IN TOXICOLOGY. American Chemical Society, Washington, DC, 26:878−895, (2013).
Impact/Purpose:
Overall, these results contribute to a novel framework for describing the interaction of environmental chemicals with important biochemical targets. By broadly surveying both the chemical landscape and biological target space, patterns of biochemical activity have been identified which can help focus future research towards potential chemical-biological interactions that may result in adverse outcomes in vivo. The use of a quantitative approach in determining potency of chemicals against each biological target, utilizing a diverse chemical library containing many reference chemicals with known activities as chemical probes, provides the context to better understand the potential for hazard of those chemicals with limited toxicity information. As these interactions become better defined through methods such as incorporation into adverse outcome pathways (Ankley, et al., 2010; Kleinstreuer and Knudsen, 2011), these in vitro screening methods may ultimately serve as an efficient means of avoiding unwanted biological activity early in the chemical design and development process.
Description:
Understanding potential health risks is a significant challenge for large numbers of diverse chemicals with poorly characterized exposures and mechanisms of toxicities. The present study analyzes chemical-target activity profiles of 976 chemicals (including failed pharmaceuticals, alternative plasticizers, food additives, and pesticides) in Phase I and II of the U.S. EPA’s ToxCast™ project. The chemical inventory was profiled across 331 cell-free enzymatic and ligand-binding high-throughput screening (HTS) assays, including multiple G-protein-coupled and nuclear receptors, kinases, phosphatases, CYPs, histone deacetylases, ion channels and transporters. Over 14,000 chemical-assay pairs were tested in 8-point concentration series from 0.023 to 50 μM (or 0.009–20 μM for CYPs). Half-maximal activity concentrations (AC50) were identified for 7,135 active chemical-assay pairs for 729 unique chemicals in 256 assays. Chemicals varied in relative specificity or promiscuity toward assay types, and assays varied by sensitivity to chemical classes. In many cases, novel findings for previously unreported chemical-target combinations were associated with known chemical-target interactions through similarity analyses. Results from this large inventory of chemical-biological interactions can inform read-across methods as well as to link potential targets to molecular initiating events in adverse outcome pathways for diverse toxicities.
