Profiling 976 ToxCast Chemicals across 331 Enzymatic and Receptor Signaling Assays

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• 作者：Nisha S. Sipes ; Matthew T. Martin ; Parth Kothiya ; David M. Reif ; Richard S. Judson ; Ann M. Richard ; Keith A. Houck ; David J. Dix ; Robert J. Kavlock ; Thomas B. Knudsen
• 刊名：Chemical Research in Toxicology
• 出版年：2013
• 出版时间：June 17, 2013
• 年：2013
• 卷：26
• 期：6
• 页码：878-895
• 全文大小：698K
• 年卷期：v.26,no.6(June 17, 2013)
• ISSN：1520-5010

文摘

Understanding potential health risks is a significant challenge due to the large numbers of diverse chemicals with poorly characterized exposures and mechanisms of toxicities. The present study analyzes 976 chemicals (including failed pharmaceuticals, alternative plasticizers, food additives, and pesticides) in Phases I and II of the U.S. EPA鈥檚 ToxCast project across 331 cell-free enzymatic and ligand-binding high-throughput screening (HTS) assays. Half-maximal activity concentrations (AC50) were identified for 729 chemicals in 256 assays (7,135 chemical鈥揳ssay pairs). Some of the most commonly affected assays were CYPs (CYP2C9 and CYP2C19), transporters (mitochondrial TSPO, norepinephrine, and dopaminergic), and GPCRs (aminergic). Heavy metals, surfactants, and dithiocarbamate fungicides showed promiscuous but distinctly different patterns of activity, whereas many of the pharmaceutical compounds showed promiscuous activity across GPCRs. Literature analysis confirmed >50% of the activities for the most potent chemical鈥揳ssay pairs (54) but also revealed 10 missed interactions. Twenty-two chemicals with known estrogenic activity were correctly identified for the majority (77%), missing only the weaker interactions. In many cases, novel findings for previously unreported chemical鈥搕arget combinations clustered with known chemical鈥搕arget interactions. Results from this large inventory of chemical鈥揵iological interactions can inform read-across methods as well as link potential targets to molecular initiating events in adverse outcome pathways for diverse toxicities.