Profiling 976 ToxCast Chemicals across 331 Enzymatic and Receptor Signaling Assays

By Nisha S. Sipes, Matt T. Martin, P. Kothiya, David M. Reif, Richard S. Judson, Ann M. Richard, K. Houck, D. Dix, R. Kavlock, T. Knudsen. 2013

202 citations recorded by the source corpus.

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’s 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–assay 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–assay 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–target combinations clustered with known chemical–target interactions. Results from this large inventory of chemical–biological interactions can inform read-across methods as well as link potential targets to molecular initiating events in adverse outcome pathways for diverse toxicities.

Subfields: Computational Theory and Mathematics, Health, Toxicology and Mutagenesis, Pharmacology

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Citations in the corpus

T3DB: the toxic exposome database (2014, background): “In addition to these endogenous compounds an additional set of 49 known or suspected carcinogens from IARC (the International Agency for Research on Cancer), a set of more than 175 new drugs from DrugBank (14), a collection of more than 300 common pesticides, cosmetic agents, drugs and workplace che”
Integrated Model of Chemical Perturbations of a Biological Pathway Using 18 In Vitro High-Throughput Screening Assays for the Estrogen Receptor. (2015, methodology): “These include 3 cell-free biochemical radioligand ER binding assays [Novascreen/NVS: (Knudsen et al. , 2011; Sipes et al. , 2013)]; a set of 3 protein complementation assays that measure formation of ER homodimers or hetero-dimers and test for activity against both ER-alpha and ER-beta, (each…”