Profiling Bioactivity of the ToxCast Chemical Library Using BioMAP Primary Human Cell Systems

Abstract

The complexity of human biology has made prediction of health effects as a consequence of exposure to environmental chemicals especially challenging. Complex cell systems, such as the Biologically Multiplexed Activity Profiling (BioMAP) primary, human, cell-based disease models, leverage cellular regulatory networks to detect and distinguish chemicals with a broad range of target mechanisms and biological processes relevant to human toxicity. Here the authors use the BioMAP human cell systems to characterize effects relevant to human tissue and inflammatory disease biology following exposure to the 320 environmental chemicals in the Environmental Protection Agency's (EPA's) ToxCast phase I library. The ToxCast chemicals were assayed at 4 concentrations in 8 BioMAP cell systems, with a total of 87 assay endpoints resulting in more than 100,000 data points. Within the context of the BioMAP database, ToxCast compounds could be classified based on their ability to cause overt cytotoxicity in primary human cell types or according to toxicity mechanism class derived from comparisons to activity profiles of BioMAP reference compounds. ToxCast chemicals with similarity to inducers of mitochondrial dysfunction, cAMP elevators, inhibitors of tubulin function, inducers of endoplasmic reticulum stress, or NFkappaB pathway inhibitors were identified based on this BioMAP analysis. This data set is being combined with additional ToxCast data sets for development of predictive toxicity models at the EPA.

In Vitro and Modelling Approaches to Risk Assessment from the U.S. Environmental Protection Agency ToxCast Programme

“…In total, there are up to 700 assays or assay end-points being used as part of the ToxCast programme. These cover a large range of technologies, including cell-free biochemical assays, assays targeting nuclear and other receptors and other molecular targets, assays measuring downstream integrated cell processes and model organisms (especially zebrafish) [5,6,[13][14][15][16][17][18][19][20][21][22][23][24]. The complete set of assay descriptions can be found at the ToxCast website.…”

The opportunities of mining historical and collective data in drug discovery

“…Protein changes upon small molecule treatment are calculated and combined into a BioMAP 1 profile. Multiple studies have demonstrated the ability of these profiles to capture small molecule MoAs [31][32][33][34]. Importantly, although many BioMAP 1 systems monitor inflammatory pathway signaling, characteristic compound profiles can be established for compounds that target other pathways.…”

A Phenotypic Screening Approach in Cord Blood–Derived Mast Cells to Identify Anti-Inflammatory Compounds

“…28 In addition, broadening the fingerprint of compound activity by profiling across a range of disease-relevant phenotypic assays can be highly effective, for example, by using the BioMAP platform. 29 In summary, there is a current renaissance in phenotypic screening approaches to identify novel compounds and targets for drug discovery. The mast cell tryptase screen described enables significant diversity screening approaches to be prosecuted, in a time-and cost-efficient manner.…”