Tox21-Based Comparative Analyses for the Identification of Potential Toxic Effects of Environmental Pollutants

Chemical pollution has become a prominent environmental
problem.
In recent years, quantitative high-throughput screening (qHTS) assays
have been developed for the fast assessment of chemicals’ toxic
effects. Toxicology in the 21st Century (Tox21) is a well-known and
continuously developing qHTS project. Recent reports utilizing Tox21
data have mainly focused on setting up mathematical models for in vivo toxicity predictions, with less attention to intuitive
qHTS data visualization. In this study, we attempted to reveal and
summarize the toxic effects of environmental pollutants by analyzing
and visualizing Tox21 qHTS data. Via PubMed text mining, toxicity/structure
clustering, and manual classification, we detected a total of 158
chemicals of environmental concern (COECs) from the Tox21 library
that we classified into 13 COEC groups based on structure and activity
similarities. By visualizing these COEC groups’ bioactivities,
we demonstrated that COECs frequently displayed androgen and progesterone
antagonistic effects, xenobiotic receptor agonistic roles, and mitochondrial
toxicity. We also revealed many other potential targets of the 13
COEC groups, which were not well illustrated yet, and that current
Tox21 assays may not correctly classify known teratogens. In conclusion,
we provide a feasible method to intuitively understand qHTS data.