NTP screens for genotoxicity with high-throughput techniques
National Toxicology Program (NTP) researchers and collaborators evaluated the usefulness of quantitative high-throughput approaches to assess the genotoxicity, or the ability to cause DNA damage, of compounds in the Tox21 library of 10,000 compounds. To do this, they assessed p53 activity in human colon cancer cells (HCT-116). p53 is a transcription factor that is activated in response to cellular stress, particularly DNA damage.
The Tox21 high-throughput screening program is part of a collaborative effort to institute new methods for toxicity testing. Standard toxicology tests cannot keep pace with the number of new and existing chemicals used in the United States. The goal of the Tox21 program is to develop rapid, predictive, mechanism-based methods to broaden the coverage of compounds with toxicological characterization using a library of 10,000 diverse compounds. To date, screening has focused on nuclear receptor and stress response pathway signaling. The p53 assay falls into the second category.
Results showed that 4.7 percent of compounds activated p53. Additional data mining revealed significant associations between these compounds and elevated expression of p53 downstream genes. Further analysis revealed specific associations between p53 activation and specific chemical substructures. The authors concluded that assessment of p53 activation was useful for characterization of genotoxic potential. (KS)
Citation: Witt KL, Hsieh JH, Smith-Roe SL, Xia M, Huang R, Zhao J, Auerbach SS, Hur J, Tice RR. 2017. Assessment of the DNA damaging potential of environmental chemicals using a quantitative high-throughput screening approach to measure p53 activation. Environ Mol Mutagen 58(7):494–507.