NTP develops screening method for androgen receptor pathway activation
Researchers from the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods, working with the U.S. Environmental Protection Agency, designed an efficient and cost-effective computational model to determine whether a chemical harbors androgen receptor (AR) pathway activity. The team validated the model by building a database of reference chemicals that included a wide range of AR activity, which ultimately allowed the testing strategy to be incorporated into a regulatory setting.
The researchers integrated both experimental and computational data from a suite of 11 ToxCast and Tox21 in vitro high-throughput screening assays that map key biological events along the AR pathway. Use of these assays was supplemented with an antagonist confirmation assay to distinguish true activity from cytotoxicity. At the same time, the scientists conducted a systematic literature review to externally validate the method, compiling a library of 158 reference chemicals with pre-existing experimental data. They determined that the new pathway model was more than 95 percent accurate for detecting both agonist and antagonist activity. An agonist is substance that initiates a biochemical action, and an antagonist is a substance that inhibits a biochemical action.
After screening 1,855 chemicals, the researchers predicted that 220 chemicals had clear AR pathway activity and 174 chemicals had weak AR pathway activity. Future efforts will connect AR pathway disruption by these chemicals to relevant human exposures and implications for human health. (AD)
Citation: Kleinstreuer NC, Ceger P, Watt ED, Martin M, Houck K, Browne P, Thomas RS, Casey WM, Dix DJ, Allen D, Sakamuru S, Xia M, Huang R, Judson R. 2016. Development and validation of a computational model for androgen receptor activity. Chem Res Toxicol; doi: 10.1021/acs.chemrestox.6b00347 [Online 18 November 2016].