title: Prediction of Estrogenic Bioactivity of Environmental Chemical Metabolites.
abstract: The US Environmental Protection Agency's (EPA) Endocrine Disruptor Screening Program (EDSP) is using in vitro data generated from ToxCast/Tox21 high-throughput screening assays to assess the endocrine activity of environmental chemicals. Considering that in vitro assays may have limited metabolic capacity, inactive chemicals that are biotransformed into metabolites with endocrine bioactivity may be missed for further screening and testing. Therefore, there is a value in developing novel approaches to account for metabolism and endocrine activity of both parent chemicals and their associated metabolites. We used commercially available software to predict metabolites of 50 parent compounds, out of which 38 chemicals are known to have estrogenic metabolites, and 12 compounds and their metabolites are negative for estrogenic activity. Three ER QSAR models were used to determine potential estrogen bioactivity of the parent compounds and predicted metabolites, the outputs of the models were averaged, and the chemicals were then ranked based on the total estrogenicity of the parent chemical and metabolites. The metabolite prediction software correctly identified known estrogenic metabolites for 26 out of 27 parent chemicals with associated metabolite data, and 39 out of 46 estrogenic metabolites were predicted as potential biotransformation products derived from the parent chemical. The QSAR models estimated stronger estrogenic activity for the majority of the known estrogenic metabolites compared to their parent chemicals. Finally, the three models identified a similar set of parent compounds as top ranked chemicals based on the estrogenicity of putative metabolites. This proposed in silico approach is an inexpensive and rapid strategy for the detection of chemicals with estrogenic metabolites and may reduce potential false negative results from in vitro assays.
authors: Office of Chemical Safety and Pollution Prevention, US Environmental Protection Agency , 1200 Pennsylvania Avenue, N.W., Washington, DC 20460, United States.|Oak Ridge Institute for Science and Education , MC-100-44, P.O. Box 117, Oak Ridge, Tennessee 37831-0117, United States.
authors: Caroline L
authors: CL
authors: Pinto
authors: Oak Ridge Institute for Science and Education , MC-100-44, P.O. Box 117, Oak Ridge, Tennessee 37831-0117, United States.|Office of Research and Development, US Environmental Protection Agency , Research Triangle Park, North Carolina 27711, United States.
authors: Kamel
authors: K
authors: Mansouri
authors: Office of Research and Development, US Environmental Protection Agency , Research Triangle Park, North Carolina 27711, United States.
authors: Richard
authors: R
authors: Judson
authors: Office of Chemical Safety and Pollution Prevention, US Environmental Protection Agency , 1200 Pennsylvania Avenue, N.W., Washington, DC 20460, United States.
authors: Patience
authors: P
authors: Browne
mesh_terms: D003198:Computer Simulation; D019992:Databases as Topic; D052244:Endocrine Disruptors / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D004785:Environmental Pollutants / Q000378:metabolism / Q000633:toxicity*; D004967:Estrogens / Q000737:chemistry*; D005544:Forecasting; D006801:Humans; D021281:Quantitative Structure-Activity Relationship; D014481:United States; D014484:United States Environmental Protection Agency
chemical_list: D052244:Endocrine Disruptors; D004785:Environmental Pollutants; D004967:Estrogens