Citation:

Rooney, J., N. Ryan, R. Houtman, R. van Beuningen, J. Hsieh, S. Chen, AND C. Corton. Identification of Novel Chemical Modulators of the Estrogen Receptor α (ERα) in a Gene Expression Compendium. Society of Toxicology, Baltimore, Maryland, March 13 - 16, 2017.

Impact/Purpose:

Identification of chemicals that affect hormone-regulated systems will help to predict endocrine disruption. In our previous study we characterized a gene expression biomarker that was found to be an accurate predictor of ERα modulation in chemically-treated human breast cancer MCF-7 cells. Here, the biomarker was used to identify potential endocrine disrupting chemicals that alter the activity of ERα.

Description:

Identification of chemicals that affect hormone-regulated systems will help to predict endocrine disruption. In our previous study we characterized a gene expression biomarker that was found to be an accurate predictor of ERα modulation in chemically-treated human breast cancer MCF-7 cells. Here, the biomarker was used to identify potential endocrine disrupting chemicals that alter the activity of ERα. Out of the ~1155 chemicals from the Connectivity Map (CMAP) 2.0 collection examined at 6 hrs in MCF-7 cells, 64 were found to activate ERα and 40 to suppress ERα. These included many known agonists and antagonists of ERα as well as chemicals not previously associated with ERα modulation. The novel drugs included 5 or more in each of the categories: anti-parasitics, antihistamines, and antibiotics. The majority of the identified chemicals were also detected as active in two Tox21 ERα trans-activation assays in either agonist or antagonist modes. However, a number of chemicals were found to activate ERα in MCF-7 cells using the biomarker approach but were inactive in the Tox21 assays. These chemicals were characterized further using estrogen receptor element –luciferase trans-activation assays in aromatase expressing MCF-7 cells (AroER tri-screen) as well as cell free assays which examine the ability of human ERα to interact with ~150 peptides from coactivators and corepressors after chemical exposure. Five chemicals were active in the luciferase assays but unlike our positive control (17β-estradiol) did not induce interactions between ERα and co-regulator peptides. In addition, progesterone receptor (PR) agonists activated ERα while the one PR antagonist (RU486) tested suppressed ERα. A number of agonists of the liver X receptor and glucocorticoid receptor acted as antagonists of ERα. This study identified novel chemical modulators of ERα, some of which appear to act like non-classical activators. This abstract does not represent EPA policy.

Record Details: