Endocrine disruptors that disrupt the transcription mediated by androgen receptor

Abstract

The Ministry of Environment in Japan (formerly the Japan Environment Agency) has made a priority list of compounds, SPEED 98, to preferentially examine whether they act as endocrine active chemicals and conducted a project to scientifically address endocrine disruptor issues. Out of around 100 compounds listed in SPEED 98 and related compounds, thirty-six acted as pure androgen receptor (AR) antagonists, whereas 13 showed both AR agonist and antagonist activities based on an in vitro reporter gene assay. The structural difference between AR agonists and antagonists was explained by Comparative Molecular Field Analysis (CoMFA). The precise structural requirements for AR agonists and/or antagonists are described as follows: in the case of AR agonist, the distance between two functional groups with H-bonding ability corresponding to 3-keto and 17b-OH groups should be near 10 Å to maintain a favorable H-bond position while the length axis of antagonists should be less than or more than 10 Å so as not to make an H-bond by interaction with Asn705 and Thr877 in the steroid D ring anchoring pocket, preventing the correct positioning of helix 3 (H3) and helix 12 (H12). This hypothetical general rule is named "Near 10 Å polar Interaction Rule". © Pesticide Science Society of Japan Keywords: androgen, endocrine disruptor, nuclear receptor, environmental hormone, CoMFA, MDA-kb2. Table 2. Among the reported in vitro assays, the reporter gene assay is one of the most promising assay methods to prove the potential activity of target chemicals because, in particular, the majority of known endocrine active chemicals binds to their corresponding hormone receptors. The characterization of known reporter gene assays is summarized in Table 3. Although the yeast system is a convenient and good for their primary assay, it has a couple of unoverlooked disadvantages as follows: 1) permeability of chemicals through the cell wall and 2) difference of transactivating factors, such as recruited transcription factors. In conclusion, a human cell line is preferred to screen the activity of chemicals because its own intact signal transduction systems mediated by own intact receptors can be used. The reporter gene assay system was validated and reviewed by Körner W. et al. 9)The Ministry of Environment in Japan (formerly the Japan Environment Agency) has made a priority list of compounds, SPEED 98, to preferentially examine whether they act as endocrine active chemicals and has been conducting a project to scientifically address endocrine disruptor issues since 1998. 10)The project includes environmental monitoring to determine the concentrations of suspected endocrine active chemicals, epidemiological surveys of the general Japanese population to examine the relationship between exposure to certain suspected endocrine active chemicals and the occurrence of congenital malformations such as cryptorchism, and a series of in vitro and in vivo bioassays using established cell lines and experimental animals. We have been involved in the project and...

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