Endocrine Abstracts

The androgen receptor (AR) function is inhibited by endocrine disrupting chemicals (EDCs) such as DDT and DDE leading to problems in embryonic development and negative health outcomes for adults. EDCs may bind in the steroid binding pocket and disrupt AR function by leading to altered receptor conformations. However, this may not be the only way EDCs interfere with the receptor. Estébanez-Perpiñá et al identified binding function 3 (BF3) as a surface binding site for small hydrophobic compounds that disrupted AR activity. We found that DDT, DDE, and related compounds induced the release of bound dihydrotestosterone (DHT) from the AR ligand binding domain with IC50 values ranging from 54 to 82 µM. In addition, mutant AR genes with single amino acid changes in the BF3 site showed a reduced sensitivity for the ability of DDE to disrupt AR activity in vivo using a reporter assay. These results suggested that DDE interacts with the BF3 site and allosterically regulates AR activity. We used molecular dynamics (MD) simulations methods to test whether DDE bound to BF3 induces allosteric changes in the AR structure, altering the dynamic behavior of AR with bound steroid. Accelerated MD simulations identified possible exit pathways for DHT and steered MD simulations showed that the free energy of steroid unbinding was decreased for the exit pathways studied when DDE was bound in the BF3 site. These results suggested that AR dynamics are impacted by DDE interacting with the BF3 site, destabilizing the steroid in its binding pocket and reducing the energy required for steroid release, thus disrupting AR function.