Endocrine Abstracts

Androgen receptor (AR) is an important target for inhibition by some endocrine disrupting chemicals. Some diphenyl compounds inhibit AR activity by binding to a hydrophobic surface binding site, BF3. A similar diphenyl structure is found in 4.4’ DDT and its breakdown product 4.4’ DDE. Previous results showed that DDT, DDE, and related compounds induced the release of bound dihydrotestosterone from the AR ligand binding domain with IC₅₀ values ranging from 54 to 82 uM. We tested whetherDDE may act as an EDC by binding to BF3 and inducing allosteric changes in the AR structure. Five mutant AR genes with single amino acid changes in the BF3 site were tested for differences in the ability of DDE to disrupt AR activity. The five mutations tested were F673K, F673W, G724R, G724M, and L830D. An AR reporter system was introduced into HEK293 cells by transient transfection and AR activity was measured using a dual luciferase assay. The response of the AR protein was measured with varying concentrations of dihydrotestosterone in the presence and absence of DDE. DDE inhibited the activation of AR by dihydrotestosterone under these conditions. The inhibition of AR activity by DDE was reduced by the mutations in the BF3 site. These results suggest that DDE acts as an endocrine disrupting chemical (EDC) by interacting with the BF3 site and allosterically regulating AR activity.