Androgen receptor modulation following combination exposure to brominated flame-retardants

Endocrine disrupting compounds can interfere with androgen receptor (AR) signaling and disrupt steroidogenesis leading to reproductive failure. The brominated flame-retardant (BFR) 1, 2-dibromo-4-(1, 2-dibromoethyl) cyclohexane (TBECH), is an agonist to human, chicken and zebrafish AR. Recently another group of alternative BFRs, allyl 2, 4, 6-tribromophenyl ether (ATE), and 2, 3-dibromopropyl 2, 4, 6-tribromophenyl ether (DPTE) along with its metabolite 2-bromoallyl 2, 4, 6-tribromophenyl ether (BATE) were identified as potent human AR antagonists. These alternative BFRs are present in the environment. The aim of the present study was to determine the effect of mixed exposures to the AR agonist and the AR antagonists at environmentally relevant concentrations. In vitro reporter luciferase assay showed that the AR antagonists, when present at concentration higher than TBECH, were able to inhibit TBECH-mediated AR activity. These AR antagonists also promoted AR nuclear translocation. In vitro gene expression analysis in the non-tumorigenic human prostate epithelial cell RWPE1 showed that TBECH induced AR target genes whereas DPTE repressed these genes. Further analysis of steroidogenic genes showed that TBECH up-regulated most of the genes while DPTE down-regulated the same genes. The results indicate that when TBECH and DPTE are present together they will antagonize each other, thereby reducing their individual effects.