title: TBECH, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane, alters androgen receptor regulation in response to mutations associated with prostate cancer.
abstract: Point mutations in the AR ligand-binding domain (LBD) can result in altered AR structures leading to changes of ligand specificity and functions. AR mutations associated to prostate cancer (PCa) have been shown to result in receptor activation by non-androgenic substances and anti-androgenic drugs. Two AR mutations known to alter the function of anti-androgens are the ART877A mutation, which is frequently detected mutation in PCa tumors and the ARW741C that is rare and has been derived in vitro following exposure of cells to the anti-androgen bicalutamide. AR activation by non-androgenic environmental substances has been suggested to affect PCa progression. In the present study we investigated the effect of AR mutations (ARW741C and ART877A) on the transcriptional activation following exposure of cells to an androgenic brominated flame retardant, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane (TBECH, also named DBE-DBCH). The AR mutations resulted in higher interaction energies and increased transcriptional activation in response to TBECH diastereomer exposures. The ART877A mutation rendered AR highly responsive to low levels of DHT and TBECH and led to increased AR nuclear translocation. Gene expression analysis showed a stronger induction of AR target genes in LNCaP cells (ART877A) compared to T-47D cells (ARWT) following TBECH exposure. Furthermore, AR knockdown experiments confirmed the AR dependency of these responses. The higher sensitivity of ART877A and ARW741C to low levels of TBECH suggests that cells with these AR mutations are more susceptible to androgenic endocrine disrupters.
authors.affiliation: Biology, Örebro Life Science Center, School of Science and Technology, Örebro University, SE-701 82 Örebro, Sweden.
authors.forename: Joubert Banjop
authors.initials: JB
authors.lastname: Kharlyngdoh
authors.affiliation: Biology, Örebro Life Science Center, School of Science and Technology, Örebro University, SE-701 82 Örebro, Sweden.
authors.forename: Solomon
authors.initials: S
authors.lastname: Asnake
authors.affiliation: Biology, Örebro Life Science Center, School of Science and Technology, Örebro University, SE-701 82 Örebro, Sweden.
authors.forename: Ajay
authors.initials: A
authors.lastname: Pradhan
authors.affiliation: Biology, Örebro Life Science Center, School of Science and Technology, Örebro University, SE-701 82 Örebro, Sweden. Electronic address: per-erik.olsson@oru.se.
authors.forename: Per-Erik
authors.initials: PE
authors.lastname: Olsson
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003510:Cyclohexanes / Q000494:pharmacology*; D052244:Endocrine Disruptors / Q000494:pharmacology*; D005411:Flame Retardants / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009154:Mutation; D011471:Prostatic Neoplasms / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000728:Androgens; D003510:Cyclohexanes; D052244:Endocrine Disruptors; D005411:Flame Retardants; D011944:Receptors, Androgen; C517232:1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane
keywords: Endocrine disrupting compounds; Nuclear localization; Receptor; Steroid hormone