title: Differential ligand selectivity of androgen receptors α and β from Murray-Darling rainbowfish (Melanotaenia fluviatilis).
abstract: Androgen receptors (ARs) mediate the physiological effects of androgens in vertebrates. In fishes, AR-mediated pathways can be modulated by aquatic contaminants, resulting in the masculinisation of female fish or diminished secondary sex characteristics in males. The Murray-Darling rainbowfish (Melanotaenia fluviatilis) is a small-bodied freshwater teleost used in Australia as a test species for environmental toxicology research. We determined concentration-response profiles for selected agonists and antagonists of rainbowfish ARα and ARβ using transient transactivation assays. For both ARα and ARβ, the order of potency of natural agonists was 11-ketotestosterone (11-KT)>5α-dihydrotestosterone>testosterone>androstenedione. Methyltestosterone was a highly potent agonist of both receptors relative to 11-KT. The relative potency of the veterinary growth-promoting androgen, 17β-trenbolone, varied by more than a factor of 5 between ARα and ARβ. The non-steroidal anti-androgen bicalutamide exhibited high inhibitory potency relative to the structurally related model anti-androgen, flutamide. The inhibitory potency of the agricultural fungicide, vinclozolin, was approximately 1.7-fold relative to flutamide for ARα, but over 20-fold in the case of ARβ. Fluorescent protein tagging of ARs showed that the rainbowfish ARα subtype is constitutively localised to the nucleus, while ARβ is cytoplasmic in the absence of ligand, an observation which agrees with the reported subcellular localisation of AR subtypes from other teleost species. Collectively, these data suggest that M. fluviatilis ARα and ARβ respond differently to environmental AR modulators and that in vivo sensitivity to contaminants may depend on the tissue distribution of the AR subtypes at the time of exposure.
authors: Land and Water Flagship, Commonwealth Scientific and Industrial Research Organisation, PMB 2, Glen Osmond, South Australia 5064, Australia. Electronic address: peter.bain@csiro.au.
authors: Peter A
authors: PA
authors: Bain
authors: Division of Molecular Environmental Endocrinology, National Institute for Basic Biology, Nishigonaka-38 Myodaijicho, Okazaki, Aichi Prefecture 444-0867, Japan.
authors: Yukiko
authors: Y
authors: Ogino
authors: Division of Molecular Environmental Endocrinology, National Institute for Basic Biology, Nishigonaka-38 Myodaijicho, Okazaki, Aichi Prefecture 444-0867, Japan.
authors: Shinichi
authors: S
authors: Miyagawa
authors: Division of Molecular Environmental Endocrinology, National Institute for Basic Biology, Nishigonaka-38 Myodaijicho, Okazaki, Aichi Prefecture 444-0867, Japan.
authors: Taisen
authors: T
authors: Iguchi
authors: Land and Water Flagship, Commonwealth Scientific and Industrial Research Organisation, PMB 2, Glen Osmond, South Australia 5064, Australia.
authors: Anupama
authors: A
authors: Kumar
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000378:metabolism; D000818:Animals; D001315:Australia; D005260:Female; D005399:Fishes / Q000378:metabolism*; D008297:Male; D008856:Microscopy, Fluorescence; D010080:Oxazoles / Q000494:pharmacology; D010802:Phylogeny; D020033:Protein Isoforms; D011944:Receptors, Androgen / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity; D015533:Transcriptional Activation; D014204:Trenbolone Acetate / Q000494:pharmacology; D014770:Virilism
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; D010080:Oxazoles; D020033:Protein Isoforms; D011944:Receptors, Androgen; C025643:vinclozolin; D014204:Trenbolone Acetate
keywords: Androgen receptor; Anti-androgens; Environmental endocrine disruptors; Fish; Teleosts