title: Environmental gestagens activate fathead minnow (Pimephales promelas) nuclear progesterone and androgen receptors in vitro.
abstract: Gestagen is a collective term for endogenous and synthetic progesterone receptor (PR) ligands. In teleost fishes, 17α,20β-dihydroxy-4-pregnen-3-one (DHP) and 17α,20β,21-trihydroxy-4-pregnen-3-one (20β-S) are the predominant progestogens, whereas in other vertebrates the major progestogen is progesterone (P4). Progestins are components of human contraceptives and hormone replacement pharmaceuticals and, with P4, can enter the environment and alter fish and amphibian reproductive health. In this study, our primary objectives were to clone the fathead minnow (FHM) nuclear PR (nPR), to develop an in vitro assay for FHM nPR transactivation, and to screen eight gestagens for their ability to transactivate FHM nPR. We also investigated the ability of these gestagens to transactivate FHM androgen receptor (AR). Fish progestogens activated FHM nPR, with DHP being more potent than 20β-S. The progestin drospirenone and P4 transactivated the FHM nPR, whereas five progestins and P4 transactivated FHM AR, all at environmentally relevant concentrations. Progestins are designed to activate human PR, but older generation progestins have unwanted androgenic side effects in humans. In FHMs, several progestins proved to be strong agonists of AR. Here, we present the first mechanistic evidence that environmental gestagens can activate FHM nPR and AR, suggesting that gestagens may affect phenotype through nPR- and AR-mediated pathways.
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland , College Park, Maryland 20742, United States.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Ellestad
authors.forename: Mary
authors.initials: M
authors.lastname: Cardon
authors.forename: Ian G
authors.initials: IG
authors.lastname: Chambers
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Farmer
authors.forename: Phillip
authors.initials: P
authors.lastname: Hartig
authors.forename: Kyle
authors.initials: K
authors.lastname: Stevens
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Villeneuve
authors.forename: Vickie
authors.initials: V
authors.lastname: Wilson
authors.forename: Edward F
authors.initials: EF
authors.lastname: Orlando
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D003530:Cyprinidae / Q000378:metabolism*; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D011372:Progestins / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D012727:Sex Characteristics
chemical_list: D004785:Environmental Pollutants; D011372:Progestins; D012333:RNA, Messenger; D011944:Receptors, Androgen; D011980:Receptors, Progesterone