title: Steroid receptor profiling of vinclozolin and its primary metabolites.
abstract: Several pesticides and fungicides commonly used to control agricultural and indoor pests are highly suspected to display endocrine-disrupting effects in animals and humans. Endocrine disruption is mainly caused by the interference of chemicals at the level of steroid receptors: it is now well known that many of these chemicals can display estrogenic effects and/or anti-androgenic effects, but much less is known about the interaction of these compounds with other steroid receptors. Vinclozolin, a dicarboximide fungicide, like its primary metabolites 2-[[(3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid (M1), and 3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide (M2), is known to bind androgen receptor (AR). Although vinclozolin and its metabolites were characterized as anti-androgens, relatively little is known about their effects on the function of the progesterone (PR), glucocorticoid (GR), mineralocorticoid (MR) or estrogen receptors (ERalpha and ERbeta). Objectives of the study were to determine the ability of vinclozolin and its two primary metabolites to activate AR, PR, GR, MR and ER. For this purpose, we used reporter cell lines bearing luciferase gene under the control of wild type or chimeric Gal4 fusion AR, PR, GR, MR or ERs. We confirmed that all three were antagonists for AR, whereas only M2 was found a partial agonist. Interestingly, M2 was also a PR, GR and MR antagonist (MR>>PR>GR) while vinclozolin was an MR and PR antagonist. Vinclozolin, M1 and M2 were agonists for both ERs with a lower affinity for ERbeta. Although the potencies of the fungicide and its metabolites are low when compared to natural ligands, their ability to act via more than one mechanism and the potential for additive or synergistic effect must be taken into consideration in the risk assessment process.
authors.affiliation: INSERM Unité 540, UMI, Endocrinologie Moléculaire et Cellulaire des Cancers, 60 rue de Navacelles, 34090 Montpellier, France.
authors.forename: José-Manuel
authors.initials: JM
authors.lastname: Molina-Molina
authors.forename: Anne
authors.initials: A
authors.lastname: Hillenweck
authors.forename: Isabelle
authors.initials: I
authors.lastname: Jouanin
authors.forename: Daniel
authors.initials: D
authors.lastname: Zalko
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Cravedi
authors.forename: Mariana-Fátima
authors.initials: MF
authors.lastname: Fernández
authors.forename: Arnaud
authors.initials: A
authors.lastname: Pillon
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Nicolas
authors.forename: Nicolás
authors.initials: N
authors.lastname: Olea
authors.forename: Patrick
authors.initials: P
authors.lastname: Balaguer
mesh_terms: D000450:Aldosterone / Q000494:pharmacology; D000726:Androgen Antagonists / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D000813:Anilides / Q000737:chemistry / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D002219:Carbamates / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D015741:Metribolone / Q000494:pharmacology; D000451:Mineralocorticoid Receptor Antagonists; D010080:Oxazoles / Q000378:metabolism / Q000494:pharmacology*; D045167:Progesterone Congeners / Q000494:pharmacology; D011397:Promegestone / Q000494:pharmacology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045165:Testosterone Congeners / Q000494:pharmacology; D014316:Tritium
chemical_list: D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000813:Anilides; D002219:Carbamates; D000451:Mineralocorticoid Receptor Antagonists; D010080:Oxazoles; D045167:Progesterone Congeners; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D011980:Receptors, Progesterone; D011987:Receptors, Steroid; D045165:Testosterone Congeners; D014316:Tritium; C101851:2-(((3,5-dichlorophenyl)carbamoyl)oxy)-2-methyl-3-butenoic acid; D015741:Metribolone; D000450:Aldosterone; D004958:Estradiol; D003907:Dexamethasone; D011397:Promegestone; D008156:Luciferases; C025643:vinclozolin; C101850:3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide