title: Vinclozolin does not alter progesterone receptor (PR) function in vivo despite inhibition of PR binding by its metabolites in vitro.
abstract: Vinclozolin, a dicarboximide fungicide, alters morphological sex differentiation in male rats following perinatal exposure. The occurrence of these abnormalities correlates with the in vivo formation of two antiandrogenic metabolites of vinclozolin, (i.e. 2-[[(3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid (Mt) and 3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide (M2)), which are potent inhibitors of rat androgen receptor binding. As steroid hormone receptors exhibit promiscuity in their ability to bind different ligands, the present study evaluated the ability of these vinclozolin metabolites to bind to the estrogen (ER) and progesterone (PR) receptors in vitro, and to alter ER and PR function following in vivo exposure. To this end, in vitro ligand binding assays demonstrated that both M1 and M2 can compete with endogenous ligand for binding to the PR (Ki = 400 and 60 microM, respectively). In contrast, neither metabolite exhibited the ability to bind ER. Subsequent in vivo studies to evaluate the potential of vinclozolin to alter ER or PR function demonstrate that, (1) the estrogen-dependent increases in uterine weight and PR induction were not altered by vinclozolin; (2) the distribution of nuclear and cytosolic PR was not altered following short-term vinclozolin exposure; and (3) vinclozolin did not disrupt ovulation in cycling female rats. These studies indicate that although vinclozolin metabolites can compete for binding to the PR in vitro, concentrations of these metabolites do not reach sufficient levels to disrupt female reproductive function following short-term in vivo exposure to vinclozolin. In addition, these studies demonstrate the importance of correlating in vitro receptor binding data with in vivo studies in order to understand the physiological consequences of exposure to environmental toxicants.
authors.affiliation: Endocrinology Branch, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. slaws@herl45.herl.epa.gov
authors.forename: S C
authors.initials: SC
authors.lastname: Laws
authors.forename: S A
authors.initials: SA
authors.lastname: Carey
authors.forename: W R
authors.initials: WR
authors.lastname: Kelce
authors.forename: R L
authors.initials: RL
authors.lastname: Cooper
authors.forename: L E
authors.initials: LE
authors.lastname: Gray
mesh_terms: D000813:Anilides / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001667:Binding, Competitive; D002219:Carbamates / Q000378:metabolism / Q000633:toxicity; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005659:Fungicides, Industrial / Q000378:metabolism / Q000633:toxicity*; D066298:In Vitro Techniques; D007928:Lethal Dose 50; D008024:Ligands; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D010060:Ovulation / Q000187:drug effects; D010080:Oxazoles / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012733:Sex Differentiation / Q000187:drug effects; D012984:Software; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
chemical_list: D000813:Anilides; D002219:Carbamates; D005659:Fungicides, Industrial; D008024:Ligands; D010080:Oxazoles; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C101851:2-(((3,5-dichlorophenyl)carbamoyl)oxy)-2-methyl-3-butenoic acid; C025643:vinclozolin; C101850:3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide