title: Dysgenesis and histological changes of genitals and perturbations of gene expression in male rats after in utero exposure to antiandrogen mixtures.
abstract: We investigated the ability of a mixture of three androgen receptor antagonists to induce disruption of male sexual differentiation after perinatal exposure. The aim was to assess whether the joint effects of vinclozolin, flutamide, and procymidone can be predicted based on dose-response data of the individual chemicals. Chemicals were administered orally to pregnant Wistar rats from gestational day 7 to postnatal day 16. Changes in reproductive organ weights and of androgen-regulated gene expression in prostates from male rat pups were chosen as end points for extensive dose-response studies. With all end points, the joint effects of the three antiandrogens were dose additive. Histological evaluations showed that dysgenesis and hypoplasia of prostates, seminal vesicles, and epididymis were seen with the highest mixture doses. No changes were observed in any single-compound low-dose group for these lesions, nor were there histopathological changes in the testes. Pronounced dysgenesis of external genitals was observed with all doses of the mixture, and severe dysgenesis was seen with a mixture for which the individual compounds caused no effects. A combination of doses of each chemical that on its own did not produce significant reductions in the weights of seminal vesicles and PBP C3 expression induced a marked mixture effect. Thus, antiandrogens cause additive effects on end points of various molecular complexities such as alterations at the morphological and the molecular level. Exposure to antiandrogens, which appears to exert only small effects when judged on a chemical-by-chemical basis, may induce marked responses in concert with, possibly unrecognized, similarly acting chemicals.
authors.affiliation: Department of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, DK-2860 Søborg, Denmark.
authors.forename: Stine Broeng
authors.initials: SB
authors.lastname: Metzdorff
authors.forename: Majken
authors.initials: M
authors.lastname: Dalgaard
authors.forename: Sofie
authors.initials: S
authors.lastname: Christiansen
authors.forename: Marta
authors.initials: M
authors.lastname: Axelstad
authors.forename: Ulla
authors.initials: U
authors.lastname: Hass
authors.forename: Maria Kristina
authors.initials: MK
authors.lastname: Kiersgaard
authors.forename: Martin
authors.initials: M
authors.lastname: Scholze
authors.forename: Andreas
authors.initials: A
authors.lastname: Kortenkamp
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Vinggaard
mesh_terms: D000465:Algorithms; D000726:Androgen Antagonists / Q000633:toxicity*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000633:toxicity; D023381:Endpoint Determination; D005260:Female; D005485:Flutamide / Q000633:toxicity; D015870:Gene Expression / Q000187:drug effects*; D005837:Genitalia, Male / Q000002:abnormalities* / Q000473:pathology*; D006128:Growth / Q000187:drug effects; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000726:Androgen Antagonists; D001643:Bridged Bicyclo Compounds; D005485:Flutamide; C035988:procymidone