ToxSci Advance Access originally published online on April 9, 2007
Toxicological Sciences 2007 98(1):87-98; doi:10.1093/toxsci/kfm079
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dysgenesis and Histological Changes of Genitals and Perturbations of Gene Expression in Male Rats after In Utero Exposure to Antiandrogen Mixtures
* Department of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, DK-2860 Søborg, Denmark; and
The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom
1 To whom correspondence should be addressed. Fax: +45-72347001. E-mail: ulh{at}food.dtu.dk.
Received January 26, 2007; accepted March 12, 2007
 |
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.
Key Words: mixtures; androgen receptor antagonist; vinclozolin; flutamide; procymidone; developmental toxicity; gene expression; rat; endocrine disrupters.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. Taxvig, U. Hass, M. Axelstad, M. Dalgaard, J. Boberg, H. R. Andeasen, and A. M. Vinggaard Endocrine-Disrupting Activities In Vivo of the Fungicides Tebuconazole and Epoxiconazole Toxicol. Sci., December 1, 2007; 100(2): 464 - 473. [Abstract] [Full Text] [PDF]
|
|