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ToxSci Advance Access published online on August 8, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm208
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Evaluation of the Antiandrogenic Effects of Flutamide, DDE and Linuron in the Weanling Rat Assay Using Organ Weight, Histopathological and Proteomic Approaches

Helen Tinwell*, Claire Friry-Santini, David Rouquié, Sara Belluco, Laetitia Elies, Catherine Pallen and Remi Bars

Bayer CropScience, Research Toxicology, Sophia Antipolis, France

* To whom correspondence should be addressed at Bayer CropScience SA, 355 rue Dostoïevski, BP 153, 06903 Sophia-Antipolis Cedex, France. Fax: 33(0)4-93-95-84-54. E-mail: helen.tinwell{at}bayercropscience.com

Received June 4, 2007; revision received July 26, 2007; accepted July 26, 2007


  Abstract

The OECD is currently funding the validation of the Hershberger assay as a rapid in vivo means of identifying (anti)-androgens. However, as the assay measures weight changes in the androgen-sensitive tissues of castrated rats, the evaluation of the androgen-stimulated intact weanling as a more ethical model to use in the assay has been requested. As part of the OECD validation exercise two weak antiandrogens, DDE and linuron, were investigated in our laboratory at several dose levels in the testosterone propionate (TP) stimulated weanling using flutamide (FM) as a positive control. In addition to weight measurements (sex accessory tissues [SATs], epididymides and testes), histopathological assessment of the seminal vesicles, prostate and testes was conducted for vehicle control, TP-stimulated and TP-stimulated animals treated with FM or the top dose level of DDE or linuron. The modulation of a novel prostate protein associated with apoptosis, L-amino acid oxidase (LAO), was evaluated in these same treatment groups. Our gravimetric data (supported by the histopathology data), indicated that the weanling assay can detect SAT and epididymal weight changes induced by the antiandrogens evaluated. Inconsistent and variable data were recorded for the testicular weight and histopathological effects suggesting that the testis is of little value in the identification of antiandrogens using this model. Three isoforms of LAO were identified and all were regulated by TP. Modulation of LAO by the antiandrogens indicated that this protein could be a biomarker for endocrine disruption in male rodents.

Key Words: antiandrogens; stimulated weanling; Hershberger; L-amino acid oxidase.


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