Evaluation of the antiandrogenic effects of flutamide, DDE, and linuron in the weanling rat assay using organ weight, histopathological, and proteomic approaches.
The Organization for Economic Cooperation and Development (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, 1,1-dichloro-2,2-bis(4 chlorophenyl)ethane (DDE) and linuron (LIN), 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 LIN. 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.
Tinwell
Helen
H
Department of Research Toxicology, Bayer CropScience, 06903 Sophia-Antipolis, France. helen.tinwell@bayercropscience.com
Friry-Santini
Claire
C
Rouquié
David
D
Belluco
Sara
S
Elies
Laetitia
L
Pallen
Catherine
C
Bars
Remi
R
D000311:Adrenal Glands / Q000187:drug effects; D000726:Androgen Antagonists / Q000633:toxicity*; D000818:Animals; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003633:Dichlorodiphenyl Dichloroethylene / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000633:toxicity*; D004822:Epididymis / Q000187:drug effects; D005485:Flutamide / Q000633:toxicity*; D005837:Genitalia, Male / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000187:drug effects; D050830:L-Amino Acid Oxidase / Q000378:metabolism; D008044:Linuron / Q000633:toxicity*; D008099:Liver / Q000187:drug effects; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000187:drug effects; D040901:Proteomics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012669:Seminal Vesicles / Q000187:drug effects; D013737:Testis / Q000187:drug effects; D043343:Testosterone Propionate / Q000494:pharmacology; D013997:Time Factors; D018675:Toxicity Tests / Q000379:methods*; D014886:Weaning
D000726:Androgen Antagonists; D054316:Biomarkers, Pharmacological; D052244:Endocrine Disruptors; D008044:Linuron; D003633:Dichlorodiphenyl Dichloroethylene; D005485:Flutamide; D050830:L-Amino Acid Oxidase; D043343:Testosterone Propionate