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ToxSci Advance Access published online on March 19, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp056
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

STANDARD AND MOLECULAR NOAELS FOR RAT TESTICULAR TOXICITY INDUCED BY FLUTAMIDE

David Rouquié, Claire Friry-Santini, Frédéric Schorsch, Helen Tinwell and Rémi Bars

Bayer CropScience, Research Toxicology, Sophia-Antipolis, France

Corresponding author: David Rouquié, Bayer CropScience, 355 rue Dostoïevski, 06903 Sophia-Antipolis, France, E-mail: david.rouquie{at}bayercropscience.com, Tel: 33 (0)4 92 94 34 00, Fax: 33 (0)4 93 95 84 54

Received December 17, 2008; revision received March 4, 2009; accepted March 4, 2009


  Abstract

An important step in the safety assessment of chemicals for humans is to determine the No Observed Adverse Effect Level (NOAEL) in toxicity studies conducted in animal models. With the increasing use of molecular tools in toxicity studies a question often posed is how a NOAEL derived from molecular data compares to NOAEL established using standard methods. The objective of the present study was to address this question when considering testicular toxicity. To do this we assessed the effects of the reference antiandrogen flutamide on rat testis in a standard 28-day toxicity study using doses of 0.04 to 150 mg/kg/day. At necropsy, blood samples were collected for testosterone measurements. The testes were collected for histopathological assessment as well as for the evaluation of gene expression changes using qPCR analyses. Results showed that increases in plasma testosterone level and Leydig cell hyperplasia were detected from 6 mg/kg/day. An alteration in the level of accumulation of a selection of genes was also detected from 6 mg/kg/day. This was the case for genes functionally associated with the testicular lesion, such as lipid metabolism, cell death/cell proliferation as well as for genes not functionally associated with the lesion. Contrary to the misgivings, these data show that, using a standard 28-day toxicity study and a well characterized adverse effect, the NOAEL based on transcript changes is similar to the NOAELs based on testosterone levels and histopathological examination.

Key Words: Antiandrogen; Flutamide; Toxicogenomics; NOAEL; Dose response.


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