Low dose evaluation of the antiandrogen flutamide following a Mode of Action approach

• Published in: Toxicology and applied pharmacology Vol. 289; no. 3; pp. 515 - 524
• Main Authors: Sarrabay, A., Hilmi, C., Tinwell, H., Schorsch, F., Pallardy, M., Bars, R., Rouquié, D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.12.2015
• Subjects: 60 APPLIED LIFE SCIENCES; Androgen Antagonists - pharmacology; ANIMAL TISSUES; Animals; ANTIANDROGENS; BLOOD; CELL PROLIFERATION; Dose-Response Relationship, Drug; DOSES; EVALUATION; Flutamide; Flutamide - pharmacology; Gene Expression - drug effects; Leydig cell hyperplasia; Leydig Cells - drug effects; Low-dose; Male; Mode of action; RATS; Rats, Wistar; Reproducibility of Results; TESTES; Testicular Diseases - blood; Testicular Diseases - genetics; TESTOSTERONE; Testosterone - blood; Threshold; TOXICITY; Low-dose; Flutamide; Leydig cell hyperplasia; Mode of action; Threshold
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2015.10.009

The dose–response characterization of endocrine mediated toxicity is an on-going debate which is controversial when exploring the nature of the dose–response curve and the effect at the low-end of the curve. To contribute to this debate we have assessed the effects of a wide range of dose levels of the antiandrogen flutamide (FLU) on 7-week male Wistar rats. FLU was administered by oral gavage at doses of 0, 0.001, 0.01, 0.1, 1 and 10mg/kg/day for 28days. To evaluate the reproducibility, the study was performed 3 times. The molecular initiating event (MIE; AR antagonism), the key events (LH increase, Leydig cell proliferation and hyperplasia increases) and associated events involved in the mode of action (MOA) of FLU induced testicular toxicity were characterized to address the dose response concordance. Results showed no effects at low doses (<0.1mg/kg/day) for the different key events studied. The histopathological changes (Leydig cell hyperplasia) observed at 1 and 10mg/kg/day were associated with an increase in steroidogenesis gene expression in the testis from 1mg/kg/day, as well as an increase in testosterone blood level at 10mg/kg/day. Each key event dose–response was in good concordance with the MOA of FLU on the testis. From the available results, only monotonic dose–response curves were observed for the MIE, the key events, associated events and in effects observed in other sex related tissues. All the results, so far, show that the reference endocrine disruptor FLU induces threshold effects in a standard 28-day toxicity study on adult male rats. •Dose–response characterization of endocrine mediated toxicity is an on-going debate.•A wide range of dose levels of flutamide was evaluated on young adult male rats.•Flutamide induces threshold effects using on standard and molecular tools.