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

Journal Article · Tue Dec 15 04:00:00 EST 2015 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2015.10.009· OSTI ID:22687856

Sarrabay, A. ^[1]; Hilmi, C.; Tinwell, H.; Schorsch, F. ^[2]; Pallardy, M. ^[1]; Bars, R. ^[2]

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1. INSERM, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry (France)
2. Bayer SAS, 16, rue Jean Marie Leclair, 69009 Lyon (France)

ABSTRACT: 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 10 mg/kg/day for 28 days. 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 (< 0.1 mg/kg/day) for the different key events studied. The histopathological changes (Leydig cell hyperplasia) observed at 1 and 10 mg/kg/day were associated with an increase in steroidogenesis gene expression in the testis from 1 mg/kg/day, as well as an increase in testosterone blood level at 10 mg/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. - Highlights: • 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.

• OSTI ID: 22687856
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 289; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANIMAL TISSUES
ANTIANDROGENS
BLOOD
CELL PROLIFERATION
DOSES
EVALUATION
RATS
TESTES
TESTOSTERONE
TOXICITY