Low dose evaluation of the antiandrogen flutamide following a Mode of Action approach.
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 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 (<0.1mg/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.
INSERM, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France; UniverSud, INSERM, UMR-996 "Inflammation, Chemokines and Immunopathology", Châtenay-Malabry, France; Bayer SAS, 16, rue Jean Marie Leclair, 69009 Lyon, France.
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Sarrabay
Bayer SAS, 16, rue Jean Marie Leclair, 69009 Lyon, France.
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Hilmi
Bayer SAS, 16, rue Jean Marie Leclair, 69009 Lyon, France.
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Tinwell
Bayer SAS, 16, rue Jean Marie Leclair, 69009 Lyon, France.
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Schorsch
INSERM, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France; UniverSud, INSERM, UMR-996 "Inflammation, Chemokines and Immunopathology", Châtenay-Malabry, France.
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Pallardy
Bayer SAS, 16, rue Jean Marie Leclair, 69009 Lyon, France.
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Bars
Bayer SAS, 16, rue Jean Marie Leclair, 69009 Lyon, France. Electronic address: david.rouquie@bayer.com.
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Rouquié
D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005485:Flutamide / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D007985:Leydig Cells / Q000187:drug effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D013733:Testicular Diseases / Q000097:blood / Q000235:genetics; D013739:Testosterone / Q000097:blood
D000726:Androgen Antagonists; D013739:Testosterone; D005485:Flutamide
Flutamide; Leydig cell hyperplasia; Low-dose; Mode of action; Threshold