A study of temporal effects of the model anti-androgen flutamide on components of the hypothalamic-pituitary-gonadal axis in adult fathead minnows

Rebecca Milsk, Jenna E Cavallin, Elizabeth J Durhan, Kathleen M Jensen, Michael D Kahl, Elizabeth A Makynen, Dalma Martinović-Weigelt, Nathan Mueller, Anthony Schroeder, Daniel L Villeneuve, Gerald T Ankley
Aquatic Toxicology 2016, 180: 164-172
The aim of this study was to investigate temporal changes in the hypothalamic-pituitary-gonadal (HPG) axis of fathead minnows (Pimephales promelas) treated with the model androgen receptor (AR) antagonist flutamide. Reproductively-mature fish were exposed in a flow-through test to analytically-confirmed concentrations of either 50 or 500μg flutamide/L for 8 d, followed by an 8-d recovery period in clean water. Fish were sampled at 1, 2, 4 and 8days during each phase of the experiment. Flutamide (500μg/L) caused significant reductions in relative gonad size of the females on day 8 of the exposure and day 1 of the recovery, and reduced expression of secondary sex characteristics in males during the exposure phase of the experiment. Ex vivo gonadal synthesis of testosterone in both sexes (and 17β-estradiol in females) was reduced in the 500μg/L treatment within 2 d of exposure; however, steroid synthesis returned to levels comparable to controls by the end of the exposure portion of the test. Ex vivo testosterone synthesis in males exposed to 50μg flutamide/L was greater than in controls on days 4 and 8 of the exposure. Both the enhanced steroid production in the low treatment males, and return to control levels in the high treatment males and females during chemical exposure are indicative of a compensatory HPG response. One contributor to this response could be increased expression of genes responsible for enzymes involved in steroid synthesis; for example, transcripts for both cytochrome P450 side- chain cleavage and 11β-hydroxysteroid dehydrogenase were significantly elevated in flutamide-exposed males. Overall, responses of the HPG axis in adult male and female fathead minnows exposed to flutamide were both dynamic and comparatively rapid during exposure and recovery. These observations have ramifications both for the development of short-term fish assays to detect endocrine-active chemicals, and the derivation of robust adverse outcome pathways for AR antagonists in fish.

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