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

doi:10.1016/j.aquatox.2016.09.021

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

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Abstract

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 500 μg flutamide/L for 8 d, followed by an 8-d recovery period in clean water. Fish were sampled at 1, 2, 4 and 8 days during each phase of the experiment. Flutamide (500 μg/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 500 μg/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 50 μg 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.

Original language	English (US)
Pages (from-to)	164-172
Number of pages	9
Journal	Aquatic Toxicology
Volume	180
DOIs	https://doi.org/10.1016/j.aquatox.2016.09.021
State	Published - Nov 1 2016

Bibliographical note

Funding Information:
We thank Kellie Fay for helpful comments on an earlier draft of this paper. Funding for this work was provided in part by the US EPA Chemical Safety for Sustainability Research Program. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. The contents of this manuscript neither constitute, nor necessarily reflect US EPA policy.

Publisher Copyright:
© 2016

Keywords

Adverse outcome pathway
Androgen receptor
Antagonist
Fish
Flutamide
Reproduction

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Milsk, R., Cavallin, J. E., Durhan, E. J., Jensen, K. M., Kahl, M. D., Makynen, E. A., Martinović -Weigelt, D., Mueller, N., Schroeder, A., Villeneuve, D. L., & Ankley, G. T. (2016). A study of temporal effects of the model anti-androgen flutamide on components of the hypothalamic-pituitary-gonadal axis in adult fathead minnows. Aquatic Toxicology, 180, 164-172. https://doi.org/10.1016/j.aquatox.2016.09.021

Milsk, R, Cavallin, JE, Durhan, EJ, Jensen, KM, Kahl, MD, Makynen, EA, Martinović -Weigelt, D, Mueller, N, Schroeder, A, Villeneuve, DL & Ankley, GT 2016, 'A study of temporal effects of the model anti-androgen flutamide on components of the hypothalamic-pituitary-gonadal axis in adult fathead minnows', Aquatic Toxicology, vol. 180, pp. 164-172. https://doi.org/10.1016/j.aquatox.2016.09.021

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abstract = "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 500 μg flutamide/L for 8 d, followed by an 8-d recovery period in clean water. Fish were sampled at 1, 2, 4 and 8 days during each phase of the experiment. Flutamide (500 μg/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 500 μg/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 50 μg 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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AU - Schroeder, Anthony

AU - Villeneuve, Daniel L.

AU - Ankley, Gerald T.

N1 - Funding Information: We thank Kellie Fay for helpful comments on an earlier draft of this paper. Funding for this work was provided in part by the US EPA Chemical Safety for Sustainability Research Program. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. The contents of this manuscript neither constitute, nor necessarily reflect US EPA policy. Publisher Copyright: © 2016

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N2 - 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 500 μg flutamide/L for 8 d, followed by an 8-d recovery period in clean water. Fish were sampled at 1, 2, 4 and 8 days during each phase of the experiment. Flutamide (500 μg/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 500 μg/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 50 μg 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.

AB - 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 500 μg flutamide/L for 8 d, followed by an 8-d recovery period in clean water. Fish were sampled at 1, 2, 4 and 8 days during each phase of the experiment. Flutamide (500 μg/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 500 μg/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 50 μg 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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KW - Flutamide

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

Abstract

Bibliographical note

Keywords

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