Effects of a 3beta-hydroxysteroid dehydrogenase inhibitor, trilostane, on the fathead minnow reproductive axis

Daniel L Villeneuve, Lindsey S Blake, Jeffrey D Brodin, Jenna E Cavallin, Elizabeth J Durhan, Kathleen M Jensen, Michael D Kahl, Elizabeth A Makynen, Dalma Martinovic, Nathaniel D Mueller, Gerald T Ankley
Toxicological Sciences: An Official Journal of the Society of Toxicology 2008, 104 (1): 113-23
A number of environmental contaminants and plant flavonoid compounds have been shown to inhibit the activity of 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4) isomerase (3beta-HSD). Because 3beta-HSD plays a critical role in steroid hormone synthesis, inhibition of 3beta-HSD represents a potentially important mode of endocrine disruption that may cause reproductive dysfunction in fish or other vertebrates. The objective of this study was to test the hypothesis that exposure to the model 3beta-HSD inhibitor, trilostane, would adversely affect reproductive success of the fathead minnow (Pimephales promelas). Results of in vitro experiments with fathead minnow ovary tissue demonstrated that trilostane inhibited 17beta-estradiol (E2) production in a concentration- and time-dependent manner, and that the effect was eliminated by providing a substrate (progesterone) that does not require 3beta-HSD activity for conversion to E2. Exposure of fish to trilostane caused a significant reduction in spawning frequency and reduced cumulative egg production over the course of the 21-day test. In females, exposure to 1500 mug trilostane/l reduced plasma vitellogenin concentrations, but did not cause significant histological alterations. In males, average trilostane concentrations as low as 50 mug/l significantly increased testis mass and gonadal somatic index. Trilostane exposure did not influence the abundance of mRNA transcripts coding for 3beta-HSD or other steroidogenesis-regulating proteins in males or females. As a whole, results of this study support the hypothesis that 3beta-HSD inhibition can cause reproductive dysfunction in fish, but did not yield a clear profile of responses at multiple levels of biological organization that could be used to diagnose this mode of action.

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