ToxSci Advance Access originally published online on April 7, 2008
Toxicological Sciences 2008 104(1):113-123; doi:10.1093/toxsci/kfn073
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Published by Oxford University Press 2008.
Effects of a 3β-Hydroxysteroid Dehydrogenase Inhibitor, Trilostane, on the Fathead Minnow Reproductive Axis
Mid-Continent Ecology Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Office of Research and Development, 6201 Congdon Boulevard, Duluth, Minnesota 55804
1 To whom correspondence should be addressed. Fax: (218) 529-5003. E-mail: villeneuve.dan{at}epa.gov.
Received February 1, 2008; accepted March 31, 2008
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Abstract |
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A number of environmental contaminants and plant flavonoid compounds have been shown to inhibit the activity of 3β-hydroxysteroid dehydrogenase/
5-4 isomerase (3β-HSD). Because 3β-HSD plays a critical role in steroid hormone synthesis, inhibition of 3β-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 3β-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 17β-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 3β-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 µg trilostane/l reduced plasma vitellogenin concentrations, but did not cause significant histological alterations. In males, average trilostane concentrations as low as 50 µg/l significantly increased testis mass and gonadal somatic index. Trilostane exposure did not influence the abundance of mRNA transcripts coding for 3β-HSD or other steroidogenesis-regulating proteins in males or females. As a whole, results of this study support the hypothesis that 3β-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.
Key Words: fish; steroidogenesis; reproduction; gene expression; endocrine disruption.