ToxSci Advance Access first published online on April 7, 2008
This version published online on April 11, 2008
Toxicological Sciences, 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
US Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, 6201 Congdon Blvd, Duluth, MN, 55804, USA
* Corresponding author, Address same as above, T: 218-529-5217, F: 218-529-5003. e-mail: villeneuve.dan{at}epa.gov.
Received February 1, 2008; revision received March 11, 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 d 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.