Temporal evaluation of effects of a model 3β-hydroxysteroid dehydrogenase inhibitor on endocrine function in the...

Inhibition of enzymes involved in the synthesis of sex steroids can substantially impact developmental and reproductive processes controlled by the hypothalmic-pituitary-gonadal (HPG) axis. A key steroidogenic enzyme that has received little attention from a toxicological perspective is 3β-hydroxysteroid dehydrogenase (3β-HSD). In these studies, we exposed reproductively-active fathead minnows (Pimephales promelas) to the model 3β-HSD inhibitor trilostane at two test concentrations (300 and 1,500 µg/L) over a 16-d period that included both 8-d exposure and 8-d recovery phases. Plasma concentrations of 17β-estradiol (E2) in females were depressed within hours of exposure to the drug and remained decreased at the highest trilostane concentration throughout the 8-d exposure. Reductions in E2 were accompanied by decreases in plasma concentrations of the estrogen-responsive protein vitellogenin (VTG). During the recovery phase of the test, plasma E2 and VTG concentrations returned to levels comparable to those of controls, in the case of E2 within 1 d. Up-regulation of ovarian expression of gene products for follicle-stimulating hormone receptor (fshr) and aromatase (cyp19a1a) suggested active compensation in trilostane-exposed animals. Effects of trilostane on HPG-related endpoints in exposed males were less pronounced, although, as in females, up-regulation of gonadal fshr was seen. Data from these time-course studies provide insights as to direct impacts, compensatory responses, and recovery from effects associated with perturbation of a comparatively poorly characterized enzyme/pathway critical to sex steroid synthesis. This information is important to the design and interpretation of approaches for assessing the occurrence and effects of HPG-active chemicals in both the laboratory and the field.