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A Time-course Analysis of Effects of the Steroidogenesis Inhibitor Ketoconazole on Components of the Hypothalamic-pituitary-gonadal Axis of Fathead Minnows
Citation:
CAVALLIN, J. E., E. J. DURHAN, K. M. JENSEN, M. D. KAHL, E. A. MAKYNEN, L. M. THOMAS, L. C. WEHMAS, DAN VILLENEUVE, AND G. T. ANKLEY. A Time-course Analysis of Effects of the Steroidogenesis Inhibitor Ketoconazole on Components of the Hypothalamic-pituitary-gonadal Axis of Fathead Minnows . Presented at Society for Environmental Toxicology and Chemistry, Minneapolis, MN, March 20 - 21, 2012.
Impact/Purpose:
The objective of this study was to evaluate temporal effects of the model steroidogenesis inhibitor ketoconazole (KTC) on aspects of reproductive endocrine function controlled by the hypothalamic-pituitary-gonadal (HPG) axis in the fathead minnow (Pimephales promelas).
Description:
The objective of this study was to evaluate temporal effects of the model steroidogenesis inhibitor ketoconazole (KTC) on aspects of reproductive endocrine function controlled by the hypothalamic-pituitary-gonadal (HPG) axis in the fathead minnow (Pimephales promelas). Ketoconazole inhibits the activity of two cytochrome P450s (CYPs) key to sex steroid production in vertebrates, CYP11a and CYP17. Sexually-mature fish were exposed to KTC (30 or 300 ìg/L) for up to 8 d, following which animals were allowed to recover in clean water. Samples were collected after 1, 4 and 8 d of exposure, and after 1, 8 and 16 d of recovery. A shorter-term time-course experiment was conducted in which females were sampled on seven occasions during a 12-h KTC exposure. Ketoconazole depressed ex vivo gonadal synthesis of testosterone (T) in both sexes, and 17â-estradiol (E2) in females during exposure and recovery phases of the studies. Early in exposures plasma concentrations of T in males and E2 in females also were depressed by KTC exposure. The discrepancy between the ex vivo and in vivo data at later stages in the test is consistent with some type of compensatory response to KTC in fish. Although a number of genes related to steroid synthesis were up-regulated in male and female gonads during the exposure and early recovery phases of the experiment, this did not seem to account for the ability of KTC-exposed animals to maintain plasma steroid concentrations comparable to controls. Overall, our results demonstrate the complex, temporally-dynamic nature of the vertebrate HPG system in response to chemical stressors.