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Expression Signatures for a Model Androgen and Antiandrogen in the Fathead Minnow Pimephales promelas Ovary
Citation:
GARCIA-REYERO, N., D. L. VILLENEUVE, K. J. KROLL, L. LIU, E. ORLANDO, K. WATANABE, M. SEPULVEDA, G. T. ANKLEY, AND N. DENSLOW. Expression Signatures for a Model Androgen and Antiandrogen in the Fathead Minnow Pimephales promelas Ovary. ENVIRONMENTAL SCIENCE & TECHNOLOGY. American Chemical Society, Washington, DC, 43(7):2614-2619, (2009).
Impact/Purpose:
Trenbolone and flutamide are prototypical model compounds for, respectively, androgen and antiandrogen modes of action. Trenbolone is an anabolic steroid used in cattle industry to increase weight gain and feed efficiency, and flutamide is a pharmaceutical used to treat prostate cancer. Androgens exert profound effects on the organization, development, and function of the male reproductive system through activation of androgen receptors (ARs). Flutamide, as an antiandrogen, was expected to temper the effects of trenbolone on AR-mediated gene expression. Female fathead minnows (Pimephales promelas) were exposed for 48 hr to trenbolone, flutamide or a mixture of trenbolone and flutamide. Gene expression on ovaries was assessed using a 22,000-gene microarray. Trenbolone significantly changed the expression of roughly 750 different genes, while flutamide changed the expression of 1420 genes. Most of the genes that were regulated were distinct for the two chemicals. However, 70 genes were reciprocally regulated by the two treatments. Myelocytomatosis viral oncogene homolog (Myc), Yin Yang 1 (YY1) and interferon regulator factor 1 (IRF1) were among the transcription factors reciprocally regulated by trenbolone and flutamide, suggesting they may be specifically regulated by the AR. These regulatory molecules, in conjunction with other reciprocally regulated transcription factors, may function as early molecular switches to control phenotypic changes in gonad tissue architecture and function. Regulation of gene expression by the antiandrogen flutamide is not simply to reverse the expression of genes induced by androgens, but instead alters additional molecular pathways.
Description:
Trenbolone and flutamide are prototypical model compounds for respectively androgen and antiandrogen modes of action. Trenbolone is an anabolic steroid used in cattle industry to increase weight gain and feed efficiency, and flutamide is a pharmaceutical used to treat prostate cancer. Androgens exert profound effects on the organization, development, and function of the male reproductive system through activation of androgen receptors (ARs). Flutamide, as an antiandrogen, was expected to temper the effects of trenbolone on AR-mediated gene expression. Female fathead minnows (Pimephales promelas) were exposed for 48 hr to 0.05, 0.5 or 5 µg 17â-trenbolone/L; 50, 150 or 500 µg flutamide/L; or to a mixture of 0.5 ìg/L trenbolone and 500 ìg/L flutamide in the water. Gene expression in the ovaries was analyzed using a fathead minnow-specific 22,000-gene microarray. Trenbolone significantly changed the expression (P < 0.05) of roughly 750 different genes, while flutamide changed the expression of 1420 genes. Most of the genes that were regulated were distinct for the two chemicals. However, 70 genes were reciprocally regulated by the two treatments. Myelocytomatosis viral oncogene homolog (Myc), Yin Yang 1 (YY1) and interferon regulator factor 1 (IRF1) were among the transcription factors reciprocally regulated by trenbolone and flutamide, suggesting they may be specifically regulated by the AR. These regulatory molecules, in conjunction with other reciprocally regulated transcription factors, may function as early molecular switches to control phenotypic changes in gonad tissue architecture and function. Regulation of gene expression by the antiandrogen flutamide is not simply to reverse the expression of genes induced by androgens, but instead alters additional molecular pathways. androgen, antiandrogen, gene expression, trenbolone, flutamide, microarray, fish