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Gene expression profiles revealing the mechanisms of anti-androgen- and estrogen-induced feminization in fish
Filby, A.L.; Thorpe, K.L.; Maack, G.; Tyler, C.R. (2007). Gene expression profiles revealing the mechanisms of anti-androgen- and estrogen-induced feminization in fish. Aquat. Toxicol. 81(2): 219-231. dx.doi.org/10.1016/j.aquatox.2006.12.003
In: Aquatic Toxicology. Elsevier Science: Tokyo; New York; London; Amsterdam. ISSN 0166-445X, more
Peer reviewed article  

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Keywords
    Fish; Gene expression; Marine

Authors  Top 
  • Filby, A.L.
  • Thorpe, K.L.
  • Maack, G.
  • Tyler, C.R.

Abstract
    Environmental anti-androgens are increasingly being recognized as potential contributing factors in the chemically induced feminization of wild fish because, by blocking androgen action, they can produce phenotypic effects similar to environmental estrogens. The molecular mechanisms by which anti-androgens and estrogens exert feminizing effects, however, have not been systematically compared. Using a targeted approach, we profiled the expression responses of a suite of 22 genes involved in reproduction, growth and development (processes controlled by androgens and estrogens) in the liver and gonad in adult male and female fathead minnow (Pimephales promelas) exposed to the model anti-androgen flutamide and the model synthetic estrogen 17α-ethinylestradiol (EE2). Both flutamide (320 μg/L) and EE2 (10 ng/L) produced phenotypic effects indicative of feminization (induction of plasma vitellogenin, reduced gonadosomatic index, and reduced secondary sex characters), although for the chosen test concentrations EE2 was the more potent. For the genes studied, flutamide and EE2 produced distinct expression profiles, suggesting that they largely operate via distinct molecular mechanisms. As examples, in liver EE2 (but not flutamide) exposure up-regulated estrogen receptor (ER) α mRNA, whereas flutamide exposure increased ERβ and ERγ mRNAs in males and resulted in decreased androgen receptor (AR) mRNA in females. In the testis, flutamide up-regulated genes coding for enzymes involved in androgen biosynthesis (cytochrome P450 17 [CYP17] and 11β-hydroxysteroid dehydrogenase [11β-HSD]) implying an inhibitory action on androgen negative feedback pathways. EE2, in contrast, inhibited the expression of enzymes involved in androgen biosynthesis (CYP17, 11β-HSD and 17β-hydroxysteroid dehydrogenase [17β-HSD]). There were also some commonalities in the molecular mechanisms of flutamide and EE2 action, including the down-regulation of gonadal sex steroid receptor expression (gonadal AR and ovarian ERα), increased expression of genes coding for estrogen-producing enzymes (cytochrome P450 19A and B [CYP19A and CYP19B]), decreased expression of genes involved in testis differentiation (anti-Mullerian hormone [AMH] and doublesex and mab-3 related transcription factor 1 [DMRT1]), and decreased expression of hepatic genes which mediate wider physiological processes such as somatic growth (growth hormone [GH], GH receptor [GHR], insulin-like growth factor-I [IGF-I], IGF-I receptor [IGF-IR], thyroid hormone receptor α [TRα] and β [TRβ]).

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