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Abstract
BackgroundICI 182,780 (ICI) belongs to a new class of antiestrogens developed to be pure estrogen antagonists and, in addition to its therapeutic use, it has been used to knock-out estrogen and estrogen receptor (ER) actions in several mammalian species. In the present study, the effects and mechanism of action of ICI were investigated in the teleost fish, sea bream (Sparus auratus).MethodsThree independent in vivo experiments were performed in which mature male tilapia (Oreochromis mossambicus) or sea bream received intra-peritoneal implants containing estradiol-17 beta (E2), ICI or a combination of both compounds. The effects of E2 and ICI on plasma calcium levels were measured and hepatic and testicular gene expression of the three ER subtypes, ER alpha, ER beta a and ER beta b, and the estrogen-responsive genes, vitellogenin II and choriogenin L, were analyzed by semi-quantitative RT-PCR in sea bream.ResultsE2 treatment caused an increase in calcium levels in tilapia, while ICI alone had no noticeable effect, as expected. However, pretreatment with ICI synergistically potentiated the effect of E2 on plasma calcium in both species. ICI mimicked some E2 actions in gene expression in sea bream liver upregulating ER alpha, vitellogenin II and choriogenin L, although, unlike E2, it did not downregulate ER beta a and ER beta b. In contrast, no effects of E2 or ICI alone were detected in the expression of ERs in testis, while vitellogenin II and choriogenin L were upregulated by E2 but not ICI. Finally, pretreatment with ICI had a synergistic effect on the hepatic E2 down-regulation of ER beta b, but apparently blocked the ER alpha up-regulation by E2.ConclusionThese results demonstrate that ICI has agonistic effects on several typical estrogenic responses in fish, but its actions are tissue-specific. The mechanisms for the ICI agonistic activity are still unknown; although the ICI induced up-regulation of ER alpha mRNA could be one of the factors contributing to the cellular response.
Highlights
ICI 182,780 (ICI) belongs to a new class of antiestrogens developed to be pure estrogen antagonists and, in addition to its therapeutic use, it has been used to knock-out estrogen and estrogen receptor (ER) actions in several mammalian species
Calcium and gene expression response to E2 and/or ICI 182,780 treatment in sea bream Since in the first experiment conducted in tilapia 10 and 35 mg ICI provoked a rise in calcium of similar magnitude after three days of E2 exposure, 10 mg/kg ICI and 10 mg/ kg E2 treatments were used to investigate their short-term effects (28 h) on gene expression in sea bream
Treatment with ICI caused a significant up-regulation in ERα, vitellogenin II (VgII) and choriogenin L (ChgL), which was of the same magnitude to that of E2 treatment in the case of ERα but significantly less in the case of VgII and ChgL (1.8- and 2.5-fold increase, respectively, compared to control)
Summary
ICI 182,780 (ICI) belongs to a new class of antiestrogens developed to be pure estrogen antagonists and, in addition to its therapeutic use, it has been used to knock-out estrogen and estrogen receptor (ER) actions in several mammalian species. There is substantial evidence that estrogens function via non-classical mechanisms [1] These include indirect transcriptional activation through interaction of ligand-bound ER with other transcription factors, ER ligand-independent activation in response to intracellular signaling cascades, and rapid non-genomic actions initiated at the plasma membrane. It is not clear if these are mediated by a subset of nuclear ERs that localize to the plasma membrane, or by novel membrane receptors unrelated to ER or through both [1,6,7]
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