Transcriptional Interference Between Glucocorticoid Receptor and Estradiol Receptor Mediates the Inhibitory Effect of Cortisol on Fish Vitellogenesis1

Abstract

In oviparous species, the synthesis of vitellogenin (Vg) takes place in the liver according to a strictly estrogen-dependent mechanism that first involves an up-regulation of the estrogen receptor (ER) by its own ligand. However, reports from the literature indicate that in trout stress or cortisol may cause a reduction of cytosolic E2-binding sites in the liver and a decrease in plasma Vg levels. To investigate the mechanisms underlying these effects, in vivo and in vitro experiments were designed in rainbow trout (Oncorhynchus mykiss). The results demonstrate that cortisol implanted into maturing females caused a marked decrease of rainbow trout ER (rtER) and rainbow trout Vg (rtVg) mRNA levels in the liver. In vitro experiments on hepatocyte aggregates also showed that dexamethasone (Dex) caused a strong decrease in the basal and E2-stimulated rtER mRNA and to a lesser extent rtVg mRNA. These effects were specific as no other hormones were able to mimic the inhibitory action of Dex. A study of rtER mRNA stability indicated that the effects of glucocorticoids are likely to take place at the transcriptional level. This was further indicated by transfection experiments in CHO-K(1) cells, which showed that rainbow trout glucocorticoid receptor (rtGR) strongly inhibited the E2-stimulated transcriptional activity of the rtER promoter. Taken together, these results indicate that the rtGR exerts a transcriptional interference on the expression of the rtER that may explain some of the negative effects of stress or cortisol on vitellogenesis.

Hepatic transcriptome response to glucocorticoid receptor activation in rainbow trout

“…Although cortisol inhibited hepatic ER but not Vtg mRNA abundance in the present study, it is unclear whether this was GR specific, as RU486 also reduced ER transcript levels in trout. This agrees with results from another trout study demonstrating that RU486 did not inhibit the cortisol-mediated downregulation of ER (28). Indeed, vitelline envelope protein (a constituent of extracellular envelope around the growing oocyte) transcript levels, which are regulated by ER signaling (53), were also downregulated by cortisol and RU486.…”

“…Vtg synthesis occurs in liver in response to ER activation by estradiol-17␤ in fish (16). Cortisol was shown to inhibit hepatic ER and Vtg expression, leading to impaired vitellogenesis in salmonids (28). Although cortisol inhibited hepatic ER but not Vtg mRNA abundance in the present study, it is unclear whether this was GR specific, as RU486 also reduced ER transcript levels in trout.…”

Expression profiling of skeletal muscle in young bulls treated with steroidal growth promoters

“…Therefore, IGF-1 and myostatin pathways might represent a first level of interaction between Dex and Estr, with the two hormones having opposite effects on such signaling pathways. GCs and estrogens have also been reported to act in opposition in the regulation of several physiological processes, both in vitro (e.g., 84,66) and in vivo (e.g., 33,58). Cross talk between GCs and estrogens appears to occur at several different levels.…”

Effects of a glucocorticoid receptor agonist, dexamethasone, on fathead minnow reproduction, growth, and development

“…Furthermore, it has been demonstrated in trout that activation of the glucocorticoid receptor by cortisol interferes with the ability of estradiol to stimulate transcription from the estrogen receptor, leading to decreased plasma vitellogenin levels [21]. Finally, studies have shown that glucocorticoid receptors and estrogen receptors are coexpressed in fish brain and pituitary [19,21]. Taken together, this information indicates a potential for interactions between the hypothalamus-pituitary-interrenal and the hypothalamus-pituitary-gonadal axes.…”

“…Therefore, information derived from studies examining the effects of cortisol and other stressors led to the hypothesis that synthetic glucocorticoids, such as dexamethasone, may have detrimental effects on teleost fish reproduction. Furthermore, it has been demonstrated in trout that activation of the glucocorticoid receptor by cortisol interferes with the ability of estradiol to stimulate transcription from the estrogen receptor, leading to decreased plasma vitellogenin levels [21]. Finally, studies have shown that glucocorticoid receptors and estrogen receptors are coexpressed in fish brain and pituitary [19,21].…”