Abstract
The mechanisms and the mediators relaying Fsh action on testicular functions are poorly understood. Unlike in mammals, in fish both gonadotropins (Fsh and Lh) are able to efficiently stimulate steroidogenesis, likely through a direct interaction with their cognate receptors present on the Leydig cells. In this context, it is crucial to understand if Fsh effects are mediated through the production of steroids. To address this issue we performed transcriptome studies after in vitro incubations of rainbow trout testis explants in the presence of Fsh alone or in combination with trilostane, an inhibitor of Δ4- steroidogenesis.Trilostane significantly reduced or suppressed the response of many genes to Fsh (like wisp1, testis gapdhs, cldn11, inha, vt1 or dmrt1) showing that, in fish, important aspects of Fsh action follow indirect pathways and require the production of Δ4-steroids. What is more, most of the genes regulated by Fsh through steroid mediation were similarly regulated by Lh (and/or androgens). In contrast, the response to Fsh of other genes was not suppressed in the presence of trilostane. These latter included genes encoding for anti-mullerian hormone, midkine a (pleiotrophin related), angiopoietine-related protein, cyclins E1 and G1, hepatocyte growth factor activator, insulin-like growth factor 1b/3. A majority of those genes were preferentially regulated by Fsh, when compared to Lh, suggesting that specific regulatory effects of Fsh did not depend on steroid production. Finally, antagonistic effects between Fsh and steroids were found, in particular for genes encoding key factors of steroidogenesis (star, hsd3b1, cyp11b2-2) or for genes of the Igf system (igf1b/3). Our study provides the first clear evidence that, in fish, Fsh exerts Δ4-steroid-independent regulatory functions on many genes which are highly relevant for the onset of spermatogenesis.
Highlights
In vertebrates, reproductive function is under the control of multiple factors acting in a cascade of regulations known as the brain-pituitary-gonadal (BPG) axis.The male gonad is separated into two compartments, each with specific functions: the tubular compartment where spermatogenesis takes place to produce spermatozoa and the interstitial compartment which produces most of the steroids
This stimulating effect of Fsh and Lh is achieved through the up-regulation of genes encoding key players of steroid synthesis [10,11,12]. This particular feature can be explained by the expression of Lh receptors and Fsh receptors in the same interstitial cell type - probably Leydig cells - a situation described in an increasing number of primitive or evolutionarily advanced teleostean fish species like eel [13], African catfish [14], zebrafish [12], honeycomb grouper [15] and Senegalese sole [16]. This scheme ought to explain the potency of Fsh to stimulate steroidogenesis since we showed that Fsh was not able to activate the Lh receptor efficiently [17]
To address the issue of steroid-mediated action of Fsh on testicular transcriptome, we carried out in vitro culture of testis explants incubated in the presence of Fsh alone or in combination with trilostane (Fsh+Tri), a known inhibitor of the 3 betahydroxysteroid dehydrogenase
Summary
Reproductive function is under the control of multiple factors acting in a cascade of regulations known as the brain-pituitary-gonadal (BPG) axis. This stimulating effect of Fsh and Lh is achieved through the up-regulation of genes encoding key players of steroid synthesis [10,11,12] This particular feature can be explained by the expression of Lh receptors and Fsh receptors in the same interstitial cell type - probably Leydig cells - a situation described in an increasing number of primitive or evolutionarily advanced teleostean fish species like eel [13], African catfish [14], zebrafish [12], honeycomb grouper [15] and Senegalese sole [16]. We find that Fsh and steroids may have antagonistic regulatory effects, underlining the complex coordinated regulation of spermatogenesis by the different reproductive hormones
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