Abstract
Sulfated steroid hormones are commonly considered to be biologically inactive metabolites, but may be reactivated by the steroid sulfatase into biologically active free steroids, thereby having regulatory function via nuclear androgen and estrogen receptors which are widespread in the testis. However, a prerequisite for this mode of action would be a carrier-mediated import of the hydrophilic steroid sulfate molecules into specific target cells in reproductive tissues such as the testis. In the present study we detected predominant expression of the Sodium-dependent Organic Anion Transporter (SOAT), the Organic Anion Transporting Polypeptide 6A1, and the Organic Solute Carrier Partner 1 in human testis biopsies. All of these showed significantly lower or even absent mRNA expression in severe disorders of spermatogenesis (arrest at the level of spermatocytes or spermatogonia, Sertoli cell only syndrome). Only SOAT was significantly lower expressed in biopsies showing hypospermatogenesis. By use of immunohistochemistry SOAT was localized to germ cells at various stages in human testis biopsies showing normal spermatogenesis. SOAT immunoreactivity was detected in zygotene primary spermatocytes of stage V, pachytene spermatocytes of all stages (I–V), secondary spermatocytes of stage VI, and round spermatids (step 1 and step 2) in stages I and II. Furthermore, SOAT transport function for steroid sulfates was analyzed with a novel liquid chromatography tandem mass spectrometry procedure capable of profiling steroid sulfate molecules from cell lysates. With this technique, the cellular inward-directed SOAT transport was verified for the established substrates dehydroepiandrosterone sulfate and estrone-3-sulfate. Additionally, β-estradiol-3-sulfate and androstenediol-3-sulfate were identified as novel SOAT substrates.
Highlights
Sulfated steroid hormones for long have been merely regarded as biologically inactive steroid metabolites
Further expression analyses in the human testis focused on Sodium-dependent Organic Anion Transporter (SOAT), OATP6A1 and Organic Solute Carrier Partner 1 (OSCP1)
Quantitative Expression Analysis in Testicular Biopsies The data from the tissue cDNA panels were further verified in testes biopsies showing intact normal spermatogenesis, which all showed very high expression levels for SOAT, OATP6A1 and OSCP1 (Fig. 2)
Summary
Sulfated steroid hormones for long have been merely regarded as biologically inactive steroid metabolites. StS has been identified as a valuable drug target for estrogen and androgen deprivation therapies in hormonal diseases [3]. In addition to the provision of steroid hormones by the secretory activity of a given cell or gland, a second system controlling the availability of biologically active steroids on the cellular level might be established due to the expression of StS and/or estrogen sulfotransferases in certain organs, like the testis [4], [5]. The primary targets of the androgens in the testis are Leydig cells, Sertoli cells and peritubular cells, due to their expression of androgen receptor (AR) [10]. Expression of ERa and ERb mRNA and protein was demonstrated in spermatogonia, primary spermatocytes (ERa) and Sertoli cells (ERb) in the boar [13], as well as ERa mRNA in spermatogonia and primary spermatocytes in human, dog, mouse and horse [14], for review see [15]
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