Abstract
Although 11-ketotestosterone (11KT) and testosterone (T) are major androgens in both teleosts and humans, their 5α-reduced derivatives produced by steroid 5α-reductase (SRD5A/srd5a), i.e., 11-ketodihydrotestosterone (11KDHT) and 5α-dihydrotestosterone (DHT), remains poorly characterized, especially in teleosts. In this study, we compared the presence and production of DHT and 11KDHT in Japanese eels and humans. Plasma 11KT concentrations were similar in both male and female eels, whereas T levels were much higher in females. In accordance with the levels of their precursors, 11KDHT levels did not show sexual dimorphism, whereas DHT levels were much higher in females. It is noteworthy that plasma DHT levels in female eels were higher than those in men. In addition, plasma 11KDHT was undetectable in both sexes in humans, despite the presence of 11KT. Three srd5a genes (srd5a1, srd5a2a and srd5a2b) were cloned from eel gonads. All three srd5a genes were expressed in the ovary, whereas only both srd5a2 genes were expressed in the testis. Human SRD5A1 was expressed in testis, ovary and adrenal, whereas SRD5A2 was expressed only in testis. Human SRD5A1, SRD5A2 and both eel srd5a2 isoforms catalyzed the conversion of T and 11KT into DHT and 11KDHT, respectively, whereas only eel srd5a1 converted T into DHT. DHT and 11KDHT activated eel androgen receptor (ar)α-mediated transactivation as similar fashion to T and 11KT. In contrast, human AR and eel arβ were activated by DHT and11KDHT more strongly than T and 11KT. These results indicate that in teleosts, DHT and 11KDHT may be important 5α-reduced androgens produced in the gonads. In contrast, DHT is the only major 5α-reduced androgens in healthy humans.
Highlights
Androgens are sex steroid hormones that play a role in various physiological processes via pathways involving the androgen receptor (AR) [1]
Consistent with the results of their precursors, 11KDHT levels were similar between the two sexes, whereas DHT was at much higher concentration in females
The sexual dimorphism of plasma DHT and T levels is reversed between humans and eels
Summary
Androgens are sex steroid hormones that play a role in various physiological processes via pathways involving the androgen receptor (AR) [1]. Testosterone (T) is the most important androgen in various animal species. It is produced from cholesterol in a series of steps by cytochrome P450 hydroxylases and hydroxysteroid dehydrogenases (HSDs) (Figure 1) [2, 3]. Among the five human SRD5A genes, SRD5A1 and SRD5A2 play important roles in DHT production in gonads and peripheral tissues. SRD5A1 mainly plays roles in the production of neurosteroids involved in anxiety and sexual behavior [4]. It has activity in conversion of T into DHT, to a lesser extent than that of SRD5A2 [9]. Srd5a1 KO mice showed the abnormalities in these behaviors [10,11,12], and partial feminization of the male skeleton [13]
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