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Profiles of 5α-Reduced Androgens in Humans and Eels: 5α-Dihydrotestosterone and 11-Ketodihydrotestosterone Are Active Androgens Produced in Eel Gonads.

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.

SUBMITTER: Yazawa T

PROVIDER: S-EPMC8021924 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:To better assess the impact of contaminants on fish reproduction, it is increasingly important to collect data at multiple levels of biological organization. However, a challenge in ecotoxicology is that three of the most commonly measured reproductive endpoints; gonad histology, ex vivo steroid production, and gene expression, can be difficult to obtain in small-bodied fish (e.g. zebrafish, Japanese medaka, fathead minnow) due to limited tissue availability. Using 5α-dihydrotestosterone (DHT) as a test compound, the objectives of the current study were to assess the feasibility of measuring gene expression in tissues also used for ex vivo steroid production studies. A portion of the testes was also used for qualitative histological examination. Male mummichog were exposed to 0, 5, and 50 µg/L DHT for 21 days. Following the exposure, testes were collected and separated into three pieces for histology, ex vivo incubation to measure steroidogenic capacity [Testosterone(T), 17β-estradiol (E2), 11-ketotestosterone (11KT)] and gene expression analyses. Testis RNA at time of dissection and testis RNA at end of ex vivo incubation (18 h) was collected and assessed for RNA integrity. The expression of genes coding for estrogen receptor βa (esrba) and estrogen receptor βb (esrbb) as well as the key steroidogenic genes, steroidogenic acute regulatory protein (star), P450 side chain cleavage (p450scc) and 11β-hydroxysteroid dehydrogenase (hsd11b3) were assessed in testis before and after ex vivo incubation. There were no significant differences in RNA quality between the two time points, however the expression of esrba, esrbb and p450scc was significantly lower post-incubation, although star, hsd11b3, and all four reference gene expression levels remained unchanged over time. DHT did not affect the expression of any of the measured genes at either concentration. Histological examination showed that all fish contained mature testes dominated by spermatozoa and spermatids. DHT did not affect T production but significantly decreased 11KT production in the high treatment group. This suggests a role for DHT in androgen regulation, and has

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Profiles of 5α-Reduced Androgens in Humans and Eels: 5α-Dihydrotestosterone and 11-Ketodihydrotestosterone Are Active Androgens Produced in Eel Gonads.

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