Transgenic Male Mice Expressing Human Hydroxysteroid Dehydrogenase 2 Indicate a Role for the Enzyme Independent of Its Action on Sex Steroids

Abstract

Hydroxysteroid (17beta) dehydrogenase 2 (HSD17B2) has been shown to inactivate both estrogens and androgens and activate 20alpha-hydroxyprogesterone to progesterone. In the present study, we generated transgenic (TG) mice ubiquitously expressing human HSD17B2. The TG mice produced showed growth retardation and delayed eye opening at the postnatal age. Disrupted spermatogenesis was evident in the presence of normal serum and intratesticular testosterone, progesterone, and normal circulating LH concentrations. A proper androgen action in the target tissues was confirmed by normal histological appearance of the prostate and epididymis. Furthermore, quantitative RT-PCR analysis indicated only a slight decrease in androgen-dependent gene expression in the prostate. The disrupted spermatogenesis was not associated with increased germ cell apoptosis as analyzed by caspase-3 activation. However, it resulted in infertility in the HSD17B2 TG males after the age of 3 months, and at the age of 6 months the seminiferous tubules showed a Sertoli cell-only phenotype. The data indicate that the growth retardation and disrupted spermatogenesis are not due to a lack of proper estrogen or androgen action. Interestingly, the testicular phenotype and some of the other phenotypic changes described are typically observed in mice with reduced action of retinoic acid signaling. This, together with the rescue of the testis phenotype by a synthetic retinoic acid receptor agonist (4-[(E)-2-(5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthalenyl)-1-propenyl] benzoic acid), suggests a role for HSD17B2 in the action of retinoids, in addition to its oxidative HSD17B activity on sex steroids.

The diversity of sex steroid action: novel functions of hydroxysteroid (17β) dehydrogenases as revealed by genetically modified mouse models

“…Interestingly, the embryonic deaths of the HSD17B2KO mice occur at the time when there is a shift in the Hsd17b2 expression from the maternal to the foetal part of placenta and manifestation of the Hsd17b2 expression in the foetus. Similar to those identified in the TG mice expressing hHSD17B2 (Zhongyi et al 2007), certain phenotypic alterations in the HSD17B2KO mice closely resembled those identified in mice with altered RA metabolism (Cohlan 1953, Lohnes et al 1994, Gaemers et al 1998a. Thus, the defects in the placenta development in the HSD17B2KO mice might be due to simultaneously altered actions of RA and sex steroids.…”

“…The bi-TG mice showed features of both HSD17B1TG and HSD17B2TG mice, while the phenotypes observed in the single TG mice were not efficiently rescued in the bi-TG. The female bi-TG mice were masculinised similar to the HSD17B1TG mice (Saloniemi et al 2007), but were growth retarded at prepubertal and young adult age, and had extensive lobulo-alveolar development similar to the HSD17B2TG mice (Zhongyi et al 2007, Shen et al 2009). Furthermore, the bi-TG females did not present with vaginal opening, while they showed improper separation of vagina and urethra, suppressed nipple development and ovarian benign serous cystadenomas, similar to that previously reported for HSD17B1TG females.…”

“…In addition, studies have shown that retinoic acid (RA) induces expression of HSD17B2 in a dose-and time-dependent manner in human endometrial epithelial (Cheng et al 2008) and placental cells (Su et al 2007). In order to test the activity of hHSD17B2 in vivo, we generated TG mice ubiquitously expressing the enzyme under the chicken b-actin promoter (Zhongyi et al 2007). In these mice, the conversion of E 2 to E 1 was followed in vivo by injecting tritium-labelled E 2 into the mice, and a significantly increased oxidative HSD17B activity was detected in the TG mice compared with WT mice.…”

“…HSD17B2TG mice In HSD17B2TG male mice, there were certain phenotypes that prompted us to seek for phenotypes that are not directly known to be related to altered sex steroid action, including a delayed eye opening and growth retardation (Zhongyi et al 2007). In addition, we have previously found a lack of correlation between HSD17B2 expression and the hormonal status in female rat (Akinola et al 1997).…”

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

“…2). 17b-HSD2 also activates 20a-progesterone to form progesterone but may also be involved in the oxidation of retinoids (Zhongyi et al 2007). 17b-HSD3 (HSD17B3; Fig.…”