Retinoic acids promote the action of aromatase and 17beta-hydroxysteroid dehydrogenase type 1 on the biosynthesis of 17beta-estradiol in placental cells

Abstract

The biosynthesis of 17 -estradiol (E 2 ) in human placenta involves the actions of aromatase and 17 -hydroxysteroid dehydrogenase type 1 (17HSD1). Aromatase, an enzyme complex comprised of P450aromatase (P450arom) and NADH-cytochrome P450 reductase, converts androgens to estrogens, whereas 17HSD1 catalyzes the reduction of estrone to E 2 .In the present study, the effects of retinoic acids (RAs) on P450arom and 17HSD1 expression in placental cells were investigated. Treatment with all-trans-RA (at-RA) or 9cis-RA increased E 2 production in JEG-3 choriocarcinoma cells and cytotrophoblast (CTB) cells isolated from normal early placentas. Meanwhile, the activity of aromatase and expression of P450arom mRNA were induced by at-RA in JEG-3 cells. Northern blot analysis showed that the effect on P450arom mRNA expression occurs in a dose-and time-dependent fashion. Similar to at-RA and 9cis-RA, Ro40-6055, the retinoic acid receptor (RAR )-selective activator, increased the expression of P450arom and 17HSD1 mRNA in JEG-3 cells. On the other hand, Ro41-5253 (Ro41), the RAR -selective antagonist, blocked the stimulatory effect of RAs on P450arom expression. Surprisingly, Ro41 induced the activity and mRNA expression of 17HSD1 in JEG-3 cells, which is in contrast to the expected inhibitory effect and, moreover, remarkably potentiated the induction by at-RA and 9cis-RA. However, reporter gene analysis revealed that the influence of Ro41 on the transcription of the HSD17B1 gene, which encodes 17HSD1, is considerably milder in JEG-3 cells, and it only additively enhanced the effect of at-RA. Finally, it was found that at-RA and 9cis-RA increased the expression of P450arom and 17HSD1 mRNA in CTB cells, but to a lesser extent.The data suggest that RAs may play a role in promoting the biosynthesis of E 2 in the placenta. In addition, Ro41 has divergent effects on gene expression in JEG-3 cells.

Expression of P450 aromatase and 17β-hydroxysteroid dehydrogenase type 1 at fetal–maternal interface during tubal pregnancy

“…Our recent study clearly showed that P450arom and 17HSD1 are expressed in cultured CT cells isolated from normal human placenta of the first trimester [18]. In the cell culture system of the above investigation, VCT cells counted for the major portion of the cell population, because only the tips of chorionic villi were collected for the purification of CT cells.…”

“…In addition, 17HSD1 was immunolocalized in invasive CT cells of full-term placenta [17]. Our recent study demonstrated that cultured CT cells purified from first-trimester placenta express both P450arom and 17HSD1 and are capable of converting dehydroepiandrosterone and A-dione to E 2 [18]. However, it is not clear whether these two steroidogenic enzymes are present in various CT cells of early placenta in vivo.…”

HSD17B1 expression enhances estrogen signaling stimulated by the low active estrone, evidenced by an estrogen responsive element-driven reporter gene in vivo

“…HSD17B1 is expressed in the syncytiotrophoblast cells of the placenta [22][23][24] and ovarian granulosa cells [23,25,26], and both of these cell types are involved in de novo estrogen biosynthesis. Similarly to P450 aromatase (CYP19A1), the expression of HSD17B1 is related to follicular differentiation and positively correlates with the follicular E2 concentration.…”

Induction of A·T to G·C mutations by erroneous repair of depurinated DNA following estrogen treatment of the mammary gland of ACI rats

“…Increased biosynthesis of estrogens [estrone (E 1 ) and estradiol (E 2 )] and their oxidative metabolism to catechols and quinones in the breast have been associated with the induction of breast cancer [1][2][3][4]. Breast cells are continuously exposed to significant levels of estrogens, estimated at 50-400 pmol/g of breast tissue [5][6][7][8][9][10] and ∼2 mol/L in nipple fluid [11,12].…”