Identification of genes expressed in the rat prostate that are modulated differently by castration and Finasteride treatment

Abstract

In mammals, testosterone and 5 -dihydrotestosterone (DHT) are the principal male hormones (androgens). Testosterone is the most abundant circulating androgen, and is converted in specific tissues to DHT by the 5 -reductase enzymes. Although each of these androgens binds to the same receptor protein (androgen receptor, AR), each exerts biologically distinct effects. Theories to explain the specific effects of testosterone and DHT have centered on kinetic differences of binding of androgens to the receptor or differences in the metabolic fates of the two hormones. In the current experiments, differential display PCR (ddPCR) was used to identify genes regulated differently by testosterone and DHT. Adult male rats were treated as follows: castrated, treated with Finasteride (an inhibitor of 5 -reductase) or left intact for ten days. RNA was prepared from the dissected prostates of these animals and used for ddPCR. Genes exhibiting four distinct patterns of regulation were observed among the mRNAs.Class 1 genes showed equivalent expression in intact and Finasteride-treated animals, but were absent in castrated animals (mRNAs D1, D2, D6, D10). Class 2 genes showed higher expression in intact animals, intermediate levels following Finasteride treatment, but were absent in castrated animals (mRNA D8). Two classes of gene were particularly intriguing: class 3 showed gene expression only in the intact animal (mRNA D7, D9) and class 4 showed increased gene expression following Finasteride treatment (mRNA D3). While the patterns observed for some of these genes (e.g. D8) suggest that the different biological effects of testosterone and DHT may be due to the lower affinity of the AR for testosterone and limiting tissue concentrations of androgen, our results also suggest that some genes expressed in the rat prostate may be regulated in fundamentally different ways in response to testosterone and DHT.

Testosterone-Dependent Interaction between Androgen Receptor and Aryl Hydrocarbon Receptor Induces Liver Receptor Homolog 1 Expression in Rat Granulosa Cells

“…This is supported by crystallographic studies showing nearly identical interactions of T and DHT with the AR ligand-binding pocket (15). However, the effects of T and DHT on gene expression are not always equivalent, as they differentially regulate the expression of a subset of AR target genes in the prostate (38)(39)(40) and the ovaries (5,15,20,41). The mechanisms of the differential response of ovarian granulosa cells to T or DHT have not been previously examined.…”

Effects of dihydrotestosterone on adipose tissue measured by serial analysis of gene expression

“…On the other hand, DHT had no significant effect on either WHR or triacylglycerol uptake . Differential display PCR has already shown that testosterone and DHT have different effects on prostate gene expression (Avila et al 1998). The different and sometimes opposite actions of testosterone and DHT may indicate that testosterone effects are mediated by a compound created via the aromatization process (Jensen 2000).…”

Effects of 5α-dihydrotestosterone on expression of genes related to steroidogenesis and spermatogenesis during the sex determination and differentiation periods of the pejerrey, Odontesthes bonariensis

“…Although 5α-dihydrotestosterone (5α-DHT) is the most important androgen in tetrapod males (Avila et al, 1998), in teleost fish the 11-oxygenated androgens are considered as the more potent androgenic steroids (Borg, 1994;Kime, 1993;Lokman et al, 2002), and the general assumption has been that 5α-DHT had no major physiological role in this vertebrate group (Borg, 1994;Cavaco et al, 1998) until Margiotta-Casaluci et al (2013a reported high plasma levels in adult fathead minnow, Pimephales promelas. In the same species, exposure to 200 ng/L of 5α-DHT showed an in vivo androgenic potency comparable to 11-ketotestosterone (11-KT).…”