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Epigenetic mechanisms in the regulation of androgen receptor expression in the prostate


The prostatic differentiation, growth and function are androgen-dependent. The androgenic hormones (testosterone and dihydrotestosterone) exert their function via androgen receptor (AR). The androgen receptor acts as a transcription factor for genes associated with several aspects of male development. As a rule, estrogens have an anti-androgen effect, by down regulating the hypothalamus-hypophysis axis (HHA) and thus reducing the testosterone production by the testis. The presence of estrogen receptors in the prostate gland allows the assumption that 17--estradiol (E2) have direct effects on prostate physiology. In a recent article, we have demonstrated the existence of additive effects of local (via estrogen receptors) and systemic (via HHA) of E2 in the prostatic regression (Brazil. J. Med. Biol. Res. 38: 487, 2005). Neonatal exposure to E2 affects prostatic growth through a mechanism known as estrogen imprinting. This phenomenon is extremely important, since it may be activated by the exposure of newborns to E2 or xenoestrogens. One of the effects of the estrogen imprinting caused by high dose E2 is the negative regulation of AR expression and a reduced response to androgen reposition. Both these events seem to be largely responsible for the impaired prostatic growth. In this project we propose the investigation of the existence of epigenetic mechanism in the regulation of AR down regulation after neonatal estrogen exposure, trying to determine (1) variations in the level of DNA methylation in the AR gene promoter region; (2) changes in histone covalent modifications; (3) alterations in AR gene (and X chromosome) location in the nuclei of epithelial cells and (4) the induction of the above mentioned epigenetic markers after treatment of LNCaP cells with siRNA for the androgen receptor. Our expectation is that the execution of this project will contribute to the understanding of the estrogen effect on the prostatic biology, of the interactions between sex steroid hormones and of the regulation of the AR gene. (AU)

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(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
AUGUSTO, T. M.; BRUNI-CARDOSO, A.; DAMAS-SOUZA, D. M.; ZAMBUZZI, W. F.; KUEHNE, F.; LOURENCO, L. B.; FERREIRA, C. V.; CARVALHO, H. F.. Oestrogen imprinting causes nuclear changes in epithelial cells and overall inhibition of gene transcription and protein synthesis in rat ventral prostate. INTERNATIONAL JOURNAL OF ANDROLOGY, v. 33, n. 5, p. 675-685, . (05/02601-5)

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