title: Neonatal exposure to high doses of 17β-estradiol results in inhibition of heparanase-1 expression in the adult prostate.
abstract: Heparanase-1 (HPSE-1) is an endoglycosidase that cleaves heparan sulfate. The physiological functions of HPSE-1 include embryo development, hair growth, wound healing, tumor growth, angiogenesis, metastasis, and inflammation. HPSE-1 expression was found to increase temporarily in the rat ventral prostate (VP) after castration. The promoter region of the Hpse-1 gene has estrogen-responsive elements, suggesting that the gene is regulated by estrogens. In this study, we investigated the expression of HPSE-1 in the VP of 90-day-old rats after neonatal exposure to a high dose of 17β-estradiol. HPSE-1 was not found by immunohistochemistry in the epithelium of estrogenized animals. To determine whether inhibition of Hpse-1 expression in the epithelium was due to pre- or post-transcriptional regulation, epithelial cells were isolated by centrifugation in Percoll gradient and the presence of Hpse-1 mRNA was investigated by RT-PCR. Hpse-1 mRNA was not detected in the estrogenized animals. Considering that Hpse-1 transcription could be inhibited by DNA methylation, we used the methylation-sensitive restriction enzyme HpaII and PCR to show that a single CCGG site at position +185 was more frequently methylated in the epithelium of estrogenized than in control animals. Immunohistochemistry for 5-methylcytidine revealed that the epithelial cell nuclei in estrogenized animals were heavily methylated. These results suggest that Hpse-1 expression was blocked in the epithelial cells of the VP, by estrogen imprinting by a pre-transcriptional mechanism involving DNA methylation.
authors: Department of Anatomy, Cell Biology, Physiology and Biophysics, Institute of Biology State University of Campinas, SP, Brazil.
authors: Taize M
authors: TM
authors: Augusto
authors: Rafaela
authors: R
authors: Rosa-Ribeiro
authors: Hernandes F
authors: HF
authors: Carvalho
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019175:DNA Methylation / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D018392:Genomic Imprinting / Q000187:drug effects; D008297:Male; D011133:Polysaccharide-Lyases / Q000037:antagonists & inhibitors*; D011467:Prostate / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D004967:Estrogens; D012333:RNA, Messenger; D004958:Estradiol; D011133:Polysaccharide-Lyases; C083872:heparatinase I