Melatonin administration during sexual maturation: influence on adult prostate histophysiology and protective role against damages caused by experimental diabetes

Author(s)

Marina Guimarães Gobbo

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2015-05-26

Examining board members

Rejane Maira Góes; Valéria Helena Alves Cagnon; Valdecir Farias Ximenes; Maria Christina Werneck de Avellar; Sérgio Luis Felisbino

• Advisor: Rejane Maira Góes

Abstract

The prostate response to diabetes in rodents includes atrophy, impairment of secretory activity, imbalance in epithelial kinetics, extracellular matrix remodeling and morphofuncional changes of stromal cells. These alterations are associated to the drop of androgen levels and insulin scarcity. However, the effects of prolonged hyperglycemia, which leads to oxidative stress, cannot be neglected. Melatonin (MLT) has antitumor and antioxidant actions. Diabetic individuals have a malfunction of MLT synthesis. This investigation aimed to examine if MLT treatment to rats since prepubertal period until adulthood affects ventral prostate maturation and the effects of prolonged administration of this hormone in the gland. The protective action of MLT on alterations caused by short- and long-term diabetes was also analyzed. MLT was provided in drinking water (10 ?g/kg b.w./day) since 5th week of age until the end of experiment. Diabetes was induced by streptozotocin (STZ, 40mg/kg b.w., ip) in 13 weeks old rats. The rats were euthanized with 14 (one-week diabetes) or 21 weeks old (two months diabetes). The results of the above experimental design (8 groups/N =10) were divided in 3 chapters. In the first chapter, the activity of catalase (CAT), gluthatione S-transferase (GST) and glutathione peroxidase (GPx) and lipid peroxidation levels were assessed in prostate, testis and epidydimis. Prostate antioxidant system was the most vulnerable to diabetic condition, in which there was an increase of GPx and GST (p = 0.0186) activities at short-term, and CAT and GST (p ? 0.001) at long-term. MLT normalized the enzymatic disorders in prostate, proving its antioxidant property even at low dosage. In the second chapter, the effects of MLT in prostate maturation and injuries caused by experimental diabetes were studied regarding cell proliferation, apoptosis and androgen receptor expression (AR). This neurohormone decreased by 10% frequency of the epithelial AR-positive cells in healthy rats at early adult life. The treatment with MLT to long-term diabetic rats decreased the apoptotic index and increased the cell proliferation, and this was due to the normalization of circulating testosterone levels found in these animals. The in vitro effect of MLT on androgen-dependent (22Rv1), independent (PC3) tumor cells and human epithelial cells (PNTA1) under normal (NC) and hyperglycemic (HG) conditions were evaluated. 22Rv1 cells were the most sensitive to MLT. This hormone diminished the mitosis of 22Rv1 and PNTA1 after short pre-incubation in hyperglycemic medium. Similar to the long-term diabetic animals, MLT favored the survival of PC3 cells in hyperglycemic condition. In the third chapter, we investigated if STZ-induced diabetes favors the establishment of malignant and pre-malignant lesions in prostate. The effectiveness of MLT in avoiding these histopathological alterations in diabetic animals and if its ingestion by healthy rats affects the epithelial and stromal compartiments were evaluated. MLT was more influent in prostatic histology when administered during puberty. This treatment attenuated the atrophy of epithelium and smooth muscle cells, restored the collagen distribution and reduced the incidence of high-grade intraepithelial neoplasia (PIN), prostatitis and proliferative inflammatory atrophy (PIA). Meanwhile, low doses of MLT did not preclude the occurrence of microinvasive carcinoma. The STZ-induced diabetes allows the assessment of tumor incidence and progression under hyperglycemic conditions, but the secondary effects of STZ cannot be discarded, as the increase of DNA methylation found in diabetic animals (AU)

• FAPESP's process: 11/19467-0 - Melatonin administration during sexual maturation: influence on adult prostate histophysiology and protective role against damages caused by experimental diabetes
• Grantee: Marina Guimarães Gobbo
• Support Opportunities: Scholarships in Brazil - Doctorate