Pathological lesions and global DNA methylation in rat prostate under streptozotocin‐induced diabetes and melatonin supplementation

Abstract

Chronic hyperglycemia increases production of reactive oxygen species, which favors carcinogenesis. The association between diabetes and prostate cancer is controversial. Melatonin has antioxidant, anti-inflammatory, and antiproliferative properties. We investigated whether low doses of melatonin prevent the tissue alterations caused by diabetes and alter prostate histology of healthy rats. We also investigated whether experimental diabetes promoted the development of pathological lesions in the ventral prostate of rats. Melatonin was provided in drinking water (10 μg/kg/day) from age 5 weeks until the end of experiment. Diabetes was induced at 13 weeks by administration of streptozotocin (40 mg/kg, ip). Rats were euthanized at 14 or 21 weeks. Histological and stereological analyses were carried out and the incidence and density of malignant and pre-malignant lesions were assessed. Immunohistochemical assays of α-actin, cell proliferation (PCNA), Bcl-2, glutathione S-transferase (GSTPI), and DNA methylation (5-methylcytidine) were performed. Melatonin did not elicit conspicuous changes in the prostate of healthy animals; in diabetic animals there was a higher incidence of atrophy (93%), microinvasive carcinoma (10%), proliferative inflammatory atrophy, PIA (13%), prostatitis (26%), and prostate intraepithelial neoplasia, PIN (20%) associated with an increase of 40% in global DNA methylation. Melatonin attenuated epithelial and smooth muscle cell (smc) atrophy, especially at short-term diabetes-and normalized incidence of PIN (11%), inflammatory cells infiltrates, prostatitis (0%) and PIA (0%) at long-term diabetes. MLT was effective in preventing inflammatory disorders and PIN under diabetic condition. Although MLT has antioxidant action, it did not influence DNA methylation and not avoid carcinogenesis at low doses.

A systematic review on the role of melatonin and its mechanisms on diabetes-related reproductive impairment in non-clinical studies

“…Many animal and human research studies have shown the anti-diabetic effect of melatonin and its leading role in reducing DM-related complications, including cardiomyopathy, nephropathy, retinopathy, and neuropathy ( 27 , 90 ). The present study demonstrated that melatonin administration could be associated with declining oxidative stress, blocking the apoptosis signaling pathway, modulating endoplasmic reticulum function, and reducing inflammation in various reproductive components ( 3 , 32 , 33 , 35 – 38 ). Also, according to most of the findings, melatonin can positively affect androgen levels in diabetic male subjects ( 31 , 36 , 37 , 41 ).…”

“…Moreover, DM caused various histological abnormalities indicated by the reduced absolute frequency of epithelium, thinner and interrupted smooth muscle cell (SMC) layers, increased apoptotic cells, neoplastic lesions, and metaplasia. Melatonin administration mainly improved the alterations above ( 37 , 38 ).…”

“…The results indicated decreased prostate weight in diabetic groups compared to the control group. Melatonin treatment reversed prostate weight to normal ( 37 , 38 ). Also, experimental DM caused elevation in GPx, CAT, GST, and MDA content balanced by melatonin treatment ( 37 ).…”

Melatonin ameliorates degenerative alterations caused by age in the rat prostate and mitigates high‐fat diet damages

“…Prostate tissue expresses both MTR1 and MTR2 receptors and variations in MLT levels can play a role in the gland physiology (Gilad et al, 1998). Studies from our research group reported that indole, even at lower doses (10 μg/kg/day), was effective to decrease prostate oxidative stress and the incidence of premalignant lesions under experimental diabetes (Gobbo et al, 2015, 2017). Furthermore, MLT antimitotic properties (Shiu et al, 2012; Tam et al, 2008; Tam & Shiu, 2011) were described for both PCa or its prevention, due to the decrease of cell proliferation through MTR1/protein kinase C, which leads to nuclear exclusion and the reduction of AR transcriptional activity (Rimler et al, 2002), induction of cell cycle arrest via p27 Kip1 (Tam et al, 2007, 2008) and the modulation of cell metabolism (Tamarindo et al, 2019).…”

“…Prostate tissue expresses both MTR1 and MTR2 receptors and variations in MLT levels can play a role in the gland physiology (Gilad et al, 1998). Studies from our research group reported that indole, even at lower doses (10 μg/kg/day), was effective to decrease prostate oxidative stress and the incidence of premalignant lesions under experimental diabetes (Gobbo et al, 2015(Gobbo et al, , 2017. Furthermore, MLT antimitotic…”