Cimetidine-induced Leydig cell apoptosis and reduced EG-VEGF (PK-1) immunoexpression in rats: Evidence for the testicular vasculature atrophy

Author(s)

Beltrame, Flavia L. ^[1] ; Cerri, Paulo S. ^[2] ; Sasso-Cerri, Estela ^[2]

Affiliation

^[1] Fed Univ Sao Paulo UNIFESP, Dept Morphol & Genet, Sao Paulo, SP - Brazil

^[2] Sao Paulo State Univ UNESP, Sch Dent, Lab Histol & Embryol, Dept Morphol, Araraquara, SP - Brazil

• Document type: Journal article
• Source: REPRODUCTIVE TOXICOLOGY; v. 57, p. 50-58, NOV 2015.
• Web of Science Citations: 7

Abstract

The antiulcer drug cimetidine has shown to cause changes in the testicular microvasculature of adult rats. Since Leydig cells (LCs) produce the pro-angiogenic factor, EG-VEGF (endocrine gland-derived vascular endothelial growth factor), also known as prokineticin 1 (PK-1), this study examined the effect that cimetidine might have on LCs in testes with damaged vasculature. Rats received intraperitoneal injections of 100 mg/kg of cimetidine (cimetidine group) or saline vehicle (control group) for 50 days. Serum testosterone levels were measured by chemiluminescence immunoassay and testicular sections were subjected to TUNEL and immunohistochemical reactions for caspase-3, 17 beta-HSD6, CD163 (ED2 macrophage), PK-1 and androgen receptor (AR). LCs in the cimetidine group showed TUNEL and caspase-3 positive labeling and apoptotic ultrastructural features. Moreover, the presence of 17 beta-HSD6-positive inclusions inside macrophages and the reduced number of LCs, AR immunoreactivity and serum testosterone levels correlated with a decrease in either the number of PK-1-immunostained LCs or PK-1 immunoreactivity. Although it is not clear which cell type is the primary target of cimetidine in the testicular interstitial compartment, these findings support a direct link between cimetidine-induced testicular vascular atrophy and LCs damage. (C) 2015 Elsevier Inc. All rights reserved. (AU)

• FAPESP's process: 10/02409-5 - Histopathological evaluation of interstitial tissue in cimetidine-treated rats and role of vitamin B12 on the spermatogenic repair
• Grantee: Flávia Luciana Beltrame
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/25322-0 - Effect of cimetidine on the epididymal histoarchitecture and evaluation of sperm DNA of rats treated with cimetidine and supplemented with B12
• Grantee: Flávia Luciana Beltrame
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 12/23845-3 - Evaluation of Vitamin B12 effect on the mitotic and meiotic phases of spermatogenesis and in the sperm DNA of cimetidine-treated rats
• Grantee: Estela Sasso Cerri
• Support Opportunities: Regular Research Grants