title: Cimetidine-induced Leydig cell apoptosis and reduced EG-VEGF (PK-1) immunoexpression in rats: Evidence for the testicular vasculature atrophy.
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 100mg/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, 17β-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 17β-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.
authors.affiliation: Department of Morphology and Genetics, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.
authors.forename: Flávia L
authors.initials: FL
authors.lastname: Beltrame
authors.affiliation: Department of Morphology, Laboratory of Histology and Embryology, Dental School - São Paulo State University (UNESP), Araraquara, SP, Brazil.
authors.forename: Paulo S
authors.initials: PS
authors.lastname: Cerri
authors.affiliation: Department of Morphology, Laboratory of Histology and Embryology, Dental School - São Paulo State University (UNESP), Araraquara, SP, Brazil. Electronic address: esasso@foar.unesp.br.
authors.forename: Estela
authors.initials: E
authors.lastname: Sasso-Cerri
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000818:Animals; D000897:Anti-Ulcer Agents / Q000633:toxicity*; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001284:Atrophy; D053148:Caspase 3 / Q000378:metabolism; D002927:Cimetidine / Q000633:toxicity*; D008297:Male; D046529:Microscopy, Electron, Transmission; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D013737:Testis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D013739:Testosterone / Q000097:blood; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / Q000378:metabolism; D000098902:CD163 Antigen
chemical_list: D000897:Anti-Ulcer Agents; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D011944:Receptors, Androgen; D011956:Receptors, Cell Surface; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived; D013739:Testosterone; D002927:Cimetidine; D015067:17-Hydroxysteroid Dehydrogenases; C505410:Casp3 protein, rat; D053148:Caspase 3
keywords: Antiandrogen; Cimetidine; H(2) receptor; Leydig cells; Testis; Testosterone