Endoplasmic reticulum stress mediating downregulated StAR and 3-beta-HSD and low plasma testosterone caused by hypoxia is attenuated by CPU86017-RS and nifedipine

Adult male Sprague-Dawley rats were randomly divided into control, hypoxia for 28 days, and hypoxia treated (mg/kg, p.o.) during the last 14 days with nifedipine (Nif, 10) and three doses of RS (20, 40, 80), and normal rats treated with RS isomer (80). Serum testosterone (T) and luteinizing hormone (LH) were measured. The testicular expressions of biomarkers including StAR, 3-beta-HSD, immunoglobulin heavy chain binding protein (Bip), double-strand RNA-activated protein kinase-like ER kinase (PERK) and pro-apoptotic transcription factor C/EBP homologous protein (CHOP) were measured.In hypoxic rats, serum testosterone levels decreased and mRNA and protein expressions of the testosterone biosynthesis related genes, StAR and 3-beta-HSD were downregulated. These changes were linked to an increase in oxidants and upregulated ER stress chaperones: Bip, PERK, CHOP and distorted histological structure of the seminiferous tubules in the testis. These abnormalities were attenuated significantly by CPU86017-RS and nifedipine.Downregulated StAR and 3-beta-HSD significantly contribute to low testosterone in hypoxic rats and is associated with ER stress which mediates testis damage caused by oxygen deprivation. CPU86017-RS is potential in ameliorating hypoxia-induced testicular injuries, possibly by its calcium antagonist effects on the testis.Male hypogonadism is defined as low serum testosterone under 300 ng/dL that has been considered as one of the major concerns in the modern society [1]. Regarding the possible mechanisms underlying, oxidative stress in the testis serves as the main causal factor actively involved in the pathogenesis of male hypogonadism [2]. Among various etiologies, hypoxia causes oxygen deprivation in the testis contributing to reduced production of androgen, in which a combination with pro-inflammatory factors including ET-1 (endothelin -1), leptin and ROS in initiating testicular abnormalities is likely involved [3]. Oxygen deprivation induces a series o