Assessment of the effects of subchronic exposure to bupropion and/or rosuvastatin on reproductive parameters in adult rats

• Grant number: 16/20722-9
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): March 06, 2017
• Effective date (End): September 03, 2017
• Field of knowledge: Health Sciences - Pharmacy - Toxicological Analysis
• Principal Investigator: Wilma de Grava Kempinas
• Grantee: Patrícia Villela e Silva
• Supervisor: Gary Robert Klinefelter
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
• Research place: United States Environmental Protection Agency, Research Triangle Park (EPA), United States
• Associated to the scholarship: 14/15566-2 - Effects of subchronic and prolonged exposure to sibutramine and/or rosuvastatin on reproductive parameters and fertility of adult male Wistar rats, BP.DR

Abstract

Obesity is a public health problem that is growing worldwide in recent years. This disease, characterized by presenting cardiovascular risk factors such as dyslipidemia, is intrinsically associated with several morbidities such as diabetes, metabolic syndrome and cancer. Several drugs have been used in the treatment of obese patients, such as statins and bupropion. Statins have been highlighted among drugs used for reducing cholesterol levels, preventing manifestations of cardiovascular disease. These hypolipemiant drugs inhibit HMG-CoA reductase required in cholesterol biosynthesis, which is used in testosterone synthesis, important for spermatogenesis. Among the new generation of statins on the market, rosuvastatin has greater efficiency in reduction of circulating levels of low density lipoprotein. A recent study reported that testosterone production in vitro by Leydig cells exposed to statins such as atorvastatin, mevastatin and simvastatin was inhibited by 40%. Bupropion is a drug used in the treatment of obesity that inhibits dopamine and norepinephrine reuptake, increasing their levels in the synapse. The mechanisms by which bupropion promotes weigh loss are not clear; however, they are possibly related to its action on these neurotransmitters, regulating appetite. This drug increases blood levels of a range of medications, through inhibition of hepatic P450 cytochrome 2D6 enzyme. Studies in our laboratory have shown that adult rats exposed to bupropion and prepubertal male rats exposed to rosuvastatin showed changes in reproductive parameters. Currently, these drugs have been widely used in the treatment of obesity, however, effects of the coexposure on the reproductive parameters of obese patients were not investigated. Thus, this study aims to evaluate the effects of subchronic exposure to bupropion and/or rosuvastain on sperm parameters and fertility of adult male rats. For this, adult male rats (70 days) will be allocated in the control group (saline solution; vehicle), bupropion (30 mg/kg), rosuvastatin (5 mg/kg) and bupropion combined with rosuvastatin (n = 20/group), treated orally for 30 days. After treatment, the following parameters will be analyzed: serum hormonal levels, reproductive organ weights, sperm number, motility and morphology and transit time through epididymis, SP22 (biomarker of fertility)quantification, androgen receptor quantification, fertility after in utero artificial insemination, in vitro synthesis of testosterone by Leydig cells, proteomic analysis and testicular and epididymal histology. This study is of great importance, considering the widespread use of these drugs in the treatment of obesity. (AU)