Effects of exposure of adult male Wistar rats to statins and neurotransmitter reuptake inhibitors on reproductive parameters and fertility

Author(s)

Patrícia Villela e Silva

• Document type: Doctoral Thesis
• Press: Botucatu. 2018-04-20.
• Institution: Universidade Estadual Paulista (Unesp). Instituto de Biociências. Botucatu
• Defense date: 2018-03-05
• Advisor: Wilma De Grava Kempinas

Abstract

Obesity is a global public health problem associated with an increased risk of metabolic syndrome, dyslipidemia, and other comorbidities. The drugs used to treat obese patients include statins, as rosuvastatin and simvastatin, which reduce serum levels of cholesterol, a precursor of testosterone, and neurotransmitter reuptake inhibitors, such as sibutramine and bupropion, used to reduce body weight. Previous studies reported adverse effects of the isolated exposure to these drugs on male reproductive parameters. Considering the exposure of obese patients to statins and neurotransmitter reuptake inhibitors, the present study aimed to investigate the effects of the co-exposure to rosuvastatin and sibutramine, as well as the co-exposure to simvastatin and bupropion, on reproductive parameters in adult male rats. For this, two experiments were conducted. In the first experiment, adult male rats (90 days) allocated into control (saline and dimethylsulfoxide), rosuvastatin (5 mg/kg rosuvastatin), sibutramine (10 mg/kg sibutramine) and rosuvastatin combined with sibutramine (n = 26-28 / group) were treated orally for 70 days. In the second experiment, adult male rats (70 days) allocated into control (distilled water), simvastatin (50 mg/kg simvastatin), bupropion (30 mg/kg bupropion) and simvastatin combined with bupropion (n = 20 / group) were treated for 52 days. In the first experiment, treatment with rosuvastatin, alone or in combination with sibutramine, resulted in hyperplasia in the clear cells of epididymis. Exposure to sibutramine, alone or in combination with rosuvastatin, resulted in reduced food intake, body and reproductive organ weights, serum testosterone levels, and increased index of spermatozoa with cytoplasmic droplets compared to the control and rosuvastatin groups. Sperm reserves and transit time through the epididymis were also reduced in these groups and potentiated by co-exposure to the drugs. No alterations in the testicular morphology, sperm morphology and motility, as well as expression of 3β-HSD enzyme were observed, however, the co-exposure resulted in delayed ejaculation and reduction of fertile potential after natural mating, compared to the control and rosuvastatin groups, suggesting possible synergism between the drugs. In the second experiment, all the experimental groups presented reduction in serum and intratesticular testosterone levels, compared to the control group. Alteration in sperm motility and reduction of testosterone synthesis by Leydig cells were observed in the simvastatin-treated group. Exposure to simvastatin, isolated or associated with bupropion, resulted in hyperplasia of clear cells from the epididymis and increased index of sperm with cytoplasmic droplet. No alterations in the reproductive organ weights, sperm morphology, testicular morphology and morphometry, and expression of 3β-HSD enzyme were observed, however, the co-exposure resulted in reduced fertility potential, suggesting synergism between the drugs. Considering that rats have a higher reproductive efficiency compared to humans, the results obtained in these two experiments may indicate reproductive risks in men co-exposed to statins and neurotransmitter reuptake inhibitors. (AU)

• FAPESP's process: 14/15566-2 - Effects of subchronic and prolonged exposure to sibutramine and/or rosuvastatin on reproductive parameters and fertility of adult male Wistar rats
• Grantee: Patrícia Villela e Silva
• Support Opportunities: Scholarships in Brazil - Doctorate