Male rats exposed to rosuvastatin during pre-puberty in the absence or presence of vitamin C: short- and long-term effects on the genital system and the fertility of generations F0 and F1

Author(s)

Gabriel Adan Araujo Leite

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2018-04-02

Examining board members

Wilma De Grava Kempinas; Patricia Aline Boer; Mary Anne Heidi Dolder; Arielle Cristina Arena; Camila Contin Diniz Almeida Francia

• Advisor: Wilma De Grava Kempinas

Abstract

Obesity is affecting children and adolescents in several countries. It is known that dysfunctions on lipid profile are related to obesity, inappropriate lifestyle and sedentary habits. Rosuvastatin is a first-line therapy medication that decreases serum cholesterol and triglycerides levels. Ascorbic acid is an important antioxidant compound that is essential for fertility and sperm integrity. The study aimed to investigate the reproductive parameters and fertility of generations F0 e F1 of male rats exposed to rosuvastatin and evaluate the role of ascorbic acid preventing these adverse effects. Pre-pubertal male rats were distributed into six experimental groups that received saline solution 0.9% (vehicle) , 3 or 10 mg/Kg/day of rosuvastatin, 150 mg/day of ascorbic acid, or 3 or 10 mg/Kg/day of rosuvastatin co-administered with 150 mg/day of ascorbic acid by gavage from post-natal day (PND) 23 until PND 53. Male rats (n=10/group) were euthanized on PND 53 to assess the short-term reproductive effects of rosuvastatin exposure and the possible preventive role of ascorbic acid in reproduction. The remaining rats (n=10/group) were maintained until sexual maturity (PND 100) when sexual behavior test and fertility were evaluated. Males were mated with an additional non-treated female rat to obtain their male and female offspring. On PND 110, the control and treated males (n=10/group) were euthanized and the reproductive parameters were assessed. Female offspring were evaluated at puberty and adulthood, and male offspring were evaluated on sexual maturity in relation to their reproductive parameters. Rosuvastatin-treated groups showed delayed puberty installation, androgen depletion and impairment on testicular and epididymal morphology at puberty. Additionally, they showed lower sperm quality, decreased testosterone concentrations, weaker androgen receptors nuclear staining in Sertoli cells at stages IX-XIII, increased germ cell death and augmented oxidative stress at adulthood. Male offspring from rosuvastatin-exposed groups showed increased sperm DNA fragmentation, androgen depletion, an augmented rate of germ cell death and impairment on the epididymal structure. Female offspring whose fathers were exposed or co-exposed to the higher dose of statin showed a lower number of corpora lutea during puberty. On sexual maturity, females from the group whose fathers were exposed to 3 mg showed lower uterine luminal epithelium area. Ascorbic acid co-administered to pre-pubertal male rats ameliorated the reproductive damage in the F0 and F1 generation promoted by rosuvastatin exposure. In summary, pre-pubertal exposure to rosuvastatin impaired the reproduction in the F0 and F1 generation, probably due to the androgen depletion, increased oxidative stress, augmented sperm DNA damage and the possible epigenetic changes in paternal sperm. On the other hand, ascorbic acid was able to stimulate steroidogenesis, reduce oxidative stress, and improve antioxidant status, besides to protect, at least partially, paternal sperm from the possible epigenetic changes, thus alleviating the reproductive damage in the F0 and F1 generation promoted by rosuvastatin exposure (AU)

• FAPESP's process: 13/22495-1 - Male rats exposed to rosuvastatin during prepuberty in the absence or presence of vitamin C: immediate and late effects on genital system and the fertility of generations F0 and F1
• Grantee: Gabriel Adan Araújo Leite
• Support Opportunities: Scholarships in Brazil - Doctorate