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

• Grant number: 13/22495-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: June 01, 2014
• End date: November 30, 2017
• Field of knowledge: Biological Sciences - Morphology - Embryology
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Wilma de Grava Kempinas
• Grantee: Gabriel Adan Araújo Leite
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

Dyslipidemia are frequently found in children and have been demonstrated earlier in the population due to the increase of obesity. Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase) and they are responsible to decrease total cholesterol, mainly LDL-cholesterol. Rosuvastatin is one of the last generation statin and shows pharmacological advantages and higher inhibitory effects in relation to the other statins. Vitamin C plays an important role in the sperm integrity and fertility, acts as an antioxidant agent against testicular oxidative stress and can increase serum testosterone concentrations. Considering the use of lipid-lowering agents for children and the immediate and late adverse reproductive effects promoted due to rosuvastatin administration to prepubertal male rats, as observed in previous study for us performed (Leite et al. submitted in 2013) and the important role of vitamin C on male reproduction, we propose the present study in which juvenile male rats will be exposed to rosuvastatin since post-natal day (PND) 23 until PND53. Immediate and late reproductive analysis will be conducted evaluating the reproductive parameters on male genital system and fertility of generations F0 and F1. The "window" of exposition is justified due to the attempt to mimic the human situation which some children need to use statins during childhood and adolescence. Therefore, newly weaned male rats will be divided in six experimental groups and they will receive saline solution (vehicle), 3 or 10 mg/Kg/day of rosuvastatin in the presence or absence of vitamin C at the dose of 150 mg/day from PND23 until PND53, when part of the animals will be euthanized and evaluated in relation to hormonal dosages, histopathology of testis and epididymis and the activity of antioxidant enzymes. The remaining rats will be maintained until sexual maturity, when will be assessed sexual behavior, hormonal dosages, sperm production, reserve and quality, comet assay, testicular and epididymal histopathology, immunohistochemistry and western blot for androgen receptor (AR) and Rab11a, and natural fertility test. In the male offspring (generation F1), it will be performed the following evaluations: sperm analysis, hormonal dosages, comet assay, morphology of testis and epididymis, sexual behavior and natural fertility test. Female offspring will be assessed in relation to the estrous cycle, histopathology of ovaries and uteri, TUNEL to identify apoptosis in the ovaries, sexual behavior and natural fertility test. We intend to form new human qualified resources in Biology and Toxicology of Reproduction, acquire new knowledge about the adverse effects of rosuvastatin on fertility of generations F0 and F1 and about the possible protective effects of vitamin C on reproductive development and fertility of these same generations, besides to disclose the data through publications in international and indexed journals with high impact, as well as in scientific events in the area. (AU)

Scientific publications

(5)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ARAUJO LEITE, GABRIEL ADAN; FIGUEIREDO, THAMIRIS MOREIRA; PACHECO, TAINA LOUISE; SANABRIA, MARCIANA; VILLELA E SILVA, PATRICIA; FERNANDES, FABIO HENRIQUE; KEMPINAS, WILMA DE GRAVA. Vitamin C partially prevents reproductive damage in adult male rats exposed to rosuvastatin during prepuberty. Food and Chemical Toxicology, v. 109, n. 1, p. 272-283, NOV 2017. (14/13659-3, 13/22495-1)

ARAUJO LEITE, GABRIEL ADAN; FIGUEIREDO, THAMIRIS MOREIRA; GUERRA, MARINA TREVIZAN; BORGES, CIBELE DOS SANTOS; FERNANDES, FABIO HENRIQUE; ANSELMO-FRANCI, JANETE APARECIDA; KEMPINAS, WILMA DE GRAVA. Ascorbic acid co-administered with rosuvastatin reduces reproductive impairment in the male offspring from male rats exposed to the statin at pre-puberty. Food and Chemical Toxicology, v. 118, p. 416-429, AUG 2018. (14/13659-3, 13/22495-1)

ARAUJO LEITE, GABRIEL ADAN; FRANCO DE BARROS, JORGE WILLIAN; MARTINS, JR., AIRTON DA CUNHA; ANSELMO-FRANCI, JANETE APARECIDA; BARBOSA, JR., FERNANDO; KEMPINAS, WILMA DE GRAVA. Ascorbic acid supplementation ameliorates testicular hormonal signaling, sperm production and oxidative stress in male rats exposed to rosuvastatin during pre-puberty. JOURNAL OF APPLIED TOXICOLOGY, v. 39, n. 2, p. 305-321, FEB 2019. (13/22495-1)

ARAUJO LEITE, GABRIEL ADAN; FIGUEIREDO, THAMIRIS MOREIRA; SANABRIA, MARCIANA; MOTA GONCALVES DIAS, ANA FLAVIA; VILLELA E SILVA, PATRICIA; MARTINS JUNIOR, AIRTON DA CUNHA; BARBOSA JUNIOR, FERNANDO; KEMPINAS, WILMA DE GRAVA. Ascorbic acid supplementation partially prevents the delayed reproductive development in juvenile male rats exposed to rosuvastatin since prepuberty. REPRODUCTIVE TOXICOLOGY, v. 73, p. 328-338, OCT 2017. (13/22495-1)

ARAUJO LEITE, GABRIEL ADAN; FIGUEIREDO, THAMIRIS MOREIRA; PACHECO, TAINA LOUISE; GUERRA, MARINA TREVIZAN; ANSELMO-FRANCI, JANETE APARECIDA; KEMPINAS, WILMA DE GRAVA. Reproductive outcomes in rat female offspring from male rats co-exposed to rosuvastatin and ascorbic acid during pre-puberty. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A-CURRENT ISSUES, v. 81, n. 17, p. 873-892, 2018. (14/13659-3, 13/22495-1)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

LEITE, Gabriel Adan Araújo. 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. 2018. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia Campinas, SP.