Effects of in utero betamethasone exposure on male rats reproductive parameters, with emphasis on sperm quality and fertility: a multigenerational approach

• Grant number: 12/25350-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: July 01, 2013
• End date: December 30, 2016
• Field of knowledge: Health Sciences - Pharmacy - Toxicological Analysis
• Principal Investigator: Wilma de Grava Kempinas
• Grantee: Cibele dos Santos Borges
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

Glucocorticoids are potent drugs of anti-rheumatic, anti-inflammatory and immunosuppressive action, and they are the drugs of choice for antenatal treatment, promoting fetal lung maturation and thus decreasing the incidence of respiratory distress syndrome, neonatal mortality and morbidity, especially the glucocorticoid betamethasone. Studies conducted in association with our laboratory have shown that prenatal exposure to this drug promoted changes in testosterone levels and sperm parameters of male offspring. Recently, studies observed effects on the hypothalamic-pituitary-adrenal axis extending over generations. The purpose of this work is to perform comprehensive multigenerational study of possible changes in male rats reproductive parameters with emphasis on sperm quality caused by in utero exposure to betamethasone. Therefore, pregnant Wistar rats will be allocated in the control group and treated with 0.1 mg / kg betamethasone on gestational days 12, 13, 18 and 19. The male offspring of the first (F1) and second generation (F2) will be evaluated from postnatal day (PND) 30 concerning preputial separation, on PND 45: hormone levels and testicular and epididymal histomorphometry; on PND 90: hormone levels, sperm parameters, histomorphometric analysis of the testes and epididymis, immunohistochemistry for androgen receptors, sexual behavior, fertility after artificial insemination, expression levels of sperm protein SP22, pharmacological reactivity of the sex glands and ducts isolated and comet assay for detecting damage DNA. The project subject is current and very relevant, considering the wide use of this drug on therapies with maternal risk of premature delivery and due to the known action of glucocorticoids on fetal programming. This is an experimental study with translational applications. Besides generating new knowledge, we intend to prepare qualified human resources in research. (AU)

Scientific publications

(12)

(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)

ADRIANA ABRUZZESE, GISELLE; CRISOSTO, NICOLAS; KEMPINAS, WILMA DE GRAVA; SOTOMAYOR-ZARATE, RAMON. Developmental programming of the female neuroendocrine system by steroids. Journal of Neuroendocrinology, v. 30, n. 10, SI, OCT 2018. (14/13660-1, 12/25350-1)

BORGES, CIBELE S.; PACHECO, TAINA L.; GUERRA, MARINA T.; BARROS, ALINE L.; SILVA, PATRICIA V.; MISSASSI, GABRIELA; DA SILVA, KATIUSSIA PINHO; ANSELMO-FRANCI, JANETE A.; PUPO, ANDRE S.; KEMPINAS, WILMA DE G.. Reproductive disorders in female rats after prenatal exposure to betamethasone. JOURNAL OF APPLIED TOXICOLOGY, v. 37, n. 9, p. 1065-1072, SEP 2017. (14/13660-1, 12/25350-1)

ACEVEDO-RODRIGUEZ, A.; KAUFFMAN, A. S.; CHERRINGTON, B. D.; BORGES, C. S.; ROEPKE, T. A.; LACONI, M.. Emerging insights into hypothalamic-pituitary-gonadal axis regulation and interaction with stress signalling. Journal of Neuroendocrinology, v. 30, n. 10, p. 11-pg., 2018-10-01. (12/25350-1, 14/13660-1)

ACEVEDO-RODRIGUEZ, A.; KAUFFMAN, A. S.; CHERRINGTON, B. D.; BORGES, C. S.; ROEPKE, T. A.; LACONI, M.. Emerging insights into hypothalamic-pituitary-gonadal axis regulation and interaction with stress signalling. Journal of Neuroendocrinology, v. 30, n. 10, SI, OCT 2018. (14/13660-1, 12/25350-1)

BORGES, CIBELE DOS S.; DIAS, ANA FLAVIA M. G.; SILVA, PATRICIA V.; ROSA, JOSIANE LIMA; GUERRA, MARINA T.; SILVA, RAQUEL F.; KIGUTI, LUIZ RICARDO A.; PUPO, ANDRE S.; KEMPINAS, WILMA DE G.. Long-term adverse effects on reproductive function in male rats exposed prenatally to the glucocorticoid betamethasone. Toxicology, v. 376, n. SI, p. 15-22, FEB 1 2017. (13/26557-1, 12/25350-1)

KEMPINAS, W. G.; BORGES, C. S.; LEITE, G. A. A.; FIGUEIREDO, T. M.; GREGORY, M.; CYR, D. G.. Prenatal exposure to betamethasone causes intergenerational impairment of epididymal development in the rat. ANDROLOGY, v. 7, n. 5, JUN 2019. (12/25350-1)

BORGES, CIBELE DOS SANTOS; PACHECO, TAINA LOUISE; DA SILVA, KATIUSSIA PINHO; FERNANDES, FABIO HENRIQUE; GREGORY, MARY; PUPO, ANDRE SAMPAIO; SALVADORI, DAISY MARIA F.; CYR, DANIEL G.; KEMPINAS, WILMA DE G.. Betamethasone causes intergenerational reproductive impairment in male rats. REPRODUCTIVE TOXICOLOGY, v. 71, p. 108-117, AUG 2017. (12/25350-1)

BORGES, CIBELE S.; DIAS, ANA FLAVIA M. G.; ROSA, JOSIANE LIMA; SILVA, PATRICIA V.; SILVA, RAQUEL F.; BARROS, ALINE L.; SANABRIA, MARCIANA; GUERRA, MARINA T.; GREGORY, MARY; CYR, DANIEL G.; et al. Alterations in male rats following in utero exposure to betamethasone suggests changes in reproductive programming. REPRODUCTIVE TOXICOLOGY, v. 63, p. 125-134, AUG 2016. (13/26557-1, 12/25350-1)

KIGUTI, L. R. A.; BORGES, C. S.; MUELLER, A.; SILVA, K. P.; POLO, C. M.; ROSA, J. L.; SILVA, P. V.; MISSASSI, G.; VALENCISE, L.; KEMPINAS, W. G.; et al. Gender-specific impairment of in vitro sinoatrial node chronotropic responses and of myocardial ischemia tolerance in rats exposed prenatally to betamethasone. Toxicology and Applied Pharmacology, v. 334, p. 66-74, NOV 1 2017. (12/25350-1)

ADRIANA ABRUZZESE, GISELLE; CRISOSTO, NICOLAS; KEMPINAS, WILMA DE GRAVA; SOTOMAYOR-ZARATE, RAMON. Developmental programming of the female neuroendocrine system by steroids. Journal of Neuroendocrinology, v. 30, n. 10, p. 12-pg., 2018-10-01. (12/25350-1, 14/13660-1)

BORGES, CIBELE DOS S.; DIAS, ANA FLAVIA M. G.; SILVA, PATRICIA V.; ROSA, JOSIANE LIMA; GUERRA, MARINA T.; SILVA, RAQUEL F.; KIGUTI, LUIZ RICARDO A.; PUPO, ANDRE S.; KEMPINAS, WILMA DE G.. Long-term adverse effects on reproductive function in male rats exposed prenatally to the glucocorticoid betamethasone. Toxicology, v. 376, p. 8-pg., 2017-02-01. (13/26557-1, 12/25350-1)

BORGES, C. S.; DIAS, A. F. M. G.; SILVA, P. V.; SILVA, R. F.; ROSA, J. L.; MISSASSI, G.; GREGORY, M.; CYR, D. G.; KEMPINAS, W. G.. Betamethasone causes multigenerational reproductive impairment in male rats. Toxicology Letters, v. 259, p. 1-pg., 2016-10-01. (12/25350-1)

Academic Publications

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

BORGES, Cibele dos Santos. Effects of intrauterine exposure to betamethasone on reproduction of Wistar rats. 2017. Doctoral Thesis - Universidade Estadual Paulista (Unesp). Instituto de Biociências. Botucatu Botucatu.