Evaluation of the effects of finasteride on intrauterine and early post-natal prostatic development of female and male of Mongolian gerbil (Meriones unguiculatus)

Author(s)

Juliana dos Santos Maldarine

• Document type: Master's Dissertation
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2019-03-19

Examining board members

Sebastião Roberto Taboga; Cristiane Damas Gil; Silvia Borges Pimentel de Oliveira

• Advisor: Sebastião Roberto Taboga

Abstract

The prostate is an accessory reproductive organ present in mammals, whose formation involves complex interactions between urogenital sinus (UGE) epithelium and urogenital sinus mesenchyme (UGM). Although not exclusive to males, few studies have focused on the prostate gland of females. The gerbil of Mongolia ("Meriones unguiculatus") is promising for the investigation of prostatic development, since prostate is present in about 90% of the females, unlike other laboratory rodents. However, the reason for the occurrence of gland in a portion of females (and also woman) remains obscure, as well as the role of testosterone on the initial development of the gland in females and the origin of differences in susceptibility to pathological conditions among sexes. The present project used two different dosages of finasteride, an inhibitor of 5alpha-reductase, an enzyme that converts testosterone in its most active form, dihydrotestosterone (DHT), to evaluate the effects of reducing androgenic action on prostate glands of both sexes in two different moments of its development: first in the intrauterine period, in order to evaluate the effects of this drug on the budding and branching phase of the gland, and, secondly, in the postnatal period, on the beginning of the process of morphofunctional differentiation of prostatic alveoli. For that, techniques of histochemistry, immunohistochemistry, immunofluorescence, three-dimensional reconstructions and serum hormonal dosages were used. We observed that intrauterine exposure to finasteride in a low, but environmentally relevant, dosage (100 mg/Kg/day) resulted in changes during intrauterine prostatic development in both sexes, such as increased periductal and periurethral smooth muscle thickness, increased stromal proliferation in females, and increased androgen receptor (AR) expression and estrogen receptor alpha(ERalpha) decrease in males. In addition, a dose five times higher (500 mg/Kg/day) was administered in the pre and postnatal periods. In the first, there was a decrease in the periductal smooth muscle thickness in males and an increase in the same in females, as well as an increase in epithelial proliferation in both sexes, and also an increase in epithelial RA of males and epithelial ERalpha in females. Exposure to finasteride in the postnatal period, in both sexes, increased the thickness of smooth muscle, as well as a reduction in the thickness of the developing prostatic alveoli; however, the females prostate was more altered, which was verified by the decrease in the number of alveoli in development and by the increase of the epithelial proliferation, which was not observed in males. In general, the data indicate that there are intersex differences in the effects of intrauterine and early postnatal exposure to finasteride, which demonstrates that female prostate has its own hormonal dynamics throughout its development, and that the period in which occurs such exposure is relevant, and changes are observed even at lower dosages, which raises concerns about the potential accumulation of this substance in the environment and the need to establish parameters for the female prostate, since the dosages considered environmentally safe are described for males (AU)

• FAPESP's process: 16/16509-8 - Evaluation of the effects of finasteride on intrauterine and early post-natal prostatic development of Mongolian gerbil (Meriones unguiculatus)
• Grantee: Juliana dos Santos Maldarine
• Support Opportunities: Scholarships in Brazil - Master