Bisphenol A disruption promotes mammary tumor microenvironment via phenotypic cell polarization and inflammatory response.

Inflammation in the established tumor microenvironment (TME) is often associated with a poor prognosis of breast cancer. Bisphenol A (BPA) is an endocrine-disrupting chemical that acts as inflammatory promoter and tumoral facilitator in mammary tissue. Previous studies demonstrated the onset of mammary carcinogenesis at aging when BPA exposure occurred in windows of development/susceptibility. We aim to investigate the inflammatory repercussions of BPA in TME in mammary gland (MG) during neoplastic development in aging. Female Mongolian gerbils were exposed to low (50 µg/kg) or high BPA (5000 µg/kg) doses during pregnancy and lactation. They were euthanized at 18 months of age (aging) and the MG were collected for inflammatory markers and histopathological analysis. Contrarily to control MG, BPA induced carcinogenic development mediated by COX-2 and p-STAT3 expression. BPA was also able to promote macrophage and mast cell (MC) polarization in tumoral phenotype, evidenced by pathways for recruitment and activation of these inflammatory cells and tissue invasiveness triggered by tumor necrosis factor-alpha and transforming growth factor-beta 1 (TGF-ß1). Increase of tumor-associated macrophages, M1 (CD68 + iNOS+) and M2 (CD163+) expressing pro-tumoral mediators and metalloproteases was observed; this aspect greatly contributed to stromal remodeling and invasion of neoplastic cells. In addition, the MC population drastically increased in BPA-exposed MG. Tryptase-positive MCs increased in disrupted MG and expressed TGF-ß1, contributing to EMT process during carcinogenesis mediated by BPA. BPA exposure interfered in inflammatory response by releasing and enhancing the expression of mediators that contribute to tumor growth and recruitment of inflammatory cells that promote a malignant profile.

Postnatal exposure to finasteride causes different effects on the prostate of male and female gerbils.

The development and maintenance of prostate function depend on a fine balance between oestrogen and androgen levels. Finasteride inhibits 5α-reductase, which is responsible for the conversion of testosterone into its most active form, dihydrotestosterone. Enzymes that metabolize these hormones have a highly relevant role in both the normal prostate metabolism and in the occurrence of pathological conditions. There are few studies on the impact of finasteride on male prostate development and fewer studies on the female prostate and possible intersexual differences. Therefore, we treated male and female gerbils from 7 to 14 days in postnatal life with a high dose of finasteride (500 µg/kg/day); the prostate complexes were then removed and submitted to immunohistochemistry, immunofluorescence and three-dimensional reconstruction. In addition, hormonal serum dosages were administered. Treatment with finasteride resulted in an increased thickness of the periductal smooth musculature in the prostate of both male and female gerbils, such as well as a reduction in the thickness of developing prostate alveoli in both sexes. In addition, intersexual differences were observed as increased epithelial proliferation and decreases in the number of developing alveoli in females. Together, the data indicate that postnatal exposure to finasteride causes greater changes in the female gerbil prostate than in the male.

Prenatal exposure to finasteride promotes sex-specific changes in gerbil prostate development.

Finasteride is a drug that is widely used in the treatment of benign prostatic hyperplasia, hair loss and even as a chemotherapeutic agent in the treatment of prostatic adenocarcinoma. However, its use is known to cause several side effects in adults and it can also cause changes in the embryonic development of the male prostate, which is a cause for concern given the possibility of the accumulation of finasteride in the environment. Nevertheless, no studies have investigated the effects of finasteride on the development of the prostate in females, which occurs in several species of mammals. To evaluate the effects of intrauterine exposure to finasteride (500µgkg-1 day-1) on postnatal prostate development in the Mongolian gerbil in the present study, we used immunohistochemistry, immunofluorescence, serological analysis and three-dimensional reconstruction techniques. Differences were observed in the effects of finasteride on periductal smooth muscle and cell proliferation between the sexes, as well as intersex differences in the presence of the androgen receptor, which was elevated in males, and the oestrogen receptor ERα, which was increased in females. Together, the data indicate that the female prostate has its own hormone dynamics and that there are sex-specific differences in the way in which the female prostate reacts to prenatal exposure to finasteride.