Late effects of bisphenol A exposure in the mammary gland of female gerbils during pregnancy and lactation

Author(s)

Thalles Fernando Rocha Ruiz

• Document type: Master's Dissertation
• Press: São José do Rio Preto. 2022-03-08.
• Institution: Universidade Estadual Paulista (Unesp). Instituto de Biociências Letras e Ciências Exatas. São José do Rio Preto
• Defense date: 2022-02-25
• Advisor: Sebastião Roberto Taboga

Abstract

Mammary glands present a great morphological plasticity due to their remodeling associated to hormonal modulation during the phases of life. The establishment of breast cancer has been related to compounds called endocrine disruptors. Bisphenol A (BPA), a xenoestrogen widespread in environments, is the target of in-depth studies on its carcinogenic potential due to its action on several levels of biological systems. Furthermore, exposure to this endocrine disruptor causes persistent effects in organisms observed in long term. Thus, the aim of the present study was to evaluate the deregulatory potential of BPA in the mammary glands of aged females exposed during two windows of mammary remodeling, pregnancy and lactation. Mongolian gerbils (Meriones unguiculatus) were used as an experimental model due to their potential for the spontaneous development of neoplasias. Twenty females were divided into 4 experimental groups: control (gavaged with water); vehicle (gavaged with corn oil); BPA (50 µg/kg/day); and BPA (5000 µg/kg/day). Females were exposed for 39 days (pregnancy and lactation) and euthanized at 18 months of age (aging). Histopathological analyses demonstrated the onset of tumor development, associated with epithelial-mesenchymal transition (EMT) of epithelial cells. Also, exposure to BPA showed an increase in the expression of TGF-β1, indicated as a marker of the EMT process. A microinvasive profile was observed by the expression of metalloproteases (MMP-2, MMP-3, MMP-9) by the tumor cells. BPA promoted a stromal microenvironment with increased cancer-associated fibroblasts and remodeling of collagen and elastic fibers. Regarding receptors, BPA-induced carcinoma showed an expressive increase in the estrogen receptor ERα, and a loss of expression of ERβ, progesterone and prolactin receptors. In cells expressing ERα, was observe co-localization of the epigenetic marker EZH2, related to ERα-positive tumor establishment. Also, BPA modulated androgen receptor (AR) and HER2/ErbB2 localization in the mammary epithelial cells. Finally, BPA exposure promotes a tumor microenvironment (TME) that corroborates with mammary neoplastic development. Recruitment of elements, such as cancer-associated phenotypes of macrophage and mast cells, that express inflammatory mediators was observed in the stroma. Also, COX-2 and phospho-STAT3 expression in neoplastic cells contribute to epithelium-stroma signaling for TME development. In conclusion, BPA presents as a carcinogenic inducer of mammary cancer during aging, especially when exposure occurs in the gestational/lactational window (AU)

• FAPESP's process: 20/01240-9 - Late effects of bisphenol A exposure in the mammary gland of female gerbils during pregnancy and lactation
• Grantee: Thalles Fernando Rocha Ruiz
• Support Opportunities: Scholarships in Brazil - Master