Impacts of hormonal therapies on the mammary gland and prostate of aged females under the influence of the endocrine disruptor bisphenol A

Abstract

The mammary glands and female prostate are organs associated with the female reproductive system that undergo hormone-responsive changes. Pathologies associated with these glands are the result of endocrine deregulation via endogenous or exogenous pathways. Endocrine disruptors (ED) are chemical compounds disseminated in the environment that show activity via hormone receptors and interact with molecular pathways promoting neoplastic development. Bisphenol A (BPA) is an ED of the xenoestrogen class with carcinogenic potential in hormone-responsive glands. Moreover, co-exposure with other agents, such as hormone therapy (HT), has been the subject of recent studies. Thus, the present study will aim to evaluate the histopathological repercussions in the mammary gland and female prostate after exposure to BPA and co-exposure to different HT. In vivo experiments will be conducted, using the Mongolian gerbil experimental model, since both glands are functional in the same individual; and in vitro, in cells of normal (MCF-10A) and adenocarcinoma (MCF-7) mammary cell lines. Females will be exposed to BPA during gestation and lactation and subsequently to different HT used as contraceptive and hormone replacement methods. Histopathological analyses of the organs will be performed, evaluating preneoplastic and neoplastic lesions, as well as changes in tissue compartments. Proliferation and apoptosis rates will be evaluated in the epithelial and stromal compartments, as well as stromal remodeling elements, such as metalloproteases (MMP) and its inhibitors (TIMP), and reactive stromal cell elements (activated fibroblasts). The expression of hormone receptors (ER±, ER², PR, HER2, AR, PRL-R) and its co-expression with epigenetic markers (EZH2 and BRCA) as well as tissue inflammatory repercussions will be evaluated. For the in vitro studies (cell culture), both will be sensitized to the different treatments, as a comparison to the in vivo method. Also, the study of intracellular pathways altered by TH in an endocrine-disrupting environment, such as PTEN/PI3K, AKT/mTOR, YAP (Hippo pathway), MAPK, and NF-ºB signaling pathways, as well as their phosphorylated isoforms, will be performed by IHC and Western Blot in both models. From these analyses, it will be possible to demonstrate the effect of different HT in an environment of endocrine disruption as possible potentiators or suppressors of the neoplastic process. (AU)