Mammary Gland Reactive Stroma Characterization at Aging After Bisphenol A Exposure During Hormonal Susceptibility Windows

Abstract

Mammary glands development is influenced by endocrine signaling, which remodels epithelial and stromal compartments. Reactive stroma phenotype is observed when stromal disturbances occur, leading to changes in extracellular matrix composition and occurrence of reactive cell types. One of the triggers of these alterations is endocrine-disrupting chemical exposure, such as bisphenol A (BPA). Studies suggest that BPA acts on receptor binding sites of several hormones interfering the endocrine response. The aim of this study was to investigate the reactive stroma features on mammary glands of aged female gerbils (Meriones unguiculatus) exposed to BPA during windows of susceptibility. Thus, the analysis of cellular profile and growth factor expressions was provided. Fibroblastic population changed in BPA-exposed mammary glands, with a remarkable increase of myofibroblasts (vimentin⁺/α-SMA⁺) and active fibroblasts (FAP⁺). Normal fibroblasts (vimentin⁺/α-SMA^-) were decreased mainly associated with the increase of FGF-10, an inductor of fibroblastic polarization. CD34⁺ stromal cells were also identified and detected among epithelial cells after BPA-induction disruption. Angiogenesis was supported by VEGF increasing in the gland tissue, which promoted an increase in blood vessel density. Thus, our results demonstrated that reactive stroma was raised in the mammary gland after BPA exposure. This profile was supported by changes in the fibroblastic population due to an induction to synthetic phenotypes and the expression of FGF-10, as well as the angiogenic activity that could corroborate with the malignancy and aggressiveness induced by BPA exposure.