Molecular mechanisms of mammary gland remodeling: A review of the homeostatic versus bisphenol a disrupted microenvironment

Mammary gland (MG) undergoes critical points of structural changes throughout a woman's life. During the perinatal and pubertal stages, MG develops through growth and differentiation to establish a pre-mature feature. If pregnancy and lactation occur, the epithelial compartment branches and differentiates to create a specialized structure for milk secretion and nurturing of the newborn. However, the ultimate MG modification consists of a regression process aiming to reestablish the smaller and less energy demanding structure until another production cycle happens. The unraveling of these fascinating physiologic cycles has helped the scientific community elucidate aspects of molecular regulation of proliferative and apoptotic events and remodeling of the stromal compartment. However, greater understanding of the hormonal pathways involved in MG developmental stages led to concern that endocrine disruptors such as bisphenol A (BPA), may influence these specific development/involution stages, called "windows of susceptibility". Since it is used in the manufacture of polycarbonate plastics and epoxy resins, BPA is a ubiquitous chemical present in human everyday life, exerting an estrogenic effect. Thus, descriptions of its deleterious effects on the MG, especially in terms of serum hormone concentrations, hormonal receptor expression, molecular pathways, and epigenetic alterations, have been widely published. Therefore, allied to a didactic description of the main physiological mechanisms involved in different critical points of MG development, the current review provides a summary of key mechanisms by which the endocrine disruptor BPA impacts MG homeostasis at different windows of susceptibility, causing short- and long-term effects.