Proteomic Basis for the Increased Susceptibility of the Mammary Gland to Carcinogenesis After Perinatal Exposure to Bisphenol A

Abstract

Bisphenol A (BPA) is a compound used to produce a myriad of popular consumer goods, such as food and beverage containers, the lacquer lining of canned food, infant formula bottles, and some dental sealants. Recent studies have shown BPA to leach from these products in appreciable amounts, resulting in nearly ubiquitous exposure to humans. In this chapter, we review two key studies performed in our laboratory which investigate the ability of early life exposure to BPA to alter susceptibility to mammary cancer during adulthood. Prepubertal exposure to BPA (2-20 days of age only) increased mammary carcinogenesis and altered cell proliferation and apoptosis in the mammary gland in a classical model of chemically induced rodent mammary carcinogenesis (dimethylbenz(a)anthracene {[}DMBA] administered at 50 days of age). However, prenatal exposure to BPA (gestational days 10-21) failed to significantly alter tumorigenesis. However, genomic and proteomic data indicated that 100 days of age, as opposed to 50 days of age, represented a time in which the mammary gland had the most changes to gene and protein expressions. Accordingly, when the DMBA was administered at 100 days of age, prenatal BPA significantly altered mammary tumorigenesis. However, purely descriptive studies of chemical carcinogens do little to further our understanding into the molecular functions underpinning these deleterious effects. Thus, using prenatal exposure to BPA as a model, we utilized discovery proteomics technology in order to identify novel targets of the latent molecular action of BPA. Using bioinformatics software, these novel protein identifications allowed us to perform targeted analysis of the activation and expression of interconnected, downstream signaling pathways. These studies suggest potential adverse health effects to low concentrations of exposure during early life exist. Further, our work emphasizes the emerging role of new technology, such as proteomics, in prompting hypothesis-generating research which can be utilized in deciphering the molecular mechanisms causing these deleterious effects.