Schematic diagram of our hypothesis on how neonatal estrogen (E2) and bisphenol A (BPA) alter the prostate genome via DNA methylation and histone modifications with phosphodiesterase type 4 variant 4 (PDE4D4) used as an example. Without exposure to E2 and BPA, PDE4D4 is silenced with aging. A group of enzymes, including histone deacetylases (HDACs), DNA methyltransferases (DNMTs), and methylated DNA-binding protein (MeCP2), may be involved in gene silencing. Nevertheless, after exposure to E2 and BPA, PDE4D4 fails to “shut-off” and is actively transcribed throughout life. We propose that chromatin structure is remodeled by opening the chromatin in the presence of histone acetyltransferase (HAT), methylation binding domains (MBDs) and other unknown factors and that this remodeling further prevents HDACs, DNMTs, and MeCP2 from binding to silence the gene. Persistent elevation of PDE4D4 expression is associated with the increase in incidence of prostate cancer later in life