Molecular pathways: environmental estrogens activate nongenomic signaling to developmentally reprogram the epigenome.

Exposure to environmental xenoestrogens is a major health concern because of the ability of these compounds to perturb estrogen receptor (ER) signaling and act as endocrine disrupting compounds (EDC). Inappropriate exposure to EDCs during development, even at low doses, can predispose individuals to an increased lifetime risk of disease, including cancer. Recent data indicate that perinatal exposure to EDCs increases cancer risk by (re)programming the epigenome via alterations in DNA and histone methylation. We and others have begun to dissect the mechanisms by which xenoestrogens disrupt the epigenetic machinery to reprogram the epigenome and induce developmental reprogramming. Our studies revealed that xenoestrogens induce nongenomic ER signaling to activate PI3K/AKT, resulting in AKT phosphorylation and inactivation of the histone methyltransferase EZH2, thus providing a direct link to disruption of the epigenome. Other epigenetic "readers, writers, and erasers" may also be targeted by nongenomic signaling, suggesting this is a central mechanism by which xenoestrogens and other EDCs disrupt the epigenome to induce developmental reprogramming. Elucidating mechanisms of developmental reprogramming of the epigenome is important for understanding how environmental exposures increase cancer risk, and provides a rationale for developing epigenetic interventions that can reverse the effects of environmental exposures to reduce cancer risk.