In Utero Exposure to Diethylstilbestrol (DES) or Bisphenol-A (BPA) Increases EZH2 Expression in the Mammary Gland: An Epigenetic Mechanism Linking Endocrine Disruptors to Breast Cancer

Abstract

Diethylstilbestrol (DES) and bisphenol-A (BPA) are estrogen-like endocrine-disrupting chemicals that induce persistent epigenetic changes in the developing uterus. However, DES exposure in utero is also associated with an increased risk of breast cancer in adult women. Similarly, fetal exposure to BPA induces neoplastic changes in mammary tissue of mice. We hypothesized that epigenetic alterations would precede the increased risk of breast neoplasia after in utero exposure to endocrine disruptors. Enhancer of Zeste Homolog 2 (EZH2) is a histone methyltransferase that has been linked to breast cancer risk and epigenetic regulation of tumorigenesis. We examined the effect of BPA and DES on EZH2 expression and function in MCF-7 cells and in mammary glands of mice exposed in utero. DES and BPA treatment approximated human exposure. EZH2 functional activity was assessed by measuring histone H3 trimethylation. Treatment of MCF-7 cells with DES or BPA led to a 3- and 2-fold increase in EZH2 mRNA expression, respectively (p<0.05) as well as increased EZH2 protein expression. Mice exposed to DES in utero showed a >2-fold increase in EZH2 expression in adult mammary tissue compared with controls (p<0.05). EZH2 protein was elevated in mammary tissue of mice exposed to DES or BPA. Histone H3 trimethylation was increased in MCF-7 cells treated with BPA or DES. Similarly, mice exposed to BPA or DES in utero showed increased mammary histone H3 trimethylation. Developmental programming of EZH2 is a novel mechanism by which in utero exposure to endocrine disruptors leads to epigenetic regulation of the mammary gland.

High Intake of Dietary Sugar Enhances Bisphenol A (BPA) Disruption and Reveals Ribosome-Mediated Pathways of Toxicity

“…In some cases, the phenotypes are accompanied by disrupted expression of DNA methyltransferase 1 and 3A, two enzymes responsible for the incorporation of methyl marks on the DNA (Doherty et al 2010;Itoh et al 2012;Kundakovic et al 2013). Alternative pathways for BPA modulation of the epigenome have been postulated; indeed, despite evidence showing that BPA might affect DNA methylation, it is unclear whether this is a direct outcome of BPA action or a correlated change in the epigenome.…”

Mutagenicity and DNA Damage of Bisphenol a and its Structural Analogues in Hepg2 Cells

“…Moreover, endocrine disruptors may induce carcinogenic effects due to epigenetic events or due to genotoxic effects. One potent endocrine disruptor and evidenced carcinogen, diethylstilbestrol (DES), is structurally related to BPA (17)(18). Both DES and BPA have a hydrophobic core with two OH groups at each end of the backbone whose distance is similar (9.0 Å to 9.2 Å for BPA and 9 Å to 11.5 Å for DES at different conformations) (19).…”

The Toxic Effects BPA on Fetuses, Infants, and Children

“…BPA also causes both disruption in the function and structure of the brain and irregularities in the low of hormones from the brain, which controls and regulates life processes. However, the probable developmental or reproductive hazard is not convincing because of incomplete data [8,9]. Nonetheless, BPA exerts unexpected exposure outcome relationships, because low doses frequently exert stronger toxicity than higher doses because of its estrogenic and other biotic features [10]; BPA ≤5 mg/kg body weight/day during the critical phases of growth might afect healthiness later in life [11].…”