In Utero Exposure to DES or BPA increases EZH2 Expression in the Mammary Gland

DES and BPA are estrogen-like endocrine-disrupting chemicals that induce persistent epigenetic changes in the developing uterus.

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.

Conclusion

We have demonstrated a novel mechanism by which endocrine-disrupting chemicals regulate developmental programming in the breast. Exposure to DES or BPA in utero alters mammary tissue expression of EZH2, a histone methyltransferase with known associations to tumorigenesis. EZH2 function, measured by examination of histone H3 (tri methyl K27), also increases as a result of exposure to DES or BPA. Increased expression of EZH2 within the breast, even in morphologically normal appearing tissue, may prove to be a marker of increased breast cancer risk. The increase in EZH2 expression and function shown here in mice after in utero exposure to these chemicals is a potential mechanism for the increased risk of breast cancer as a result of exposure to these EDCs. This study also generates important safety concerns about exposures to environmental endocrine disruptors such as BPA and suggests a potential need to monitor women exposed to these chemicals for the development of breast lesions as adults.

Sources and full study

• 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, NCBI PMID: 21761357, Horm Cancer. 1(3):146-55. doi: 10.1007/s12672-010-0015-9, 2010 Jun.
• Full text PMCID: PMC3140020, NIHMSID: NIHMS309412, doi: 10.1007/s12672-010-0015-9, Jul 20, 2011.

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