Environmental Estrogens and Developmental Reprogramming
Cheryl L. Walker, Ph.D., Tiffany Bredfeldt, Ph.D., Shuk-Mei Ho, Ph.D.
University of Texas MD Anderson Cancer Center, University of Cincinnati Medical Center
NIEHS Grants RC2ES018789, P30ES007784, R01ES008263, F32ES016509, and P30ES006096
An animal study by NIEHS grantees shows that environmental estrogens have distinct epigenetic effects in the developing uterus. The research provides insight into how early-life exposures to environmental estrogens can increase susceptibility to later development of hormone-dependent tumors.
The researchers studied the environmental estrogens genistein and bisphenol A (BPA), finding that genistein promoted the development of uterine fibroids in rats, while BPA did not. In the developing uterus, genistein and BPA both induce estrogen receptor signaling in a genomic manner, so how can they each activate the same receptor system but result in completely different outcomes?
The authors showed that genistein activated membrane-bound estrogen receptor via nongenomic mechanisms that were directly linked to pathways that caused histone phosphorylation. This histone phosphorylation reprograms estrogen-responsive genes in a way that makes them more responsive to hormones and increases the incidence of uterine fibroids later in life. However, BPA bound to the nuclear estrogen receptor without activating the membrane receptor and, therefore, did not activate the nongenomic histone phosphorylation pathway in the neonatal uterus. BPA, therefore, resulted in less estrogen-responsive gene expression in the adult uterus and no increase in uterine fibroids.
Citation: Greathouse KL, Bredfeldt T, Everitt JI, Lin K, Berry T, Kannan K, Mittelstadt ML, Ho SM, Walker CL. 2012. Environmental estrogens differentially engage the histone methyltransferase EZH2 to increase risk of uterine tumorigenesis. Mol Cancer Res 10(4):546-557.
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