Chronic Exposure of Mice to Bisphenol-A Alters Uterine Fibroblast Growth Factor Signaling and Leads to Aberrant Epithelial Proliferation

Alison M. Neff, Sean C. Blanco, Jodi A. Flaws, Indrani C. Bagchi, Milan K. Bagchi

Research output: Contribution to journalArticle

Abstract

Uterine epithelial proliferation is regulated in a paracrine manner by a complex interplay between estrogen (E) and progesterone (P) signaling, in which E stimulates proliferation and P inhibits it. Perturbation of steroid hormone signaling within the uterine milieu could contribute to the development of endometrial hyperplasia and cancer. It is well established that bisphenol-A (BPA) is an endocrine-disrupting chemical with weak estrogenic effects, although little is known about how it affects steroid hormone signaling in the adult uterus. Because BPA acts as a weak E, we hypothesized that chronic exposure to BPA would create an imbalance between E and P signaling and cause changes in the uterus, such as aberrant epithelial proliferation. Indeed, exposure to an environmentally relevant dose of BPA had a uterotrophic affect. BPA-treated mice showed increased proliferation, notably in the glandular epithelium, which are sites of origin for endometrial hyperplasia and cancer. Increased proliferation appeared to be mediated through a similar mechanism as E-induced proliferation, via activation of the fibroblast growth factor receptor pathway and phosphorylation of the ERK1/2 mitogen-activated protein kinases in the epithelium. Interestingly, BPA reduced expression of heart and neural crest derivatives expressed 2 (HAND2), a known mediator of the antiproliferative effects of P. BPA also increased methylation of a CpG island in the Hand2 gene promoter, suggesting that BPA may promote epithelial proliferation through epigenetic silencing of antiproliferative factors like HAND2. Collectively, these findings establish that chronic exposure to BPA impairs steroid hormone signaling in the mouse uterus, and may contribute to the pathogenesis of uterine hyperplasia and cancer.

Original languageEnglish (US)
Pages (from-to)1234-1246
Number of pages13
JournalEndocrinology
Volume160
Issue number5
DOIs
StatePublished - Jan 1 2019

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Fibroblast Growth Factors
Uterus
Endometrial Hyperplasia
Neural Crest
Steroids
Hormones
Endometrial Neoplasms
Estrogens
Epithelium
bisphenol A
Endocrine Disruptors
Fibroblast Growth Factor Receptors
Uterine Neoplasms
CpG Islands
Mitogen-Activated Protein Kinase 1
Epigenomics
Methylation
Hyperplasia
Progesterone
Phosphorylation

ASJC Scopus subject areas

  • Endocrinology

Cite this

Chronic Exposure of Mice to Bisphenol-A Alters Uterine Fibroblast Growth Factor Signaling and Leads to Aberrant Epithelial Proliferation. / Neff, Alison M.; Blanco, Sean C.; Flaws, Jodi A.; Bagchi, Indrani C.; Bagchi, Milan K.

In: Endocrinology, Vol. 160, No. 5, 01.01.2019, p. 1234-1246.

Research output: Contribution to journalArticle

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