All ETDs from UAB

Advisory Committee Chair

Coral A Lamartiniere

Advisory Committee Members

Clinton Grubbs

Mark Carpenter

James Mobley

Helen Krontiras

Isam Eltoum

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Bisphenol A (BPA) is a synthetically made compound used to produce a myriad of consumer goods. Recent studies have shown BPA to leach from these products in appreciable amounts, resulting in nearly ubiquitous exposure. In this study, we assessed whether chronic administration to a range of low concentrations of BPA could accelerate spontaneously developing mammary cancer using a transgenic model that over-expresses wild type ErbB2/neu transgene (MMTV-erbB2). MMTV-erbB2 mice were provided drinking water containing 0 (control), 2.5 (BPA 2.5), 25 (BPA 25), 250 (BPA 250), or 2500 (BPA 2500) µg BPA/L from eight weeks of age until sacrifice. This range of BPA concentrations can be divided into two categories: 1) environmentally relevant doses of BPA (BPA 2.5 and BPA 25), and 2) regulatory-based doses of BPA (BPA 250 and BPA 2500). Chronic consumption of BPA 2.5 and BPA 25 significantly decreased tumor latency and increased tumor multiplicity, burden, and the rate of pulmonary metastasis. All doses of BPA significantly increased cell proliferation in the mammary gland. The rate of apoptosis was increased in the higher doses, with BPA 2500 achieving statistical significance. When these end points were taken together to estimate a ratio of cell-proliferation-to-apoptosis in the mammary gland, a non-monotonic dose response resulted. This end point provided the best prediction of effects induced by each concentration of BPA on mammary tumor development in MMTV-erbB2 mice. Changes in response to representative doses from environmentally relevant (BPA 25) and regulatory-based (BPA 2500) doses of BPA were noted. BPA 25 treatment significantly stunted mammary gland development. It suppressed ductal tree length, extension, and area while increasing the average number of terminal end buds present in the mammary gland. BPA 25 significantly decreased the protein expression of estrogen receptor alpha and progesterone receptor A while significantly increasing expression and activation of erbB2, erbB3, IGF-1 receptor, and Akt. These effects were absent from BPA 2500. Collectively, these effects are likely due to the ability of BPA 25, but not BPA 2500, to retard mammary gland growth and development and cause aberrant activation of growth factor receptor and Akt signaling in the mammary gland.

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