In utero exposure of low dose bisphenol A and high fat reprograms breast cancer susceptibility Shuk-Mei Ho, PhD, Department of Environmental Health, Center for Environmental Genetics, Cancer Institute, University of Cincinnati Medical Center, Cincinnati, OH
During prenatal development cells of the embryo and the fetus are rapidly dividing and undergo tissue differentiation by taking on specific functions. Epigenetics is at work to remove the paternal and the maternal marks and lay down the ones unique to the individual by repackaging the genes in each tissue into active and inactive domain for tissue-specific gene expression throughout life. For most tissues/organs, this process takes weeks, months or perhaps years to be completed. Before the completion, tissues/organs are susceptible to reprogramming by endogenous and external factors via a process referred to as developmental plasticity. This interaction may in part explain developmental reprogramming of breast cancer (BCa) risk .
Exposure to environmental endocrine disruptors such as bisphenol A (BPA) has been shown to increase breast cancer risk and alter the window of cancer susceptibility. A number of studies have also suggested that lifestyle, especially adopting high fat diet, could predispose to higher BCa risk. Though BPA and high-fat diet exposure have been independently investigated, the synergistic action of both factors in breast cancer has not been determined.
In this talk we will provide evidence that prenatal exposure to different oral doses of BPA in a high-fat diet background influence BCa risk in a complex manner.
The postnatal day (PND) 50-DMBA induced mammary tumorigenesis Sprague-Dawley rat model was used as a model system in our studies. The dams were fed a high fat-butter diet (HFB) with or without BPA (0, 2.5, 25, 250, 2,500 µg/g BW) or ethinylestradiol as an estrogen-control group. The control dams were fed a low fat diet AIN diet.
Overall, the various gestational exposure regimens did not affect sex ratio of live birth, dam or daughter food consumption and body weight gains, nor did they alter serum concentrations of leptin, adiponectin, estradiol or progesterone in daughters on postnatal day PND21 and PND50. However, daughters born to dams fed HFB and a low dose BPA diet had (1) a delay in vaginal opening, (2) an increase in the number of terminal end buds (TEB), and (3) significant increases in TEB cell proliferation. Importantly, daughters born to dams fed with HFB diet and a low dose BPA exhibited a significant increase in tumor incidence (90%) observed 90 day after DMBA-treatment on PND50 when compared to other HFB + higher BPA groups (50-60%). Previously studies reported that treatment with BPA alone delays the DMBA-susceptible window to Day 100. In this study, treatment with HFB moved this window back to PND50. Finally, daughters born to dams fed HFB only had a small but significant decrease in tumor incidence (45.5%) when compared to those born to dams fed control diets, yet, the tumors developed in this group were found to grow a lot faster than those developed in all other groups.
In conclusion, prenatal exposure to BPA and the HFB displayed complex interaction to affect mammary gland development, DMBA-susceptible window, tumor incidence and tumor growth in a complex, non-monotonic manner.
Acknowledgements: This work was support by National Institutes of Health grants U01ES019480 and P30ES006096, and a VA merit award I01BX000675.