From the Special Topic of
One of the key papers in the Research Front Map on
Epigenetic Gene Regulation, part of our Special Topics
analysis of epigenetics research over the past decade, is
the June 2006 Cancer Research paper,
"Developmental exposure to estradiol and bisphenol A
increases susceptibility to prostate carcinogenesis and
epigenetically regulates phosphodiesterase type 4 variant
4" (Ho SM, Tang WY, de Frausto JB, Prins GS, 66:
5624-32). This paper has accumulated 79 citations in the
field of Clinical Medicine in
Essential Science IndicatorsSM from
In the interview below,
ScienceWatch.com talks with one of the authors, Dr. Gail
Prins, about the paper and the impact it has had on the field.
Dr. Prins is Professor of Physiology in the Department of
Urology and the Department of Physiology and Biophysics at the
University of Illinois at Chicago.
Would you please describe the significance
of your paper and why it is highly cited?
The significance of this work is twofold. First, it is the first study to
show that exposure to an environmental disrupting chemical (EDC), in this
case Bisphenol A (BPA), an environmental estrogen, during early development
could increase the sensitivity of the prostate gland to develop
precancerous prostate lesions in response to elevated hormones with aging.
Previous studies had not found prostate pathology after early-life exposure
to BPA and thus it was assumed that this widely used chemical, which
leaches from polycarbonate plastics and expoxy resins, did not pose any
harm to this cancer-prone tissue. Our work found that while it did not
drive cancer by itself, it markedly increased the sensitivity of the
prostate to develop neoplastic lesions following a second estrogenic
exposure as adults.
"We now have evidence that something
as common as an environmentally relevant dose
of BPA, a ubiquitous environmental
contaminant found in most humans, can alter
epigenetic memories that determine our
The second significant aspect of this study was that it went on to identify
the molecular process whereby a brief early-life exposure can cause
life-long effects. We found that the epigenetic memory of the prostate
cells had been altered through permanent changes in the DNA methylation
patterns of several genes. Thus we conclude that early-life chemical
exposures reprogram the epigenome of the developing prostate gland and, in
so doing, predispose to prostate disease with aging.
How did you become involved in this research, and
were there any particular successes or obstacles that stand
We (Drs. Prins and Ho) have been involved in prostate research our entire
careers with a focus on the role of estrogens and prostate cancer. After
learning how the brain can be feminized or masculinized by early hormone
exposures during development, I asked whether this might also occur in
hormone-sensitive end organs such as the prostate gland. With the evolution
of the field of epigenetics, it made perfect sense that alterations in the
epigenome could be a molecular underpinning of estrogen "imprinting" of the
The major obstacle over the years has been convincing people that events
during development could have an impact on prostate health over a lifetime.
In particular, people have been skeptical that estrogen, a "female"
steroid, could have an effect on the male prostate gland. The successes
have been slowly accumulating evidence to document a developmental basis
for prostate disease and to finally convince skeptics that this phenomenon
is real. The present study went a long way towards accomplishing that task.
Where do you see your research and the broader
field leading in the future?
First, it will be important in future studies to connect the dots between
the epigenetically altered genes that we have identified and the disease at
hand. The altered genes, phosphodiesterase 4 and several others, have not
been previously connected to prostate cancer, and we next need to determine
if they play a previously unidentified role in the disease.
I see future work leading to identifying higher-order chromatin and
microRNA events as intimately involved in the developmental estrogenization
process. I also would like to document whether the findings in our animal
models are applicable to the human. If so, this could translate into better
policy-making decisions about EDCs in the environment.
What are the implications of your work for this
The implications of this work revolve around epigenetic memory. We now have
evidence that something as common as an environmentally relevant dose of
BPA, a ubiquitous environmental contaminant found in most humans, can alter
epigenetic memories that determine our fate. Even if they appear to have no
"harm" in the present, it appears that repressed epigenetic memories may
loom in our genes, only to be triggered by future events that may drive
disease. This work emphasizes the complexity of gene-environmental
interactions and the role they play in complex diseases.
Gail S. Prins, Ph.D.
Department of Urology
Department of Physiology and Biophysics
University of Illinois at Chicago
Chicago, IL, USA
Gail Prins's current
most-cited paper in
Indicators, with 79
Ho SM, et al., "Developmental exposure to
estradiol and bisphenol A increases susceptibility to
protate carcinogenesis and epigenetically regulates
phosphodiesterase type 4 variant 4," Cancer Res.
66(11): 5624-32, 1 June 2006. Source:
Essential Science Indicators from
KEYWORDS: DEVELOPMENTAL EXPOSURE, ESTRADIOL, BISPHENOL A,
BPA, PROSTATE CARCINOGENESIS, PHOSPHODIESTERASE TYPE 4 VARIANT 4,
ENVIRONMENTAL DISRUPTING CHEMICAL, EPIGENETICS, EPIGENOME, PROSTATE
GLAND, EPIGENETIC MEMORY.