"An important and controversial health concern is whether low-dose
exposures to hormonally active environmental estrogens, such as
bisphenol A, can promote human diseases, including prostate cancer. This
study's finding indicate that low-dose exposures to ubiquitous
environmental estrogens affect the prostate during development and, in
so doing, promote prostate disease with aging. The researchers also
found a marker, PDE4D4, for precancerous changes in that changes in
estrogen-exposed prostates. They suggest that PDE4D4 is "a candidate
molecular marker for prostate cancer risk assessment as a result of
endocrine disruptors."

June 1, 2006. A study in the June 1 issue of Cancer Research presents
the first evidence that exposure to low doses of environmental estrogens
during development of the prostate gland in the male fetus may result in
a predisposition to prostate cancer later in life.
The study, done in an animal model, also demonstrates how the
predisposition may arise, and a way to identify those at risk.
Man-made compounds that can mimic the hormone action of estrogens
(xenoestrogens) are widespread in the environment. One of these agents
is bisphenol A (BPA), used in the manufacture of plastics and epoxy
resins. These plastics are used worldwide in used in the manufacture of
food can liners, food storage containers, baby bottles, water supply
pipes and dental
resins. Over 6 billion pounds per year of bisphenol A are used in
manufacturing. The United States alone produces over 1.6 million pounds
of BPA annually. BPA, which can leach from plastics when heated, is
found nowdays in stream water, in adults' blood and in even higher
concetrations in amniotic fluid and placental and fetal tissues. Today,
lifelong exposure to this pervasive environmental compound may be hard
to avoid.
At high doses, estrogens may reduce growth of prostate cancer cells.
Estrogen is a well-known hormonal therapy for prostate cancer. High
doses of the estrogen mimic may also reduce prostate cancer cell growth.
But an earlier study found that at low doses equivalent to environmental
exposure BPA stimulates the hormone-refractory mutated androgen receptor
AR-T877A, which is activated "not only by androgens but also by
non-androgenic steroids, such as estrogen, progestins, glucocorticoids,"
and by the anti-androgen Flutamide. Data suggest that "a therapeutic
outcome in prostate cancer patients with an advanced disease can be
influenced by the exposure to ubiquitous environmental contaminants such
as BPA."
In this new study, a research team led by Dr. Gail Prins of the
University of Illinois at Chicago and Dr. Shuk-Mei Ho of the University
of Cincinnati exposed rats to low doses of estradiol, a natural
estrogen, or to BPA during the developmental period corresponding to the
second and third trimester of human pregnancy. They found that this
early exposure predisposed male rats to precancerous lesions of the
prostate in old age.
"Most remarkably, early BPA exposure sensitized the prostate to
precancerous lesions brought on by exposure of the adult animal to
elevated estradiol," said Prins, professor of urology at UIC and senior
author of the study. "This is highly relevant to people, because
relative estradiol levels increase in aging men as a result of their
increased body fat and declining testosterone levels."
The doses of estradiol and BPA used in the study were similar to levels
found in human serum; in the circulation of some pregnant women; and in
the fetus. Transfer of BPA from mother to fetus has been reported, and
levels in male fetuses have been shown to be higher than those of female
fetuses.
The researchers were able to demonstrate that early estrogen or BPA
exposure permanently changed the methylation, or tagging, of specific
stretches of DNA in the neonate's prostate cells, a phenomenon referred
to as epigenetic reprogramming. In epigenetic reprogramming, gene
expression is altered without changing DNA sequences or content. Several
of the epigenetically altered sites turned out to be in important genes
that regulate cellular functions.
The researchers conclude that exposure to environmental estrogens, such
as BPA, or natural estrogens affect the pattern of gene expression in
the prostate during development, and in so doing promote prostate
disease with aging.
One of the altered genes, phosphodiesterase 4 (PDE4D4), was examined in
greater detail. The researchers found that the methylation of PDE4D4 can
permanently change its pattern of expression in the prostate. This gene
should normally shut down in adult life, but after early exposure to
estradiol or BPA, the exposed animals' prostates continued to express it
at high levels. Similar high levels due to methylation of the gene were
found in prostate cancer cells but not in normal cell lines.
Because the methylation marks of epigenetic reprogramming were found
before any disease was observed, the methylation may be useful as a way
to identify men at higher prostate disease risk, Prins said, which may
have resulted from early exposure to endocrine disruptors.
"These findings are true for an animal model, and application to human
prostate disease will await future studies," the authors concluded. Ho
is first author of the study and professor and chairman of environmental
health at the University of Cincinnati.
Wan-Yee Tang, of the University of Cincinnati, and Jessica Belmonte de
Frausto of UIC also contributed to the study, which was funded by grants
from the National Institutes of Health and the Department of Defense.
Sources: University of Illinois at Chicago.
[ Cancer Research 66, 5624-5632, June 1, 2006]
Developmental Exposure to Estradiol and Bisphenol A Increases
Susceptibility to Prostate Carcinogenesis and Epigenetically Regulates
Phosphodiesterase Type 4 Variant 4
Shuk-Mei Ho 1 , Wan-Yee Tang 1 , Jessica Belmonte de Frausto 2 and Gail
S. Prins 2. 1 Department of Environmental Health, University of
Cincinnati, Cincinnati, Ohio and 2 Department of Urology, University of
Illinois at Chicago, Chicago, Illinois

knowledge is power - growing old is mandatory - growing wise is optional    
"Many more men die with prostate cancer than of it. Growing old is
invariably fatal. Prostate cancer is only sometimes so."
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