YB, CE Petre, KR Monk, A Puga, and KE Knudsen. 2002. The
Xenoestrogen Bisphenol A Induces Inappropriate Androgen Receptor
Activation and Mitogenesis in Prostatic Adenocarcinoma Cells.
Cancer Therapeutics 1: 515–524.
sense recommendations for men undergoing prostate cancer treatment...
previous work on endocrine disruption by bisphenol
A has focused on exposures in the womb. This study identifies
a new target of vulnerability: adult men undergoing hormonal treatment
for prostate cancer. Wetherill et al. report that
extremely low doses of bisphenol A increase a process in prostate
cancer cells that renders them less responsive to the standard hormone
treatment used to force prostatic adenocarcinomas into remission.
The effects, observed in cell culture, take place at levels
that have been measured in circulating blood of adult men.
background on prostate cancer (adapted from Wetherill et al):
early stages of prostate cancer, treatment focuses on the androgen
sensitivity of prostate cancer cells. These cells require serum
androgen to proliferate and survive. Targeting this vulnerability,
doctors use hormone treatments that reduce androgen levels as
one of the first lines of therapy, or that inhibit the biochemical
pathways that are stimulated by androgen receptor activity. Deprived
of androgen stimulation, the androgen-dependent tumors go into
remission is not permanent. The median time for a relapse is between
12 and 30 months. For reasons that are not completely understood,
tumors begin to appear in the cancer that do not require androgen
for proliferation. The cancer becomes androgen-independent (also
called androgen-refractory) and no longer responds to this intervention.
the tumors are not androgen-dependent, they still have active
androgen receptors. It appears that mutations in these receptors
are involved in the formation of androgen-independent tumors.
These mutations apparently make the AR less discriminating in
its response to potential hormonal stimulation, i.e., instead
of being responsive only to androgens, the androgen receptor will
also respond to 17ß estradiol, progesterone and some anti-androgens.
Wetherill et al.'s finding that bisphenol A (BPA) initiates
the proliferation of androgen-independent prostate cancer cells
at extremely low exposure levels is of great interest. Their work
was done in cell culture. If the same mechanisms take place
in adult men, BPA could be interfering with one of the key weapons
used against treatment for prostate cancer.
did they do? Wetherill et al. used a series of
cell culture experiments and biochemical techniques to tease apart
the effects of exposing human prostatic adenocarcinoma cells (called
LNCaP cells) to low levels of BPA, first to establish the effects
and then to hone in on their biochemical mechanisms.
their first round of experiments, they exposed LNCaP cells to
BPA at levels ranging from 0.1 nanoMolar to 100 nM to determine
a dose-response relationship for the impact of BPA on cell proliferation.
second round was performed to confirm that BPA was directly responsible
for stimulating proliferation, by comparing BPA's impact on gene
expression with that of a natural androgen, DHT, and a control.
performed additional experiments to determine whether the impact
of BPA on cell proliferation was related to the activation of
mutated androgen receptors.
did they find? Wetherill et al. first observed
a dramatic nonmonotonic
dose-response relationship between bisphenol A exposure and proliferation
of prostatic adenocarcinoma cells. Their experiments were all conducted
at very low levels of BPA (the "nanomolar" range, parts
per billion). As shown in the figure below, the largest
response to BPA was observed mid-way along the dose-response curve,
at 1 nanomolar. As required, for a successful experiment,
the positive control, dihydrotestosterone, increased proliferation.
Low levels of BPA also stimulated proliferation while the highest
level of BPA used, 100 nM, actually suppressed proliferation slightly.
stimulates LNCaP proliferation. Wetherill et al.
used a standard assay of DNA synthesis (BrdUrd
incorporation rate) to monitor the proliferation of prostatic
adenocarcinoma cells. BPA effects were compared to a vehicle
control (ETOH, labelled 'control') and a positive control,
would be expected on the basis of these results, cell numbers of
the positive control (DHT) and BPA-exposed cultures increased over
time, demonstrating proliferation.
proliferation following exposure to 1 nanomolar BPA (note
the log scale).
research in their laboratory at the University of Cincinnati had
characterized the way that DHT stimulates a series of biochemical
events in LNCaP cells that allows them to proliferate. In the next
round of experiments, Wetherill et al. showed that BPA
is capable of stimulating the same series, demonstrating that BPA
can initiate proliferation in prostatic adenocarcinoma cells via
the same biochemical pathways and thus allowing the cells "to
bypass the requirement for androgen."
more deeply into the biochemical mechanisms involved, Wetherhill
et al. demonstrated through a series of experiments that
BPA activates a mutant form of the androgen receptor present in
androgen independent prostate cells (AR-T877A) and that the BPA-AR-T877A
complex then induces gene expression, exploiting the same biochemical
pathway used by DHT in androgen dependent cells. Their data demonstrate
that "AR-T877A activation results in induction of endogenous
AR target genes."
they showed that BPA exposure caused accumulation of one of the
mutant forms of the androgen receptor, AR-T877A, in the nucleus
of proliferating cells after BPA exposure, as does DHT exposure.
This observation links BPA-induced cell division to the activation
of the mutant androgen receptor. Nuclear accumulation takes place
when the receptor binds to its ligand (hormone), becomes activited
and migrates into the cell nucleus; unless it has been activated
it won't accumulate.
hours after treatment, most prostate cancer cells have accumulated
AR-T877A in the presence of DHT and BPA.
they showed that BPA can activate the binding of the mutated AR-ligand
complex to the DNA sequences specific to where the DHT-activated
complex binds. The BPA activation can take place even in the absence
of other steroids.
they studied PSA, a protein secreted by the prostate and under
the control of a gene that is expressed following androgen activation
of the unmutated AR receptor. [PSA, or prostrate specific antigen,
is elevated in patients with prostate cancer and hence is used
as a marker for prostate cancer.] First they established that
PSA gene expression was not increased by BPA via the unmutated
androgen receptor. This is what they expected because the unmutated
form is responsive to a narrow suite of androgens but not to BPA.
In contrast, PSA expression was increased by BPA activation
of the mutated form of the androgen receptor, AR-T877A.
In fact, BPA induced a 5-fold increase in PSA expression, compared
to DHT's 5.9 fold increase.
fourth, they demonstrated that AR-T877A activity was required
for BPA to have a proliferative effect. In otherwords, unless
the androgen receptor has mutated into a form that is less ligand-specific
(called "promiscuous"), BPA cannot initiate AR-dependent
processes. This makes sense because BPA does not bind to the normal
does it mean? As the authors observe, "these data
implicate BPA exposure as a potential mechanism that could
facilitate the transition of prostatic adenocarcinomas to androgen
independence." Transition is what causes the failure
of hormonal treatment for prostate cancer, leading to patient morbidity
makes this finding even more important is the nanomolar levels at
which the effects were highly significant. These are levels that
have measured in adult men leading normal lives (1.4 to 6.5 nM).
scientific questions arise. Is the AR-T877A mutant androgen receptor
the only mutant form with which bisphenol A binds and then activates
gene expression? Do other xenoestrogens exert similar effects, through
AR-T877A or other forms? Is this mechanism at work in prostate cells
in men? Are there detectable effects of BPA or other xenoestrogens
on the progression of prostate cancer? Currently, none
of these questions can be answered.
do these results mean for men undergoing treatment for prostate
cancer? Until further study establishes that BPA does not
exert this influence in men with prostate cancer (as opposed to
cells in cell culture), men undergoing hormone treatment for prostate
cancer who are looking for ways to make their treatment more effective
should consider taking steps to reduce their exposure to
bisphenol A as a precautionary measure.
exposure comes from multiple sources. For example, bisphenol A-based
polycarbonate is used as a plastic
coating for teeth to prevent cavities, as a coating
in metal cans to prevent the metal from contact with food contents,
and as the plastic in food containers, refrigerator shelving, baby
bottles, returnable containers for juice, milk and water, micro-wave
ovenware and eating utensils (more...).
simplest and least controversial of these exposures to reduce
is via food items that have been heated (e.g., microwaved) in polycarbonate
containers. Don't do it. The leaching rate from polycarbonate
is temperature-dependent: the hotter it gets, the faster the leaching.
There are other, readily available containers in which to heat food.
Food stored in refrigerators in polycarbonate containers is not
likely to be a major source because of the cold temperatures. Also
worth noting is that old polycarbonate leaches much more rapidly
than new polycarbonate. While this recommendation is simple to implement
at home, it is more of a challenge with fast food, where plastic
of a number of varieties, including polycarbonate, is commonly used
a food container for heating.
use of bisphenol A to coat the interior of food cans
is problematic because it is impossible to tell, given current labeling
requirements, which food cans use it and which don't. For those
cans with bisphenol A lining, the type of food (fatty?) and the
way it was placed in the can (still hot?) will also affect how much
leaching will occur. A cautionary step would be to reduce
consumption of canned food, especially with fat (like meat- or milk-based
soups), at least until labeling catches up with this issue.
British "Food Standards Agency" surveyed
canned foods for bisphenol A content and found wide variability
among products and countries. They concluded that there was no health
risk. This conclusion was reached (2001) when there was lingering
controversy about low level effects of BPA because of claims by
industry that results demonstrating adverse effects could not be
replicated. Those debated results have now
been confirmed, and many
other studies have been added to the litany of concerns about
BPA, including this one by Wetherill et al. The Food Standards
Agency's decision needs review in Britain. The US Food and Drug
Administration should review this also.
plastic dental sealants leach bisphenol A, others do not. According
estimates, the use of bisphenol A in sealants is declining and
no sealants currently recommended by the American Dental Association
leach BPA. Ask your dentist about the details of the sealants
he/she is using.