Synopsis by Dr. Richard Stahlhut, MD, Dr. Susan Nagel and Wendy Hessler

Very low doses of the synthetic estrogen, bisphenol A (BPA), increased expression of genes in fetal mouse prostate cells that are responsible for directing production of hormone receptors. Its impact was quite similar to responses caused by the natural estrogen, estradiol: Both boosted genetic production of androgen and estrogen receptors.

BPA affected the tissues at the low parts per billion levels, levels commonly found in human and fetal blood. For estradiol, low and medium doses in the parts per trillion range triggered more gene expression than the highest doses. This is a common pattern for hormone action.

Under normal use bottles made of polycarbonate, like those above, will leach meaningful amounts of bisphenol A

Context: Nutrition, stress and other triggers can cause changes during fetal development that lead to diseases (e.g., heart illness, diabetes) later in life. Symptoms may not be evident until adulthood.

This phenomenon is known as fetal programming or 'developmental origins of adult disease.' The triggers alter physiological development in a way that leads to changes in how individuals affected in the womb respond to conditions-- nutrition, environment, stress, etc.-- in adulthood. The fetal triggers include abnormal hormone exposures-- either too much or too little-- that can also initiate disease during development although symptoms may not be seen until adulthood (Barker et al. 2002).

Chemical exposure early in life can cause fetal programming. Developmental exposures to toxic chemicals, such as the hormonally active substances, diethylstilbestrol, tributyl tin, bisphenol A and genistein, can increase the incidence of reproductive abnormalities, metabolic disorders, including obesity and diabetes, and cancer.

Hormones influence how the cells and tissues that become the prostate gland form. Hormones work through specific receptors. The natural estrogen, estradiol, binds to the estrogen receptor (ER), and the natural androgen, testosterone, binds to the androgen receptor. Binding triggers the receptors to begin associated gene expression.

The prostate gland is a male organ and its growth and development are mainly controlled by androgens, such as the primary male hormone testosterone. But, estrogens are important, too. Previous research in mice shows developing fetal prostate tissues are permanently changed by exposure to estrogens (Timms et al. 2005).

During development, the amount of estrogen the prostate tissue is exposed to will determine how many estrogen and androgen receptors the prostate cells will ultimately have. This in turn affects the sensitivity to these hormones later in life-- the more receptors, the more responsive the prostate, and the more growth occurs. Estrogen exposure is, in effect, setting the hormone “thermostat” that permanently determine how the tissues will respond to estrogens and androgens throughout life.

Although this effect was first discovered with naturally occurring estrogens, synthetic or environmental estrogenic chemicals can produce the same or similar responses. One such chemical, bisphenol A, is present at measurable levels in 95% of Americans because of its widespread use in commercial products, such as plastic water and baby bottles, dental sealants and food can linings (Welshons et al. 2006).

Female mice were mated, and 18 days later (1 day before birth), the fetal male mice were removed from the womb. Tissues were removed from the area that develops into the prostate gland, and the mesenchyme cells were isolated. Research has established that the prostate's mesenchyme cells control the prostate’s future development so were the best cells to use.

The cells were grown in culture dishes using serum filtered to remove all traces of hormones. Cells were then exposed to 10 concentrations of estradiol and BPA ranging from 0.0001 to 100,000 nanomolar (nM). One nanomolar of BPA is approximately one part per billion.

This extremely wide range of exposures allowed was essential because exposure impacts can be different at different doses-- and not always in the simple "higher dose means larger effect" way. Endocrinologists regularly report that hormones can stimulate gene expression at low levels and suppress it at high levels (more...).

The antiestrogen tamoxifen (a breast cancer drug), was also added to treated cells to determine if estradiol and BPA worked through the estrogen receptor to affect the prostate tissues.

Cell growth was measured by isolating and quantifying total DNA. The research team then used methods from molecular genetics to measure the expression of genes involved in making hormone receptors. Gene expression is the first step in making new proteins, so changes in gene expression are a measure of how many androgen and estrogen receptors are made in cells.

What did they find? Both estradiol and bisphenol A stimulated cell growth in the prostate cells with a low effect level of 0.01 nM estradiol and 1,000 nM bisphenol A.

Estradiol and bisphenol A induced the expression of androgen receptor with a low effect dose of 0.001 nM estradiol and 1 nM bisphenol A. This stimulation was blocked by the estrogen receptor antagonist tamoxifen, which shows these effects were due to stimulation of the estrogen receptor.

Over a wide range of doses, BPA altered the expression of androgen receptor mRNA. The lowest concentration to significantly change AR mRNA was 1 nM (1 ppb). The shaded area shows the range of concentrations of BPA observed in people.

Estradiol and bisphenol A both stimulated estrogen receptor alpha production with a low effect dose of 0.1 nM estradiol and 1 nM bisphenol A.

BPA altered expression of estrogen receptor mRNA. The maximum dose was obtained at 10,000 nM. The lowest dose to cause a significant change was 1 nM (1 bbp). The dose-response curve is another example for BPA of non-monotonicity.

Bisphenol A stimulation was blocked by the estrogen receptor antagonist tamoxifen indicating that this effect was again through the estrogen receptor. Interestingly, the estradiol effect was not blocked significantly by tamoxifen.

What does it mean? Synthetic estrogens, like natural estrogens, can affect growth and development of prostate tissue by increasing the number of hormone receptors in cells. In this study, both BPA and estradiol acted through the estrogen receptor to direct androgen and estrogen receptor production. BPA’s effects were seen at concentrations currently reported in people’s blood.

According to the authors “these results are consistent with the hypothesis that prenatal exposure to elevated estrogen or xenoestrogen levels within the physiological range results in an increase in androgen receptor and estrogen receptor 1 number in the developing prostate mesenchyme, which increases androgen and estrogen responsiveness and growth.”

Earlier research suggested that these changes are permanent. Here, researchers demonstrate the effects of estrogen on mouse prostate tissue development are not specific to naturally occurring estrogens, but also occur with bisphenol A. Since the effects of BPA were found at levels currently present in the bloodstream of people – including pregnant mothers – it is reasonable to be concerned that these effects may be happening in human populations today.

It is possible that human baby boys may have altered prostate gland development due to BPA exposure in their mother’s wombs. The current human exposure levels of BPA may be changing the development of babies, despite assurances that these low levels of exposure are incapable of causing harm.

The results may also underestimate the adverse effects estrogenic chemicals are having on our children. Since multiple estrogenic chemicals given simultaneously have been shown to add together in effect (Rajapakse et al. 2002), and since people are exposed to many other estrogenic chemicals, the cell and tissue changes associated with exposure to chemical mixtures in the environment may be even greater than shown in this study with either bisphenol A or estradiol alone.