Solvent, common drug plus hormones raise risk of reproductive failures and breast cancers

April 19, 2004

DURHAM, N.C. -- Researchers have identified an industrial solvent in the environment and a frequently prescribed drug, valproic acid, as compounds that so potently boost estrogen and progestin activity inside cells that they likely trigger the reproductive failures -- and potentially even breast cancers -- seen among women exposed to these chemicals.

Moreover, many women who are unknowingly exposed to these compounds could be at increased risk for hormonally related cancers, miscarriages and irregular ovulation, said the researchers from the Duke Comprehensive Cancer Center and the department of pharmacology and cancer biology at Duke University Medical Center.

Their findings suggest that estrogen and progestin alone may not be the sole triggers for the increased risk of invasive breast cancers in postmenopausal women who take hormone replacement therapy. Rather, it may be that select women who are exposed to hormone-sensitizing compounds are put at higher risk for cancer and cardiovascular events.

In fact, there may be dozens or even hundreds of similar compounds throughout the environment that can sensitize cells in the body to hormones such as estrogen, progestin and even testosterone, said Duke pharmacologist Donald McDonnell, Ph.D. Such compounds are known as "endocrine disrupters" because they alter the normal course and behavior of hormones in the body.

McDonnell is principal investigator of a study describing these results, to be published in the April 19, 2004, issue of the Proceedings of the National Academy of Sciences. The lead author is Michelle Jansen, Ph.D., pharmacology research associate at Duke.

"Our study demonstrates that these chemicals boost the activity of estrogens and progestins inside cells eight- to 10-fold," said McDonnell. "These data should prompt caution for patients who are exposed to either of these chemical compounds while taking any estrogen- or progesterone-containing medications, such as hormone therapy, oral contraceptives or tamoxifen for breast cancer."

McDonnell said the activities of these compounds wouldn't necessarily be deleterious in all cases, but they do mandate vigilance by the medical community because the duration of exposure to estrogens, progestins and androgens is associated with increased risks of breast, ovarian and prostate cancers.

For decades, scientists have firmly believed that estrogen "mimics" -- chemicals in the environment that act like estrogen inside cells -- have been responsible for various illnesses and anomalies within the animal and human populations. Yet few, if any, estrogen mimics have been definitively proven to compete with estrogen for its activation site inside cells.

McDonnell's team decided to test compounds already known to have some effect on the reproductive system and, by doing so, proved that two compounds of similar chemical structure can sensitize cells to estrogen and progestin without acting like them at all.

The first chemical, ethylene glycol methyl ether (EGME), is an industrial solvent found in varnishes, paints, dyes, fuel additives and the semiconductor industry. The second compound -- valproic acid (trade name Depakote) -- has a similar chemical structure as EGME and is among the top 100 drugs prescribed in the U.S., used to treat bipolar disorder, seizures and migraines.

Exposure to this class of compounds is known to induce reproductive toxicity in people and rodents. In men, they cause reduced sperm counts and in women they cause spontaneous abortion and irregular ovulation. However, the mechanism behind these effects has been unclear. McDonnell's team analyzed the compounds' behavior inside cells to determine how they affected hormonal activity.

They found that both compounds accelerate the process called gene transcription -- the "reading" of the cell's genes to build the cell's machinery. Transcription is required for cells to thrive and carry out their intended purpose in each respective organ or tissue. Yet uncontrolled or inhibited transcription can result in any number of diseases and dysfunctions, including cancer.

In the current study, McDonnell's team found that EMGE is converted by the liver into a derivative compound called methoxyacetic acid (MAA). Valproic acid is administered in an already active state.

Once inside cells, MAA inhibits a class of enzymes (histone deacetylases) that normally slows the process of gene transcription, in which a portion of the genetic code is read, copied, and prepared for action within the cell. Without these enzymes there to inhibit gene transcription, the process loses its brakes and proceeds at an elevated pace.

MAA has an additional effect inside cells whereby it activates an enzyme (called mitogen-activated protein kinase or MAP kinase), one of its primary jobs being to accelerate the rate of transcription.

Thus, not only are the brakes removed from the transcription process, but the accelerator on transcription is firmly applied. The dual impact of both enzymes revs up the cell's activity and potentially fuels its growth beyond what is normal and healthy -- a hallmark of developing cancer and other dysplasias, said McDonnell.

"Estrogen produces effects inside cells in a very tightly controlled manner, so skewing that process by accelerating transcription can produce a variety of problems," said McDonnell.

In order for MAA to accelerate the transcription process, however, estrogen or some other hormone must be present inside cells to initiate it, McDonnell added. This symbiotic relationship between hormone and chemical is critical because it highlights MAA's mechanism of action as well as a previously unrecognized drug-drug interaction, said McDonnell. MAA does not bind to the estrogen receptor inside the cell, as estrogen "mimics" were long believed to have done. Instead, it acts directly upon the two aforementioned enzymes to accelerate the transcription process that estrogen has triggered. Thus, MAA could be considered a new class of endocrine disrupter, said McDonnell.

He said his current findings should raise awareness in the scientific and medical community about the importance of developing screening technologies to analyze various chemicals of this mechanistic class for their activity on hormones.

"Clearly, these chemicals are affecting the cellular environment where estrogen works, and our goal would be to identify other chemicals with the same effect and alert the public to the potential for such drug-drug interactions."
-end-


Duke University Medical Center

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