The health concerns about bisphenol-A (BPA), a component of hard polycarbonate plastic, has been extended once again (see here, here, here for previous posts on BPA). BPA, a ubiquitous contaminant of human bodies, leaches from water and baby bottles, the lining of tin cans, dental sealants and many other sources. BPA also looks a lot like potent hormones, like estradiol and the synthetic estrogenic agent, diethylstilbesterol (DES), the cause of transplacental carcinogenesis in humans. So there have been plausible concerns that BPA might increase the risk of cancer in humans, especially in hormonally sensitive tissues like breast. A new paper from Nira Ben-Jonathan’s laboratory at the University of Cincinnati now adds another concern: that BPA may be increasing resistance to chemotherapy for breast cancer.

The unfolding story of BPA is a good example of how the things we should fear the most are not what we don’t know but what we think we know but are wrong about. BPA is an estrogenic compound and hence attention focused on known mechanisms whereby estrogen and related hormones initiated their actions. One of the main ways estrogen works is through a receptor molecule, essentially a protein that combines with estrogen. The combination then sets in motion other effects, resulting eventually in genes being turned on or off, which in turn causes proteins to be made or not made. BPA can also push the main estrogen receptor button (ERalpha) but it takes a lot of BPA to do it. Then another estrogen receptor was discovered, ERbeta. Same story with BPA. So when BPA was tested for biological effects relatively high doses (relative to those circulating in the blood as a result of environmental exposure) were tested in the laboratory. This led some to conclude BPA could not be a problem at environmentally relevant doses. But data from the laboratory continued to accrue showing that there were biological effects at doses 100 to 1000 times lower than those used in those studies, i.e., doses at concentrations commonly found in the blood of the majority of residents of the US (typically 0.5 to 40 nanomoles/ml). Moreover, biological responses were actually higher for the lower doses than the higher doses, a phenomenon seen in hormones and other biological signalers and co-factors (like vitamins). The higher doses, based on the estrogen receptor mode of action, may have been masking effects that would have been seen at lower doses. While the naysayers continued to explain that nothing designed like a bumblebee could possibly fly, the BPA bumblebee was flying in study after study. There was clearly more to it than the known estrogen receptors.

Now there is good evidence for “non-classical” mechanisms (i.e., not through the two estrogen receptors) for estrogen action, including the G-protein coupled receptor GPR30 and members of the estrogen related receptor family: ERRalpha, ERRbeta and ERRgamma. It turns out that BPA binds to ERRgamma particularly strongly at concentrations normally found in environmentally exposed people. And one of the biological effects seen in tissue culture studies at environmentally relevant doses is induction of resistance of breast cancer cells to chemotherapy agents:

“Resistance to chemotherapy is a major problem for cancer patients, especially those with advanced or metastatic disease,” says Ben-Jonathan, a professor of cancer and cell biology at UC who has studied BPA for more than 10 years. “Finding out what contributes to that resistance can give us an idea of what to target in order to make chemotherapy as effective as possible.”

Researchers have suspected that BPA could play a role in cancer because of the chemical’s structural similarities to a cancer-promoting compound called diethylstilbestrol (DES). But Ben-Jonathan’s team found that BPA isn’t exactly mimicking the action of DES.

“BPA does not increase cancer cell proliferation like DES does,” she says. “It’s actually acting by protecting existing cancer cells from dying in response to anti-cancer drugs, making chemotherapy significantly less effective.”

Ben-Jonathan’s team studied human breast cancer cells, subjecting them to low levels of BPA consistent with levels found in the blood of human adults. The team found that BPA is acting in cancer cells similar to the way estrogen does–by inducing proteins that protect the cells from chemotherapy agents.

[snip]

“These data,” study authors write, “provide considerable support to the accumulating evidence that BPA is hazardous to human health.” (U. of Cincinnati press release)

There is more to this interesting paper. Using breast cancer cells that are both estrogen responsive and non-responsive Ben-Jonathan and colleagues were able to show that BPA was not working through the classical estrogen receptor, ERalpha or ERbeta. More likely, BPA was preventing cancer cells altered by the routine chemotherapy drugs Doxorubicin, cisplatin and vinblastine from being eliminated by the normal process of programmed cell death (apoptosis). Interestingly, each of these drugs works by a different mechanism:

Doxorubicin causes DNA damage by chelating metal ions, generating free radicals and inhibiting topoisomerase, thereby blocking transcription. Cisplatin, a platinum based compound, causes DNA intrastrand crosslinking and inhibits replication. Vinblastine acts by interfering with microtubule dynamics, resulting in mitotic arrest and cell death. As mentioned above, estradiol protects against a microtubule altering, as well as a DNA damaging drug. (LaPensee, Tuttle, Fox,Ben-Jonathan, Bisphenol A at Low Nanomolar Doses Confers Chemoresistance in Estrogen Receptor Alpha Positive and Negative Breast Cancer Cells, Environ Health Perspect doi:10.1289/ehp.11788 available via http://dx.doi.org/ [Online 8 October 2008])

This study simultaneously sheds light on chemotherapy resistance of breast cancer but also suggests that a ubiquitous environmental agent might be interfering with breast cancer treatment. BPA has a very short half-life in the body and thus there is a possibility that the BPA effect, if it is real, could be ameliorated in breast cancer patients by preventing any further exposure to BPA.

In any event, this paper is another entry in BPA’s rap sheet. How many more will it take before US FDA decides BPA isn’t so innocent, after all.