Effect Measure

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.

Comments

  1. #1 floormaster squeeze
    October 10, 2008

    I liked this line.

    “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.”

  2. #2 biopunk
    October 11, 2008

    Can anyone tell me when BPA was widely introduced into consumer products? I’m old enough to remember soda pop coming in glass bottles, but I don’t recall what kind of plastic the replacements were like…

    Was/is there a benchmark that studies of tissue samples establish as a before/after with regards to the BPA related estrogenic compounds? And what about the containers these same tissue samples are contained in? How great is the probability that BPA in the container is affecting these findings and not actually the individual’s exposure?

    It seems to me the ubiquity of BPA in the environment and in labware would make this even more problematic. Could you shed some more light on this?

  3. #3 biopunk
    October 12, 2008

    In regards to my previous post, I found this:

    “(Patricia) Hunt, now with the School of Molecular Biosciences at Washington State University, started studying bisphenol A when she ran an experiment one week with normal results and then ran it the next, “and the control numbers were just completely bonkers.” Sterilizing the animals’ cages with high heat and accidentally washing them with a high pH soap damaged their polycarbonate cages and water bottles. Hunt found that bisphenol A leached from the water bottles and into their drinking water, and likely contaminated their food and penetrated their skin. Rather than pinpoint the exposure routes, however, she wanted to determine whether bisphenol A caused the anomaly. She did that by deliberately exposing her mice to bisphenol A.”

    http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0050193&ct=1

  4. #4 Perimenopausal Hell
    June 1, 2009

    I’m a 48 year old woman in excellent physical condition, who doesn’t smoke or drink. I’m also perimenopausal, and am being treated for severe (and I mean SEVERE) Dysfunctional Uterine Bleeding. Until recently, I’d never had any problems with menstruation, cramping, bleeding, hormonal imbalances, etc. However, five years ago, I moved into the woods, build my own cabin, and have been living without indoor plumbing or electricity. Since I haven’t had refrigeration and rarely buy ice, my consumption of canned goods skyrocketed — especially from October until June. Obviously, at my age, hormone fulgurations, etc, is normal. But is there any chance that the sudden and relatively consistent and high daily consumption of BPA is a contributing factor in my perimenopausal hell?

  5. #5 perimenopausal hell
    June 1, 2009

    Don’t know where “fulgurations” came from! Should have said “fluxuations.” So sorry!

  6. #6 otakucode
    June 1, 2009

    So BPA prevents cell death. Does it only prevent cell death in cancer cells, or is its sabotage of apoptosis more widespread?