Web edition: June 10, 2009
Heart arrhythmias in females and permanent, deleterious modifications of a gene that plays a pivotal role in reproduction are two new problems being linked to bisphenol A. Best known simply as BPA, this chemical is a building block of polycarbonate plastics — the hard, clear type used in kitchenware and baby bottles — and of resins used to line most U.S. food cans.
Data on BPA’s hormonal alter ego first emerged in 1938, when researchers reported the chemical could trigger biological changes normally seen with estrogen. That’s the primary female sex hormone. By the early 1990s, studies showing how strong this estrogen mimic is and how ubiquitous BPA has become began to trickle out — a flow that has since developed into a wholesale torrent.
At the Endocrine Society meeting in Washington D.C., this week, three different research teams will report new and troubling data from animals experimentally treated with BPA. The scientists shared their findings with reporters, late this morning. Formal presentations of their data are scheduled for later this week.
Reprogramming fertility gene
Decades ago, research showed that exposures in the womb to diethylstilbestrol, an estrogenic drug, could harm uterine development and, ultimately, the reproductive health of adult women. Now, researchers at Yale University are investigating how another synthetic estrogen — BPA — might affect reproduction. They’re focusing on genes associated with uterine development and the capacity of a female to support a full-term pregnancy.
Hugh Taylor and his colleagues exposed mice on days 9 to 16 of the animals’ pregnancies to 5 milligrams of BPA per kilogram body weight. Once the female offspring reached adulthood, the researchers analyzed uterine cells in these mice.
At the Endocrine Society meeting, these researchers will report finding permanent and irreversible alterations in a gene known as HOXA10. It plays an important role in uterine development and the fertility of many animals (including humans), Taylor says. Among fetally exposed mice, HOXA10 genes tended to lose a methyl-group appendage (a carbon bound to three hydrogen atoms). This demethylation, known as an epigenetic change, rendered uterine tissue hypersensitive to the effects of estrogen.
Hormones orchestrate the activity of cells and organs. The most demethylated segment of DNA, Taylor reports, was the patch where estrogen binds to the HOXA10 gene. Only rodents that had been exposed to BPA in the womb showed this inappropriate demethylation. So what? The new study shows it takes far less estrogen to trigger hormone action in uterine cells hosting this demethylated gene.
That’s probably not a good thing, Taylor says, because “many of the diseases we have as adults really have their origins in the fetal time period” — when genes or their action become inappropriately modified.
Toying with the female heart
A second study indicates that fetal development is far from the only period when animals — including people — may be vulnerable to BPA’s toxicity. When it comes to the female heart, premenopausal adult exposures may also wreak havoc. At least if one can extrapolate to humans from rodent data collected by Scott Belcher of the University of Cincinnati and his colleagues.
Although fewer premenopausal women experience heart attacks than do men their age, “women actually have a worse prognosis following a heart attack,” Belcher points out. Indeed, prior to menopause, “their mortality rate after a heart attack is more than double that of men.” And much of the reason, he says, “is due to arrhythmias.”
It’s seemed possible that estrogen might play a role in this, he says, since “there are unique sensitivities to arrhythmias during pregnancy.” Ones that he says “correlate with increasing concentrations of estrogen.”
In one new set of experiments, his team investigated contraction rates of heart-muscle cells living in a test tube. Both estrogen and BPA altered contraction rates — and nearly identically, the researchers found. Very low doses of each triggered significant contractile changes, even at picomolar concentrations. (Pico, by the way, is a prefix meaning trillionth — as in very tiny.) Peak changes, he reports, occurred at levels “present in human populations,” Belcher reports.
But expose the cells to both estrogen and BPA and contractile abnormalities skyrocketed — well beyond what would be expected from simply adding effects due to either hormone alone.
In another set of experiments, pacemakers controlled the rate of contractions in the muscle cells. When the pacemaker was turned off, Belcher reports, cells that had been exposed to estrogen or BPA suddenly experienced “pro-arrhythmic events.”
Whole hearts responded similarly to the isolated cells: Picomolar concentrations of BPA and estrogen triggered arrhythmic events that were far worse when the organ was exposed to both.
Interestingly, “the male heart does not respond in this way,” Belcher notes. His team found that a heart’s sensitivity to estrogens and/or BPA reflected the amount of a certain type of estrogen receptor in cells — the beta form. It’s present at higher concentrations in the female heart.
So at concentrations of estrogen typically found in premenopausal women, Belcher says, the addition of BPA would “likely” spike vulnerability to potentially deadly arrhythmias.
Human intakes: Greatly underestimated?
Finally, new data hint that people may face far larger BPA exposures than previously thought. That’s a conclusion that Frederick vom Saal of the University of Missouri-Columbia draws from his team’s new study with rhesus monkeys, an animal that he says models human responses to hormones and hormone mimics.
The Food and Drug Administration estimates typical daily human BPA consumption at roughly one microgram of BPA per kilogram of body weight in babies; adult per-kilogram body weight intake is perhaps one-tenth that much. Vom Saal’s group administered 400 µg/kg/day to its 11 monkeys, then monitored how much this elevated the adult animals’ blood concentrations of BPA. The surprise, vom Saal says, is that blood residues in the spiked monkeys ended up being only one-eighth as high as measured in one German study of pregnant women.
That suggests, vom Saal says, that if these monkeys indeed metabolize BPA at rates comparable to people, “humans would have to be exposed to over 1,000 µg/kg/day in order to achieve the kind of [blood] levels that are seen in multiple studies, not just the [German] one.”
Keep in mind, vom Saal says, FDA and the Environmental Protection Agency have estimated that a safe upper limit for daily human consumption of BPA is only 50 µg/kg/day. And that value was set 20 years ago, he points out, before the publication of dozens of recent animal studies showing that BPA concentrations well below 50 µg/kg/day can cause harm.
Bottom line: BPA appears harmful even at concentrations present in the U.S. population, the researchers said. So people should do what they can to reduce their exposures.
Belcher, S.M., et al. 2009. Estrogen Receptor-Mediated Mechanisms Underlie Sex-Specificity of Rapid Actions of 17β-Estradiol and Bisphenol A in Ventricular Myocytes (Abst. P2-56). Endocrine Society annual meeting, Washington, D.C. (June 13). [Go to]
Taylor, J.A., . . . and F.S. vom Saal. 2009. Serum Bisphenol A Concentrations Following Oral Adminstration in Adult Female CD-1 Mice (Abst. P2-66). Endocrine Society annual meeting, Washington, D.C. (June 11). [Go to]
VandeVoort, C.A., . . . and F.S. Vom Saal. 2009. Oral Exposure of Female Rhesus Monkeys to 8-Times More Bisphenol A Than the FDAs “Safe” Daily Dose Results in Plasma Unconjugated Bisphenol A below Mean Levels in People [Abst. P2-61]. Endocrine Society annual meeting, Washington, D.C. (June 11). [Go to]
Bromer, J.G., . . . and H.S. Taylor. 2009. Bisphenol-A (BPA) Exposure In Utero Leads to Epigenetic Changes and Altered Developmental Programming [Abst. OR33-4]. Endocrine Society annual meeting, Washington, D.C. (June 13). [Go to]
Wang, H.S., . . . and S.M. Belcher. 2009. Low-Dose Bisphenol-A Promotes Arrhythmogenesis in the Female Heart Via Alteration of Calcium Handling (Abst. OR33-3). Endocrine Society annual meeting, Washington, D.C. (June 11).
Alderson, N. 2008. Statement on Bisphenol-A (BPA) before the House Energy and Commerce Subcommittee on Commerce, Trade and Consumer Protection (June 10). [Go to]
Environmental Protection Agency. 2008. Integrated Risk Information System (IRIS) Review on Bisphenol A (Jan. 10). [Go to]