From the Special Topic of
Bisphenol A (BPA)
According to our Special Topics analysis of bisphenol A
research over the past decade, the work of Dr. Ana Soto
ranks at #2 by total cites, based on 27 papers cited a
total of 930 times. In
Essential Science IndicatorsSM from
Reuters, Dr. Soto's record includes 74 papers cited a
total of 1,820 times between January 1, 1999 and April 30,
2009. She is also a
Highly Cited Researcher in both
Ecology/Environment and Pharmacology.
Dr. Soto heads up her own lab at the Tufts University
School of Medicine, where she is Professor of Anatomy and
In the interview below,
ScienceWatch.com correspondent Gary Taubes talks with
Dr. Soto about her highly cited research relating to
When did you first get interested in the
subject of endocrine disruptors and what prompted it?
That was in 1989, when I was working, as I still am, with Professor Carlos
Sonnenschein. We had come to the conclusion, contrary to perceived wisdom,
that estrogen does not directly induce cells to proliferate, but rather,
blocks the action of a plasma-borne inhibitor. This was something really
iconoclastic, but really important. Although I'm always being interviewed
for my work on endocrine disruptors, this research related to control of
cell proliferation is, conceptually speaking, more important. We, like
everyone else, thought that in order for cells to proliferate, they had to
be stimulated—we thought that's what estrogen did. But we found out,
much to our surprise, that cells could proliferate without estrogen in
culture conditions even though the same cells in animals could only
proliferate when estrogen was present. That was a paradox and, to make a
long story short, what we found was that estrogens do not actually induce
cells to proliferate; rather, they block the action of the above-mentioned
That was very interesting, but it brought us to another puzzle: why
everyone was thinking along the positive control of cell proliferation and
we were finding just the opposite, i.e., that cell proliferation was under
negative control. We started looking at the literature and found a great
paucity of data regarding this issue. Eventually we published a book on the
implications of this finding: The Society of Cells.
Now back to the endocrine disruptors. In 1989, we were trying to determine
what it was in serum that inhibited the action of estrogen in the animal.
We had developed an assay that worked like this: in the absence of serum,
cells would proliferate, but if you added a fraction of the serum that was
inhibitory, they wouldn't. Then, if you added estradiol back, these cells
proliferated again. So we used this assay for years until all of a sudden
it stopped working. The cells would proliferate even in the presence of the
inhibitor. It didn't matter if we added estrogen or not. It smacked of
contamination with estrogen. We spent four months trying to figure out
where the unknown estrogen came from until we verified that it was
something shedding from the test tubes that we used to store the serum
How did you identify what the active compound was?
At that point, we called the manufacturers and told them about our strange
experience. They said that they didn't know where the estrogen could be
coming from, but they agreed to send us four or five batches of these
plastic tubes. We called them back two weeks later and told them which
batch had the estrogens. They then traced those batches to a change in the
formulation of the plastic manufacturing—they had made it sturdier,
more impact-resistant. We asked them what it was they had added, but they
said it was a trade secret.
We spent another year purifying the "trade secret." It turned out to be
nonylphenol, an antioxidant that's also used in the synthesis of
detergents. Carlos and I published our findings and then went looking for
other places where nonylphenol was used. It turned out that it's also in
the spermicides used in condoms and in creams applied with
diaphragms…right there we knew it could be a big problem.
Was that first paper noticed? Did anyone pay
attention at the time?
Theo Colborn became aware of our work and invited us to a conference she
organized in 1991 in Wingspread, Wisconsin. At the time, she was concerned
about the problems in the Great Lakes with animals that looked feminized.
The idea was that DDT is also estrogenic, as are polychlorinated biphenyls.
These two chemicals had already been banned; however, if they were the
causal agents of these changes, there was nothing to be done but wait until
the levels of these chemicals decay, hoping that enough individuals of each
species of animals would have survived the consequences of these exposures
If, instead, the problem in the Great Lakes was due to the kind of
chemicals we were now studying, additional regulatory measures could be
taken to protect the environment. Colborn put together a panel with 20
scientists and I was one of them, and we came up with this term "endocrine
disruptors" and shared in the writing of what's called the Wingspread
We then wrote the first paper on endocrine disruptors together with Theo
Colborn and Fred vom Saal, which was published in 1993. We also decided to
test other chemicals used in the environment. So Carlos and I tested a
battery of these chemicals and found that several of them were estrogenic.
They're less potent than the natural ovarian hormone, but it prompted us to
ask what would happen if animals are exposed to them.
What other evidence was there that these compounds
could be problematic?
There was the diethylstilbestrol story. That's DES, the synthetic estrogen
given to pregnant women in the 1950s with the stated purpose of preventing
miscarriages. Some of the women exposed to DES during fetal life developed
cancer of the vagina. This finding led to the banning of its use in
pregnancy in 1971. This unintended consequence demonstrated that the fetal
system is exquisitely sensitive and a target of these hormonally active
chemicals. So we had to figure out what else could happen to fetuses
exposed to estrogenic chemicals released from plastics.
Instead of using nonylphenol, we used bisphenol A (BPA), which another
group had identified as estrogenic and also present in plastic. The use of
BPA is also more widespread than that of nonylphenol. We exposed animals to
what, to us, seemed to be environmentally relevant doses during pregnancy,
and then followed their offspring development. The first thing we noticed
was that we got much more than we bargained for; namely, we saw some things
you'd expect with estrogens—that is reproductive effects—but in
addition we also noticed obesity and even behavioral problems. It also
produced masculinization of the female hypothalamus, alterations in control
of ovulation, alterations in development of the mammary gland, and
increased propensity of the mammary gland to develop cancer. This portion
of our studies was done in collaboration with Professor Beverly Rubin.
Meanwhile, research done by Dr. Antonia Calafat and her colleagues at the
CDC revealed high levels of BPA in human urine from a cross-section of the
American population. These studies confirmed that the BPA levels used in
our experiments were environmentally relevant.
When was this follow-up work published?
These were all published between 2001 and now. The cancer papers were
published in 2007.
And this work was in rodents, not humans?
Yes, mice and rats.
What was the context of your highly cited 1999
paper on tests for endocrine disruptors that was published in
Environmental Health Perspectives (Anderson HR, et
al., "Comparison of short-term estrogenicity tests for
identification of hormone-disrupting chemicals," 107:89-108, Suppl. 1,
I mentioned before the contamination with the plastic tubes. We realized
that the assay we were using to purify the serum-borne inhibitor of the
proliferation of estrogen-sensitive cells could also be used to detect
estrogen. As the saying goes, if you've got lemons, make lemonade. Thus, we
further reasoned, "Fine, if we discovered nonylphenol with it, we can use
this method to detect all types of estrogen; so, let's make it an assay."
"These chemicals are ubiquitous in
modern life and thus very difficult to avoid,
even with conscious
We developed an assay called E-SCREEN, which we described in
Environmental Health Perspectives in 1991, together with the
discovery of nonylphenol in plastic. The 1999 paper by Anderson is a
comparison of all the tests that existed then for estrogenicity. E-SCREEN
was the oldest of all these in vitro assays and the one used most
widely, this is the "reference" assay. Most of the environmental estrogens
discovered in the '90s were identified using the E-SCREEN assay.
Why do you think that paper has been so influential
and cited so frequently?
I'm guessing, but maybe people considered the assay in this paper as one of
the most sensitive and reliable assays available. The first
Environmental Health Perspectives paper on nonylphenol and the
E-SCREEN have been cited well over 1,000 times, as has the 1993 paper with
Theo Colborn about endocrine disruptors.
How much has the thinking on endocrine disruptors
evolved in the past decade? What do we know now that we didn't know in
Things have changed a lot. In 1999, we didn't have a lot of information
about any of these chemicals. There's now a body of evidence that has led
countries like Canada, for example, to regulate exposure of BPA, so
newborns are not exposed. Denmark has done the same. I also mentioned DES
earlier, which was given during pregnancy to avoid miscarriages, and it was
then discovered that of girls born to these mothers, one in 1,000 developed
vaginal cancer. This had been an exceedingly rare cancer until then, only
seen before in elderly women. In 2006, it was reported that women exposed
to DES in utero have an increased risk of breast cancer. What our
work is showing is that this fetal period is exceedingly important, and
that exposure in utero to estrogens may have long-term
implications for offspring—significant increased risk of breast
cancer being one of them. This is one of the take-home messages of this
The other message is that chemicals that are not mutagens can cause cancer.
This finding points to a very current and important issue, namely, that
there has been a shift in the way we study cancer. While the dominant view
is still that cancer is a cell-based problem allegedly caused by mutations
in genes that control cell proliferation, we have proposed an alternative
theory. It considers cancer a problem of tissue organization comparable to
organogenesis. From this perspective, it is expected that abnormal
morphogenesis due to exposure to endocrine disruptors may increase the risk
to develop cancer.
What message would you like to give to the general
public about your research and about endocrine disruptors in
I don't believe that the general public can individually accomplish very
much just by trying to decrease their own exposure to these chemicals. Each
of us can try to do it by not using plastics, eating organic food, etc.,
but at the end of the day you don't know by how much you have decreased
your exposure (95% or 5%). These chemicals are ubiquitous in modern life
and thus very difficult to avoid, even with conscious effort. Instead, we
believe that an effective community approach is desirable.
Take water, for example. We want to be ecologically sound so we buy the
water in glass bottles rather than in plastic ones—water in the glass
bottle has less estrogen, but it won't have zero, because it depends on how
the water was filtered. Usually the holder of the filter is made out of
plastic, and some filters are still made of polycarbonate, which contains
BPA. So the fact that you buy water that doesn't come in a plastic bottle
or comes in plastic that doesn't contain BPA, doesn't mean it doesn't have
estrogens in it.
If we're going to decrease our exposure significantly, it has to be a
societal measure. We are all dealing here with a public health problem, not
an individual one. Governments have to get involved. You may reduce your
exposure by doing what I said, but you may be better off, ultimately, by
calling your representative or senator and saying "I want you to regulate
this stuff. I want to get my exposure decreased. This action will benefit
me and my community." The technology and the required know-how to tackle
the related problems are beyond a well-meant but isolated approach. This
type of effort can only happen reliably if the government assumes its
natural responsibility to take care of the welfare of its
Ana M. Soto, M.D.
Department of Anatomy & Cellular Biology
School of Medicine
Boston, MA, USA
Ana Soto's current most-cited
Indicators, with 221
Andersen HR, et al., "Comparison of short-term
estrogenicity tests for identification of
hormone-disrupting chemicals," Environ. Health
Perspect. 107: 89-108, Suppl. 1, February 1999.
Essential Science Indicators from
Ana Soto is featured in
From October 2001 (in-cites.com): In this essay,
Dr. Ana M. Soto relates the
pathways of her career that led her to become a highly
cited author in the field of Environment & Ecology.
KEYWORDS: BISPHENOL A, ESTROGEN DISRUPTORS, PLASMA-BORN
INHIBITOR, PLASTIC, NONYLPHENOL, WINGSPREAD STATEMENT,
DIETHYLSTILBESTROL, EXPOSURE, PREGNANCY, OBESITY, BEHAVIORAL
PROBLEMS, FEMALE HYPOTHALAMUS, MAMMARY GLAND, CANCER, E-SCREEN,
ESTROGENICITY TESTS, IN UTERO EXPOSURE, PUBLIC HEALTH,