PA, KE Koehler, M Susiarjo, CA Hodges, A Ilagan, RC Voigt, S Thomas,
BF Thomas and TJ Hassold. 2003. Bisphenol A exposure causes
meiotic aneuploidy in the female mouse. Current
Biology 13: 546-553.
Small prospective study in people finds similar effects
research links a common contaminant, bisphenol
A, to an error in cell division called aneuploidy
that causes spontaneous miscarriages and birth defects in people,
including Down Syndrome, and is also associated with a series of
cancers. Hunt et al. report that in mice, bisphenol A causes
aneuploidy even at extremely low doses.
here for a detailed explanation of aneuploidy
is a condition in which cells have the wrong number of chromosomes.
It is thought to result from errors in chromosome alignment
during cell division.
microscopic photographs to the left show two examples of chromosomal
alignment during cell division. The upper is normal. Chromosomes
(stained red) are aligned properly. The lower figure shows
alignment in a cell exposed to bisphenol A. Chromosomes are
scattered throughout the cell. When cell division is completed
by the lower cell, chromosomes are unlikely to be distributed
properly between the two daughter cells, resulting in aneuploidy.
from Hunt et al. 2003
results open up a dramatic new front on the study of human aneuploidy
and point toward possible interventions that may help avoid many
human birth defects. Hunt's work provides strong new support for
measures to reduce
exposures to bisphenol A as quickly as possible.
Hunt and Terry Hassold are two of the world's leading researchers
on aneuploidy, and in using animal experiments to understand
the causes and impacts of aneuploidy in people. Their laboratories
were engaged in collaborative research testing proposed reasons
for why aneuploidy, and thus Down Syndrome, is more common in
the babies of older women.
the midst of these experiments, Hunt witnessed an unexplained, eight-fold
surge in aneuploidy . Careful study revealed that a lab technician
had used a particularly harsh form of detergent to wash the water
bottles and the cages.
to companion paper describing the accident that
first suggested bisphenol A causes aneuploidy
out of polycarbonate plastic, which itself is manufactured with
bisphenol A, the bottles leached bisphenol A into the water and
thus into the mice in the experiments. The cages were made out of
they also leached bisphenol A after exposure to the detergent. Hunt
describes the details of the accident and the detective work to
figure out what had happened in
a companion paper. Now in this paper she tests BPA's impact
at low levels, instead of the high levels that were produced by
the harsh detergent.
did they do? In the first round of experiments, Hunt et
al. examined chromosomal aberrations in the oocytes
of mice raised in new polyphthalate carbonate cages
exposed to two different dilutions of the
that had caused aneuploidy in the accident, and compared them to
the oocytes of females raised in cages made from materials not containing
bisphenol A. All animals drank from glass water bottles (no bisphenol
chose to measure the rate of a chromosomal aberration called "congression
failure." This aberration is readily and efficiently detected
by examining prepared oocytes in the microscope, and Hunt's earlier
work has strongly indicated it is involved in the causation of aneuploidy.
Importantly, congression failure is known to increase in older human
oocytes, consistent with the increased frequency of aneuploidy in
the oocytes of older women.
did they find?
et al. found that oocytes from female mice living in the
polyphthalate carbonate cages with the heaviest exposure to the
detergent had the highest rate of congression failure.
repeated the experiment with the polyphthalate carbonate water bottles,
and found that drinking water from bottles that had been degraded
by detergent also increased the rate of chromosomal aberrations.
then repeated the experiments again, this time with a type of water
bottle made only out of polycarbonate. This was to eliminate the
possibility that the effects above were caused by the polyester
carbonate instead of the bisphenol A. Mice drinking water out of
these bottles also showed a highly significant increase in chromosomal
showed that bisphenol A was present in water samples exposed to
carbonate water bottles. Those bottles with more severe damage leached
more bisphenol A.
confirmed that the effect was caused by bisphenol A, Hunt et
al. then focused on the amount of BPA necessary to cause damage.
To do this, they performed a series of experiments providing different
oral doses of BPA to juvenile female mice and then determining the
frequency of congression failure.
the first of these experiments, mice were treated with 20, 40 or
100 nanograms/g body weight (parts per billion) for 6-8 days prior
to analyzing the effects on their oocytes.
seen in the graph to the right, the rate of congression failure
increased significantly with dose of BPA. An effect was apparent
at the lowest dose tested.
from Hunt et al., Table 3
the final round of experiments, Hunt et al. asked what
effect the duration of exposure had on oocyte health. To do this,
they exposed juvenile female mice to 20 ng/g (the lowest dose, above)
for 3, 5 or 7 days and then examined their oocytes. In each of the
treatments, the exposed animals had a higher frequency of congression
failure, although only in animals exposed for 7 days was the effect
do they conclude?
et al. state unequivocally that they do not know with scientific
certainty whether the effect of BPA they show on mice occurs in
humans. "Nevertheless, the meiotic
program is extraordinarily conserved, and the results of our
studies in mice are disturbing because brief exposures during the
final stage of oocyte growth were sufficient to cause significant
increases in meiotic abnormalities."
are also uncertain about the mechanism by which BPA causes this
effect. They suggest it is most likely to be an indirect one, via
BPA's estrogenic impact on the cellular environment in which the
oocyte is undergoing meiosis, rather than one in which BPA acts
directly on chromosomes in meiosis.
these uncertainties and the ongoing debates about what might be
safe levels of BPA exposure, Hunt et al. point out that
the effects they are seeing in mice are at "exposure levels
close to or even below those considered 'safe,' and that recent
studies indicate that current human exposure levels are within this
range. Studies from Germany
and Japan support
this conclusion; data from the US are not yet available.
fact, the levels in human tissue from Germany and Japan were similar
to the levels in delivered orally to Hunt's mice; because of the
way that BPA moves into the body, the blood stream and the womb,
the doses the mouse oocytes experienced were virtually certainly
much lower than those measured in people.
et al. conclude "Clearly, the possibility that BPA
exposure increases the likelihood of genetically abnormal offspring
is too serious to be dismissed without further study."
does it mean? With this new research, Hunt et al.
open up a dramatic new front for inquiries into the causes of aneuploidy.
Their results prove that bisphenol A causes aneuploidy in mice,
at extremely low levels.
is an important cause of birth defects in people. Most aneuploid
fetuses, however, never even make it that far along and instead
are spontaneously aborted. Hence any insights into the causes of
aneuploidy, especially insights that might also suggest steps that
can be taken to prevent this chromosomal error, will be extremely
et al.'s data join a growing body of literature confirming
low level effects of bisphenol A, far beneath the levels currently
deemed safe by regulatory authorities. BPA is now implicated in
adverse effects on prostate
development and prostate
tumors, breast tissue development,
on the rate
of sexual maturation and even on adipogenesis
(suggesting a role in obesity).
have also revealed why early controversies took place, and specifically
why efforts by industry to replicate certain low level results failed
(and indeed, that one purported failure was upon close unbiased
analysis a confirmation; statistical misrepresentation superficially
suggested it was a failure).
together, these results provide significant new support for efforts
to begin reducing human exposure to BPA now, without waiting
for final resolution of remaining scientific uncertainties. Pathways
of human exposure to bisphenol A have not been studied carefully.
Uses of BPA derived chemicals to line food cans, seal children's
teeth, and manufacture baby bottles and other food-containing consumer
products are obvious sources.