This issue of PLoS Genetics contains the second of two important papers describing
the high levels of meiotic failure caused by exposure of female mice to a chemical
known as Bisphenol A (BPA) [1]. In the first article [2], Pat Hunt and her collaborators
demonstrated high levels of meiotic failure in females exposed to BPA, suggesting
that BPA exposure affects maturing oocytes. This conclusion has been recently buttressed
by an in vitro study by Can et al. [3] that demonstrates microtubule and centrosome
changes in mouse eggs exposed to BPA, leading to an increase in aneuploidy. The new
study takes this matter alarmingly further by demonstrating high levels of meiotic
disruption, including perturbed synapsis and a greatly altered distribution of recombination
events, in oocytes of fetuses being carried by mothers exposed to BPA. Part of the
importance of these twin findings is that they provide people studying mammalian meiosis
with powerful new tools for the study of the control of meiotic progression, both
during and after meiotic prophase. Understanding the mode of action of BPA during
both periods of the meiotic process may provide key insights into the regulation of
meiosis.
But, perhaps more importantly, these observations represent the most convincing demonstration
to date that environmental exposures may affect meiotic processes in mammals. Indeed,
this discovery raises the troubling issue of whether or not this chemical, or other
similar chemicals, pose a risk to meiotic fidelity in the human population, one that
might increase the already high frequency of meiotic failures. As the authors point
out, “We are exposed to BPA daily; it is a component of polycarbonate plastics, resins
lining food/beverage containers, and additives in a variety of consumer products.
More than 6 billion pounds are produced worldwide annually, and several studies have
reported levels of BPA in human tissues in the parts per billion range.”
Mammalian oocytes enter meiotic prophase in the fetal ovary, where synapsis and recombination
occur. Alteration in the number or distribution of recombination sites is well-known
to play a major role in the origin of meiotic aneuploidy, especially in younger mothers.
Thus, the findings in mice that BPA interferes with these processes raise the disturbing
possibility that the exposure of women to BPA today might not be manifest for another
generation. It is reasonable to ask whether the potential risks of ubiquitous exposure
to BPA are sufficient to warrant the regulation of human exposure or at least to call
for well-designed human studies.
Answering this question is not going to be easy for several reasons. First, when it
comes to reproducing, we humans are terribly inefficient. No less than 15%–20% of
human conceptions end in miscarriage, and an astonishing 50% of these are chromosomally
abnormal. (Compare this to the common fruit fly, whose eggs are chromosomally normal
in more than 99.9% of cases.) Against that sort of background of meiotic failure,
it may be difficult indeed to identify any environmental component that influences
the rate of nondisjunction. Another complication is that most chromosomally abnormal
conceptions are lost before birth, so that studies of live births provide an infrequent
and nonrepresentative sample of all aneuploid conceptions.
Second, attempts to identify environmental factors associated with the frequency of
chromosome errors have been almost uniformly negative [4]. Surveys of miscarriages
in very different populations find little or no difference in the rates of trisomies,
other than those that can be explained by differences in mean maternal age, suggesting
that most environmental differences have at best a weak effect on the level of meiotic
failure. Two major studies, one in New York City, which included many African-Americans
and Hispanics [5], and one in Hawaii, which included many people of Asian and Hawaiian
descent [6], gave results that were extremely similar in all respects. We can conclude
that high levels of aneuploidy are a fact of human life that is independent of race
and socioeconomic status, factors usually associated with environmental differences.
The high rate of chromosomal anomalies in our species seems to be built into our biology
and is not usually the result of the accumulation of adverse events.
Third, the strongest predictor of the frequency of meiotic error in oocytes is increasing
maternal age. Simply put, as woman age from 25 to 45 their risk of producing an oocyte
with an extra chromosome rises by more than 10-fold. Any attempt to identify an environmental
influence on the rate of meiotic missegregation will need to be teased away from concomitant
changes in this far more significant source of variation. We have witnessed a dramatic
change in reproductive patterns in virtually a single generation. Reliable birth control
methods have provided latitude, and many women are choosing to postpone childbearing
for as long as possible. As more older women reproduce, the frequency of aneuploidy
goes up. This can be best appreciated by comparing the data from two studies of human
miscarriages conducted 20 years apart (see Figure 1). The proportion of miscarriages
with trisomy has doubled, almost certainly because of the change in the maternal age
distribution. This astoundingly strong maternal-age effect raises the possibility
that any contribution of environmental agents to trisomy frequency pales beside elevated
risk of aneuploidy caused by couples choosing to postpone childbearing till later
in reproductive life.
Fourth, Hunt and her collaborators have recently published an equally intriguing paper
showing that a mutant in the mouse Smc1β gene produces an age-dependent increase in
nondisjunction that parallels that seen in human females [7]. Thus, the rate of trisomy
or susceptibility to aneugens may also be influenced by genetic variation in the human
population. If this is indeed the case, it will seriously confound any effort to assess
the effect of any given environmental component.
Fifth, and perhaps most critically, the BPA-induced damage to meiotic pairing and
synapsis observed in mice by Hunt and her collaborators in the new study would not
manifest itself for two generations. Thus, at least some of the effects of exposing
a 26-year-old woman to chemicals such as BPA might take 20–30 years to manifest themselves
in her grandchildren. A proper study of this problem would require assessing the woman's
level of chemical exposure now and maintaining those data for two to three decades.
It's a bit like wanting to do genetics on blue whales or giant sequoia trees; a curious
problem, but not one most researchers will be willing to tackle.
Despite all these difficulties, there are nonetheless consistent rumblings that the
fertility of our species is declining and that environmental exposures are at least
partly to blame. BPA belongs to the class of endocrine disruptors that have received
a lot of attention lately, but, in humans, these questions about chromosome damage
remain in murky waters. Based on his observations in the Danish population, physician
Niels Skakkebaek has championed the hypothesis that estrogenic exposures have resulted
in a testicular dysgenesis syndrome in humans that includes a drop in sperm counts
and an increase in testicular cancer and morphological aberrations of the external
genitalia [8]. However, direct links are still lacking even in the male. What about
the female? Is the incidence of female infertility increasing? The high intrinsic
rate of aneuploidy and the changing reproductive patterns of human females will conspire
against any researcher who endeavors to address the question of declining female fertility.
And yet, with all these caveats in place, and all those obvious difficulties in view,
we still need to answer the question, “Are chemicals such as BPA aneugenic in humans?”
It is obviously not going to be an easy question to answer, and even asking it is
likely to create a storm of controversy, but it is also not a question that we have
the luxury of ignoring—our fertility is fragile enough to require careful protection.
We are convinced that the studies presented by Hunt and her collaborators will inspire
scientists in both government and industry, who are far more skilled in toxicology
than ourselves, to begin the serious task of addressing these questions. We argue
that such toxicology-based questions might best be guided by the detailed molecular
studies of BPA-induced meiotic failures in the mouse.