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| Environmental Effects On
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Fertile Grounds for Inquiry: Environmental Effects on Human
Reproduction
In a world whose population exceeds 6.5 billion, declining human
fertility might not seem to be a critical problem. After all,
overpopulation has been a global concern for decades. Declining
fertility rates in more advanced nations largely reflect the
changing role of women and their rapidly growing presence in the
workplace—fertility declines may stem at least in part from the
modern tendency to delay childbearing until later in life, when
fertility naturally declines. But this doesn't explain the fact
that, according to a December 2005 report of the CDC's National
Survey on Family Growth (NSFG), the fastest-growing segment of U.S.
women with impaired fecundity (the capacity to conceive and carry a
child to term) is those under 25. The rising incidence of
fertility-impairing health factors such as obesity also likely plays
an important role. Clues from environmental exposure assessments,
wildlife studies, and animal and human studies hint at additional
factors: exposure to low-level environmental contaminants such as
pythalates, polychlorinated biphenyls (PCBs), dioxins, pesticides,
and other chemicals may be subtly undermining our ability to
reproduce.
As recognized by the American Society of Reproductive Medicine,
infertility is a biological disease that impairs a couple's ability
to achieve a viable pregnancy. It can be caused by hormonal,
ovarian, uterine, urological, and other medical factors. Known risk
factors include advanced age, being over- or underweight, lack of
exercise, smoking, alcohol and substance abuse, sexually transmitted
diseases, and poor nutrition.
According to the American Society of Reproductive Medicine, a
medical infertility cause can be identified, or perhaps only
indefinitely suggested, in approximately 90% of cases and may be
multifactorial in 25% of cases. Male factors include low sperm count
and sperm abnormalities, such as altered morphology and low
motility. Female factors stem from ovulation problems such as
premature ovarian failure (early menopause), thyroid irregularities,
polycystic ovarian syndrome, and fallopian tube obstruction.
Up to 10% of infertility cannot be explained medically. Fertility
transcends the reproductive system, notes Louis Guillette, a
professor of zoology at the University of Florida in Gainesville.
"When you talk about infertility, you literally are talking about
probably almost every system in the body—infertility is an
integrated signal of all these different systems," he explains.
"Trying to tease out which system, or more than likely what multiple
systems have been altered, leading to that phenomenon, is very tough
work."
Infertility is generally defined as occurring when a couple cannot
become pregnant after trying to conceive for at least one year (or
six months if the woman is over age 35). According to the 2001 WHO
report Current Practices and Controversies in Assisted Reproduction,
at least 80 million people worldwide are estimated to be affected by
infertility. Infertility rates range from less than 5% to greater
than 30% depending on location and how infertility is defined, with
higher rates associated with lack of medical care access. Based on
the 2005 NSFG report, approximately 12% of American couples
experienced impaired fecundity in 2002. This is a 20% increase from
the 6.1 million couples who reported an inability to have children
in 1995.
Her side. Female factors in infertility stem from
ovulation problems, thyroid irregularities, polycystic ovarian
syndrome, and fallopian tube obstruction. A trend among women to
delay starting a family also has impacted fertility rates.
Determining whether infertility is actually increasing is more
complicated than these numbers imply, however. In a paper published
in the September 2006 issue of Fertility and Sterility, David Guzick
and Shanna Swan of the University of Rochester School of Medicine
and Dentistry noted that "impaired fecundity" as defined by the NSFG
implies a decrease in fertility, but the same study also showed that
fertility, defined there as a married woman unable to become
pregnant within 12 months, has increased.
The absence of definitive information can frustrate couples
experiencing fertility problems as well as experts. "There seems to
be more to it than can be explained from traditional understanding
about impacts," says Joseph Isaacs, president and CEO of RESOLVE:
The National Infertility Association. "As a patient advocacy group,
we believe more research into environmental impacts is needed. We
fear that future generations may be at risk because of exposures to
toxic substances as early as in utero."
Foundations of Fertility
A person's reproductive potential begins shortly after his or her
own conception. Based on the embryo's chromosomal inheritance,
hormonal signals are created to direct the structure and function of
the reproductive tract. Normal development depends upon a correct
balance of androgen and estrogen signals being delivered at
appropriate times.
Fetal development can be altered by external factors as demonstrated
by the human experience with the synthetic estrogen
diethylstilbestrol (DES), prescribed to prevent miscarriage between
1947 and 1971. The drug didn't affect mothers, and it didn't lower
miscarriage incidence; in fact, it significantly increased it. It
also induced changes in the developing reproductive tract of female
offspring.
In the 15 April 1971 issue of the New England Journal of Medicine,
it was reported that daughters with prenatal DES exposure had
significantly increased incidence of vaginal cancer, which is
normally quite rare and was virtually unknown in young women prior
to DES. Later research revealed structural abnormalities of these
women's reproductive tracts and effects in their male offspring
including increased risk of cryptorchidism (undescended testes) and
low sperm counts.
The study of endocrine disruptors has raised concerns about the
reproductive effects of exposure to certain environmental compounds
that affect the endocrine system via estrogenic, androgenic,
antiandrogenic, and antithyroid mechanisms. One key report was a 12
September 1992 review in the British Medical Journal indicating
significant declines in sperm counts in many countries between 1938
and 1990. The findings were controversial because the reviewed
studies used inconsistent designs and methods. In November 1997,
however, a review published in EHP by Swan and others confirmed the
findings for males in the United States and indicated an even
sharper decline among European men. Other studies have found
declines for specific areas or no decline at all.
"I think the evidence across studies is mixed," says Russ Hauser, an
associate professor of environmental and occupational epidemiology
at Harvard School of Public Health. "Historical studies were not
designed to explore this question. It wasn't that someone set out
forty or fifty years ago to design a study to look at how semen
quality is going to change over time." There are going to be
limitations in the data because of that, he explains, so it's hard
to determine whether there is a true temporal trend. "However," he
adds, "the data suggest there are definite geographical differences
between countries and regions within countries in semen quality."
According to Niels Skakkebæk of Rigshospitalet in Copenhagen and
colleagues writing in the February 2006 issue of the International
Journal of Andrology, comparisons of sperm quality among populations
of European men have revealed that as many as 30% of young Danish
men have low sperm count, and an additional 10% may be infertile.
Denmark also has an unusually high rate of testicular cancer. Rates
have been increasing in many countries over the last 50 years, but
the Danish rate is noticeably higher; for example, four to five
times higher than the Finnish rate.
This difference prompted researchers to also examine incidence of
hypospadias (in which the urethra opens along the underside of the
penis shaft rather than the tip) and cryptorchidism. Not only did
both disorders occur more frequently in Danish boys compared with
Finnish boys, but the Danish rates had risen in recent decades.
These findings as a whole inspired Skakkebæk and colleagues to
propose, in the May 2001 issue of Human Reproduction, an overarching
disorder, testicular dysgenesis syndrome (TDS), in which
perturbation of testis development in fetal life sets the stage for
hypospadias, cryptorchidism, testicular cancer, and reduced sperm
quality.
It's reasonable to suspect there might be a female corollary to TDS.
"We have no really good reasons not to expect that women are as
sensitive to environmental chemicals as the males are," says Jens
Peter Bonde, a professor of occupational medicine at Århus
University Hospital in Copenhagen. He points out that it's easier to
study male fertility because men can easily provide sperm samples.
"That's one basic reason that there has been so much attention on
the males, but from a biological point of view one would definitely
expect that the female reproductive system might be vulnerable
also," says Bonde.
According to Guillette, another stumbling block is the accepted, but
unproven, dogma that an embryo will develop as a normal female
barring any hormonal signals to become male. "It hasn't been an area
where there have been substantial amounts of work done. There's
certainly very good work, but not the same kind of huge body of
literature that one sees about the developing testis and the male
reproductive system," he says.
His side. Male infertility can arise from factors
such as low sperm count and sperm abnormalities including altered
morphology and low motility. Up to 10% of infertility cannot be
explained medically.
One of the few epidemiologic studies to link low-level human
exposure to an environmental contaminant with a specific end point
was Swan and colleagues' investigation of prenatal phthalate
exposure, published in the August 2005 issue of EHP. Their results
suggested a subtle change in boys' development—a shortening of the
anogenital index (the distance between the anus and the scrotum,
divided by weight)—associated with prenatal exposure to several
phthalates. This finding is not a predictor of future fertility and
needs confirmation, but it is noteworthy as the first study to link
verified prenatal exposure to a specific outcome.
Animal Findings to Human Concerns?
Consequences of disrupting the normal hormone milieu have also been
observed in wildlife. Examining alligators in polluted lakes in
northern Florida, Guillette's group has observed altered function of
the ovaries and testes, smaller penis size, and abnormalities that
extend to the thyroid gland, liver, and immune system. A robust body
of literature details reproductive effects in fish, amphibians, and
reptiles related to their exposure to endocrine disruptors. Evidence
of these effects has also been seen in wild mammals such as polar
bears and seals. Laboratory animal experiments have confirmed these
wildlife findings, demonstrating that effects are not necessarily
from steroid receptor disruption, however, but may, for example, be
observed in altered synthesis and control of endogenous hormones.
The study of fertility also encompasses pregnancy, especially the
early weeks following fertilization. Early pregnancy loss is
normally quite high in humans, with an estimated 30% of pregnancies
ending in miscarriage in the first six weeks. A frequent cause of
miscarriage is aneuploidy, an incorrect number of chromosomes in the
embryo, and mouse studies have shed some light on potential
environmental contributors to this condition.
During a 1998 investigation of age-related aneuploidy rate
increases, Patricia Hunt, a professor of molecular biosciences and a
reproductive biologist at Washington State University, and her
colleagues were amazed to see a sudden rate spike in their mouse
colony. An investigation revealed correlation between damage to the
plastic mouse cages and the chromosomal abnormality. Further
scrutiny implicated bisphenol A (BPA), a suspected environmental
estrogen used in plastics manufacture, as the potential causal
agent. In a study published in the 1 April 2003 issue of Current
Biology, the researchers replicated exposure experimentally and
found that BPA derailed proper chromosome segregation during oocyte
meiosis.
An extension of this research has been completed with amazing—but
not yet published—results, and Hunt hopes that the line of inquiry
can be extended to humans. "One of the things that my new research
on BPA has made me wonder is whether or not there could be
environmental effects that would change the frequency or in specific
populations might cause noticeable differences in aneuploidy," she
says.
Hunt says it's hard to know precise numbers of human aneuploidy
cases. "We can't see the loss that occurs pre-implantation, but we
make an assumption that there's quite a bit, based on what we can
see and what we think must happen," she says. But whether there's
been an increase in aneuploidy over time cannot be known. "Human
aneuploidy studies were done mostly in the 1970s and early 1980s,"
says Hunt. "Is this aneuploidy rate the same across all populations?
To the best of our knowledge, it has been, at least in those
previous studies. But is the rate the same as it was then? We
wouldn't know. We wouldn't be able to see a dramatic increase in
chromosomally abnormal spontaneous abortions, because those kinds of
studies aren't currently under way."
The wild side. Animal and wildlife studies of
reproductive health effects, including mouse aneuploidy data, may
help inform knowledge of human effects. Although the reproductive
system is highly conserved across species, differences in exposure,
metabolism, and anatomy make direct interspecies comparisons
impossible.
Extending animal studies to human health is a challenge, though.
Genetically, the reproductive system is highly conserved across
species, making it likely that responses to inputs would be similar.
But species differences in exposure, metabolism, and anatomy
preclude making a direct comparison.
"Wildlife studies cannot be related to humans one to one," says
Guillette. "If one's looking at the functioning of the ovary, or the
functioning of the brain, and hormones, and even the genes that seem
to be involved with the proliferation or the growth of the uterus or
the development of an egg, for example, they're incredibly
conserved." He explains that if problems are seen in these animals
at a certain level, and researchers are able to identify mechanisms
that are being disturbed leading to those abnormalities, then that
raises possible concerns for humans, even if humans are exposed in a
slightly different manner.
Worldwide Concerns
Geographic differences may suggest environmental exposures that need
investigation, wrote Swan in a paper published in the February 2006
issue of Seminars in Reproductive Medicine. For example, in the
first phase of the EPA-funded Study for Future Families, of` which
Swan is the principal investigator, she and her colleagues saw
significant reductions in sperm concentration, motility, and total
motile sperm in men from Columbia, Missouri, compared with men in
New York City, Minneapolis, and Los Angeles. In an in-depth
follow-up study comparing variables between the Columbia and
Minneapolis men, the researcher discovered that the Missouri group
had had higher exposure to agricultural pesticides. Further, men
with low sperm counts were more likely to have higher urine
metabolite levels of the pesticides alachlor, atrazine, metolachlor,
and diazinon.
Another geographically based study, INUENDO, investigates risks to
human fertility from persistent environmental organochlorines. The
European Commission project centers on Arctic populations including
Swedish fishermen and the Inuit of North America and Greenland,
whose exposure to persistent organic pollutants such as PCBs and DDT
metabolites are among the highest in the world. "There are many
indications from animal studies and from wildlife studies, but very
few indications from human studies telling us whether we have a
problem or not," says Bonde, who serves as coordinator of INUENDO.
"The basic idea [behind INUENDO] was to go to places in the world
where we know that people have high level of exposures to substances
that are suspected to cause these effects in fertility," says Bonde.
"That's the reason we went to Greenland and to Sweden, where
fishermen are known to have very high exposure levels; we have other
populations that have lower levels of exposures, so we have
contrasts of exposure." Results published in March 2006 in Human
Reproduction suggested a longer time to pregnancy related to serum
concentrations of PCB and DDE in mothers and fathers. Additional
results published in the May 2006 EHP suggested an altered sex ratio
of offspring (fewer boys than would otherwise be expected) related
to PCB and DDE exposures.
Exploring multi-compound exposures is yet another challenge in
environmental epidemiology. "Individuals are exposed to many
different phthalates, a variety of persistent and non-persistent
pesticides, different patterns of PCB congeners, as well as other
chemicals," says Hauser. "How do we take all that information, based
on the chemical assessment in urine or in blood, and use that to
assign exposure for that individual to ten, or twelve, or many more
different compounds?" he says. In the April 2005 issue of EHP,
Hauser's group described evidence suggesting a relationship between
PCBs and phthalates and human sperm motility, possibly due to PCBs'
inhibiting a key enzyme in phthalate metabolism.
Genes themselves offer another platform for investigation. Hugh
Taylor, director of the Yale Center for Research in Reproductive
Biology, leads a team investigating the role of estrogen-regulated
Hox genes that direct uterine development. The researchers initially
focused on DES effects and discovered that the compound alters
expression of the Hoxa10 gene in mice, affecting the tissue type
that grows in the uterus, cervix, and vagina. Effects were triggered
only with exposure during development, but not during adulthood, and
later experiments revealed that the pesticide methoxychlor had
similar effects.
"The important thing is that these agents really seem to imprint the
expression pattern, even long after the agent is removed or there's
no longer an exposure," says Taylor. "When we have a clear-cut
animal model and know the genes that are affected, we can start to
think about evaluating that exposure by looking for changes in the
gene expression earlier and see if it has a significant effect
rather than waiting a whole generation."
A view inside. Understanding that a person's reproductive
health can be linked to the very earliest of exposures, possibly
even paternal or maternal exposures prior to conception, points up
the critical need to elucidate the health effects of environmental
chemicals.
This is a goal of research in epigenetics, the study of how genetic
messages may be edited through methylation or other means without
changing the actual DNA sequence. For example, Rebecca Sokol and
colleagues at the University of Southern California are currently
investigating whether DNA methylation in sperm might serve as a
biomarker of environmental exposure and a means of assessing male
fertility. Additionally, preliminary work at Washington State
University and at the NIEHS indicates that an epigenetic event in
one generation can "reprogram" the germline and affect later
generations. In essence, the exposures of one's great-grandparents
could still matter today.
Expanding Understanding
Previous generations' exposures would be useful information to have,
according to Hunt. "What we really need is data on generations ago,
and we simply don't have that data," she says. "We have to wait a
generation to see. We have to wait until . . . young exposed males
grow up to the point where we can assess sperm counts."
This will require prospective studies to determine early exposures.
"If you want to look at fertility—and it's difficult to do—you
ideally would want to do a study in which you start assessing
environmental exposures preconception," says Hauser. "You'd have to
identify couples who are thinking of trying to conceive and try to
understand their environmental exposures, and then follow them
forward in time."
According to Alison Carlson, a senior fellow at The Collaborative on
Health and the Environment (CHE) in Bolinas, California, another
need is very basic: tracking the incidences of infertility and
common known causes. "For us to try to make headway studying
environmental influences on fertility, it's really hard when we
don't have good baseline data," she says. "We don't know the real
incidence and prevalence rates of premature ovarian failure and
polycystic ovarian syndrome and lots of other end points that people
study. We don't know what they are, so how can we study trends and
the environmental contributions?" she asks.
A thorough exploration of environmental effects on fertility will
require the expertise of demographers, epidemiologists, clinicians,
biologists, wildlife researchers, geneticists, molecular biologists,
exposure assessment specialists, toxicologists, and others—and
discussion requires someone "to set the table," says Carlson. A
February 2005 workshop titled "Understanding Environmental
Contaminants and Human Fertility Compromise: Science and Strategy"
demonstrated multidisciplinary fervor for investigation, and a more
in-depth conference, the "Summit on Environmental Challenges to
Reproductive Health and Fertility," cosponsored by CHE and the
University of California, San Francisco, is scheduled for 28–30
January 2007. "Reproduction is such a human, deep-seated, deeply
psychically coded thing," says Carlson. "It's hard not to care about
fertility compromise."
By Julia R. Barrett
Environmental Health Perspectives, Volume 114, Number 11, November
2006
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