Environmental Health Perspectives  [Printer-friendly version]
November 1, 2006


[Rachel's introduction: Are chemicals interfering with human
reproduction? 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.]

By Julia R. Barrett

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

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 animportant 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 phthalates, 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. image: Sebastian Kaulitzki/Shutterstock

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

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 Skakkebaek 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 Skakkebaek 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 Arhus 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.
image: Christian Darkin/Shutterstock

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 preimplantation, 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. image: Getty Images

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

Exploring multicompound exposures is yet another challenge in
environmental epidemiology. "Individuals are exposed to many different
phthalates, a variety of persistent and nonpersistent 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

"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. image:

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."