[Pharmwaste] Environmental Effects on Human Reproduction, particularly in women

DeBiasi,Deborah dldebiasi at deq.virginia.gov
Tue Nov 7 17:12:43 EST 2006


http://www.ehponline.org/members/2006/114-11/EHP114pa644PDF.PDF

Environmental Health Perspectives, November 1, 2006
VOLUME 114 | NUMBER 11 | November 2006 * Environmental Health
Perspectives

FERTILE GROUNDS FOR INQUIRY

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
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 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 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 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 exposures.

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 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. image:
geopaul/iStockphoto

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."



Deborah L. DeBiasi
Email:   dldebiasi at deq.virginia.gov
WEB site address:  www.deq.virginia.gov
Virginia Department of Environmental Quality
Office of Water Permit Programs
Industrial Pretreatment/Toxics Management Program
Mail:          P.O. Box 1105, Richmond, VA  23218 (NEW!)
Location:  629 E. Main Street, Richmond, VA  23219
PH:         804-698-4028
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