RESEARCH OBJECTIVES

Background

Many industrial and environmental chemicals mimic, antagonize,
or
indirectly alter the activity of hormones, particularly steroid
hormones.  These chemicals have been classified as "endocrine
disruptors" because they may bind to the estrogen and/or other
hormone receptors, either imitating the action of the hormone or
blocking its activity.  These chemicals impact endocrine glands
and
other target organs that depend on the endocrine system for
regulation.  Endocrine disruptors that have been identified are
commonly found in the environment include a variety of
herbicides,
fungicides, insecticides, nematocides and industrial chemicals
such
as dioxin, polychlorinated biphenyls (PCBs), and other
chlorinated
compounds.  Some of these chemicals have been shown to be weakly
estrogenic, antiestrogenic, antiandrogenic, or effect thyroid
hormone
function.  Exposure to these compounds prenatally or in early
postnatal life can disturb the development of the endocrine
system
and organs that respond to hormonal signals in animals.  Women,
who
were exposed to these chemicals during early development,
neonatally,
or later in life may have increased risk of endocrine dysfunction
leading to infertility, fibroids, endometriosis, early menopause,
osteoporosis, autoimmune diseases, and breast and other cancers.
Exposure to exogenous sources of estrogens and other endocrine
altering chemicals may also occur during critical biological
periods,
such as puberty and the childbearing years.  Exposures at these
times
may be related to changes in reproductive capacity and an
increase in
adverse women's health conditions in later life.  Untangling
issues
related to the timing of exposure are especially important to
understand the mechanism of action of these compounds and their
cellular effects during critical periods of a female's
development.

Women may be exposed to exogenous sources of estrogens through
the
use of pharmaceuticals containing synthetic estrogens, in the
workplace, through environmental contamination from industrial
or
agricultural processes, and dietary exposures from consuming
contaminated fish or vegetable sources of phytoestrogens.
Organochlorine compounds are ubiquitous in the environment and
their
biologically persistent nature makes their presence a potential
hazard for a long time period.  Body stores of compounds such as
DDT
and dioxins accumulate in adipose tissue, have long biological
half
lives and may be active in the body for more than 20 years.

In the exposed pregnant woman, endocrine disrupting chemicals can
be
passed through the placenta, exposing the fetus, or may be
expressed
in human milk through breast feeding, exposing the neonate to
significant levels of these chemicals.  National surveys of
pollutants in human milk document the presence of pesticides and
chemicals such as dioxins.  Exposures to certain pesticides have
been
shown to shorten the period a woman is able to lactate.
Exposures
during critical developmental periods during gestation may affect
the
development of the nervous, endocrine and immunologic systems in
the
fetus and may impact on the regulation of various physiologic
processes within the neuro endocrine axis.

Birth defects such as cleft palate and malformations in genitalia
may
be more common after exposures during gestation to these agents.
Abnormalities of growth and development have been reported in
cohorts
of children accidentally exposed in utero to endocrine disrupting
chemicals in Japan and Taiwan.  It is not clear whether these
chemicals are exhibiting direct neurotoxic and immunotoxic
effects or
whether these effects are mediated by alterations in the
endocrine
system.  More research is clearly needed to clarify these
pathways.

In certain ethnic groups, such as some Native American
populations
where fish eating predominates, pregnant women consuming
contaminated
fish have substantial exposures to organochlorine compounds that
they
pass on to the fetus.  It will be important to determine the
health
status of women and their offspring ingesting these contaminants
and
to follow up the children for future disease risk.

Research Goals

The goals and scope of this initiative are twofold.  The first
is to
encourage and support mechanistically based research on the
health
effects of endocrine disruptor concentrations that are commonly
found
in the environment.  Research would be encouraged to define the
action of these chemicals on the reproductive, immune, and
nervous
systems during critical periods of exposure (in utero, neonatal,
pubertal, reproductive aged adult, post menopausal) concentrating
primarily on women's health.  Experimental work on the cellular,
molecular, genetic, and systemic effects of exposures are
appropriate.  The second area of emphasis is to examine emerging
hypotheses in human populations that complement the recent
findings
in the laboratory and in wildlife.  Emphasis should be placed on
development and validation of methods to precisely measure these
exposures in human populations.

For the purpose of this RFA, endocrine disruptors are defined as
those chemicals that mimic or antagonize directly or indirectly
an
endocrine system.  Examples include, but are not limited to,
estrogenic pesticides, naturally occurring phytoestrogens, and
pesticides or industrial chemicals with antiestrogenic or
antiandrogenic activity.  This RFA is not intended to support
research that primarily focuses on the health effects of the use
of
oral contraceptives or menopausal replacement hormones.

Toxicologic testing of endocrine disruptors using bioassays or
alternative methods, which are necessary for regulatory purposes,
will be considered nonresponsive to this RFA.  Research on the
role
of endocrine disruptors in breast cancer development is also not
a
focus of research in this RFA.  Support for research on breast
cancer
is being provided under the National Action Plan for Breast
Cancer,
grants from the Department of Defense and other National Cancer
Institute and NIEHS initiatives.

Areas of research that are encouraged include, but are not
limited
to:

o  Studies of the effects of endocrine disrupting chemicals on
the
following health endpoints.  Health effects pertinent to
reproduction
would include endocrine dysfunction, infertility, endometriosis,
pregnancy outcomes, and lactation.  Health effects pertinent to
women's health would include fibroids, early menopause,
osteoporosis,
autoimmune diseases, and gynecologic cancers.  Of particular
interest
are studies that focus on exposures during critical periods of
development.  The development and validation of biomarkers of
endocrine disrupting exposure and early health effects are
encouraged.

o  Research that clarifies the transgenerational effects of in
utero
and neonatal/early postnatal effects of endocrine disrupting
chemicals.  This would include the occurrence of birth defects,
perturbations of growth and development, precocious puberty in
young
offspring and functional changes that are detected in later life.