Lung Response to Inhaled Highly Toxic Chemicals
The purpose of this program announcement (PA) is to investigate acute mucosal irritation
in the upper and lower respiratory tract occurring after aerosol exposure to toxic
chemicals with the goals to: 1) minimize initial injury promptly, 2) retard and ameliorate
progressive mucosal irritation or inflammation, and 3) offer prophylaxis against pulmonary
edema, if created by acute lung injury.
The National Heart, Lung, and Blood Institute (NHLBI) and the NIEHS are concerned
about the U.S. population’s potential inhalational exposure to aerosolized harmful
chemicals, possibly liberated as part of bioterrorism attacks against assembled groups
of the civilian populace. Therefore, research is needed on how humans and relevant
animal models respond to inhaled toxic chemicals. The goals of this PA are to develop
better bio-protective therapies and to minimize respiratory injury and illness.
Many volatile toxic chemicals are produced and utilized in industry. Some of these
are considered hazardous when they are inhaled in ambient air, introduced into food
and water supplies, or make contact with body skin surfaces. Among toxic industrial
materials that are considered highly hazardous are ammonia, chlorine, formaldehyde,
hydrogen cyanine, fuming nitric acid, phosgene, and sulfur dioxide.
From a pulmonary perspective, inhalation exposure to some of these highly hazardous
and irritative chemicals induces initial choking, inability to breathe deeply, and
excessive output of secretions in the nose and throat from acute irritation. Other
chemicals that have neurological effects—including such nerve agents as sarin, certain
organophosphate-based pesticides, soman, and others—enter the body through absorption
from the airways.
The NHLBI has a limited portfolio of existing research applicable to the respiratory
exposures discussed. This PA will stimulate and build research against airborne chemical
threats that affect the upper and lower respiratory tract, and will suggest potential
therapy to prevent or limit development of pulmonary edema, which is a major complication
of airway chemical irritation. Examples of research topics that are of interest include
the following: 1) investigating mechanisms of chemical injury (including minimal threshold
levels to establish injury) and subsequent effects at a cellular and molecular level
causing airway inflammation or hypersensitivity; 2) identifying host responses to
initial or immediate effects, and to long-term low-level exposure effects; 3) assessing
systematic amount or dose of chemical absorbed from the airways; 4) developing preexposure
preventive treatment or early use of antidotes; and 5) devising therapeutic strategies,
especially if acute alveolar lung injury occurs and pulmonary edema ensues; specific
therapies to prevent onset of pulmonary edema are sought. Development of physical
protection (including facial masks and respirators) or environmental detectors for
documenting exposure are not within the purview of this announcement.
The NIEHS encourages applications to study chemical exposures relating to civilian
terrorism attack, industrial sabotage, or large-scale accidental exposure to toxic
chemicals. Applications should focus on research that will develop or support development
of treatment strategies that prevent or minimize respiratory track injury following
exposure or that maximize repair of injured tissue. To be considered responsive to
the NIEHS, the chemical exposure should be acute.
Multiple routes of chemical exposure (respiratory tract, skin, eye, digestive tract)
are acceptable if injury resulting from the exposure is specific to the lung. Use
of animal models and appropriate human biological specimens is encouraged. Examples
of research topics for the NIEHS include but are not limited to the following: 1)
the relationship between exposure, route of exposure, and absorbed dose to onset and
magnitude of respiratory symptoms in a young, adult, and senior model; 2) cellular
and molecular mechanisms of lung injury following acute chemical exposure, including
induction of mucosal injury, pulmonary inflammation, acute alveolar injury, and pulmonary
edema; 3) cellular and molecular mechanisms of lung tissue repair following acute
chemical-induced lung injury; 4) development of postexposure strategies that prevent
or minimize lung injury, including early use of antidotes; and 5) development of therapeutic
strategies that promote lung tissue repair and that prevent or treat pulmonary edema.
This funding opportunity will use the NIH R01 award mechanism. As an applicant, you
will be solely responsible for planning, directing, and executing the proposed project.
This funding opportunity uses just-in-time concepts. It also uses the modular as well
as the nonmodular budget formats (see http://grants.nih.gov/grants/funding/modular/modular.htm).
Specifically, if you are submitting an application with direct costs in each year
of $250,000 or less, use the modular budget format described in the PHS 398 application
instructions. Otherwise, follow the instructions for nonmodular research grant applications.
Applications must be prepared using the most current PHS 398 research grant application
instructions and forms. The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html
in an interactive format. For further assistance contact GrantsInfo at 301-435-0714
or by e-mailing
GrantsInfo@nih.gov. Applications must have a Dun & Bradstreet Data Universal Numbering
System (DUNS) number as the universal identifier when applying for federal grants
or cooperative agreements. This number can be obtained by calling 1-866-705-5711 or
through the website at http://www.dnb.com/us/.
Applications must be mailed on or before the receipt date described at http://grants.nih.gov/grants/funding/submissionschedule.htm.
The complete version of this PA is available online at http://grants.nih.gov/grants/guide/pa-files/PA-05-058.html.
Contact: Herbert Y. Reynolds, Division of Lung Diseases, NHLBI, 6701 Rockledge Dr,
Two Rockledge Ctr, Ste 10018, MSC 7952, Bethesda, MD 20892 USA, 301-435-0218, fax:
301-480-3557, e-mail:
Reynoldh@nhlbi.nih.gov; Sally S. Tinkle, Cellular, Organ and Systems Pathobiology
Branch, Division of Extramural Research and Training, NIEHS, 111 TW Alexander Dr,
PO Box 12233, MD EC-23, Research Triangle Park, NC 27709 USA, 919-541-5327, fax: 919-541-5064,
e-mail:
tinkle@niehs.nih.gov. Reference PA No. PA-05-058
In Utero Exposure to Bioactive Food Components and Mammary Cancer Risk
In utero exposures are important determinants of some cancers occurring in children
and young adults. For example, exposure to ionizing radiation in utero promotes childhood
leukemia, and maternal use of diethylstilbestrol during pregnancy has been linked
to clear-cell adenocarcinoma of the vagina in these women’s daughters. In addition,
maternal diets—specifically the consumption of vegetables, fruits and protein—are
linked to decreased risk of childhood leukemia.
The prenatal period is critical in the development of the mammary gland. During this
time, the mammary gland is in a largely undifferentiated state, making it particularly
vulnerable to a host of environmental forces. Inappropriate nutritional status or
exposure to environmental chemicals and the accompanied alteration in growth and endocrine
homeostasis may permanently change the fetus’s structure, physiology, and metabolism,
thereby predisposing it to various diseases in later life including mammary cancer.
Epidemiological studies suggest that altering the intrauterine nutritional status
can increase mammary cancer risk. Failure of the materno-placental supply line to
satisfy fetal nutrient requirements can result in a range of fetal adaptations and
developmental changes. Birth weight is a gross surrogate marker for shifts in a host
of metabolic processes. Many, but not all, studies reveal a positive relationship
between increased birth weight and breast cancer risk. Likewise, other indicators
of fetal size such as increased placental weight and birth length are positively correlated
with breast cancer risk in the offspring. Recent studies suggest that birth weight
is independent from neonatal growth patterns and the timing of puberty as a risk factor
for breast cancer.
In addition to nutrition, the hormonal environment in the womb may play an important
role in programming lifelong risk for breast cancer in female offspring. A reduction
in circulating levels of estrogens and insulin-like growth factor 1 (IGF-1) and/or
elevated levels of progesterone, androgens, human chorionic gonadotrophin, IGF-1 binding
proteins 1 and 3, cortisol, and insulin have been associated with reduced risk. Such
hormonal and growth factor changes are observed during preeclampsia. Maternal preeclampsia
has been associated with a reduction in the female offspring’s later risk for breast
cancer after adjustment for a variety of potential confounders.
Proliferation of primitive ductal structures in the newborn breast leads to branching
and terminal end buds (TEBs). The expansion of TEBs represents an opportunity for
malignant transformation because they contain pluripotent mammary stem cells. In fact,
in utero exposures that bring about an increase in TEBs coincide with increased mammary
carcinogenesis. Evidence exists that providing maternal diets that contain elevated
amounts of n-6 polyunsaturated fatty acids (PUFAs) and genistein not only increased
TEBs but also reduced the differentiation of TEBs to lobuloalveolar units. These diets
also increased subsequent chemically induced mammary cancer in the offspring. In addition,
prenatal exposures to environmental agents such as bisphenol A or dioxin results in
alteration in the development of the mammary gland that may predispose to the development
of cancers later in life. Some of this response may relate to changes in hormonal
and growth factor status, including status of estrogen and IGF-1.
Greater estrogen exposure throughout a woman’s life has been identified as a major
risk factor for the development of breast cancer. In utero exposures to the mammary
gland can achieve concentrations 10–100 times the estrogen levels occurring later
in life. Dietary factors, such as genistein and fat, that influence estrogen exposure
to the fetus are related to subsequent cancer risk in several model systems. However,
the response may not be totally explained by estradiol, because diets rich in n-3
fatty acids, when fed to pregnant rats, elevate this hormone but reduce mammary cancer
incidence in the offspring.
It is possible that intrauterine exposure to other hormones or environmental hormone
mimics or antagonists may also affect breast cancer susceptibility. Androgen exposure
in utero may confer long-term protection against breast cancer by antagonizing the
effects of estrogens on fetal breast ductal development. Dietary fatty acids, phytoestrogens,
alcohol, and lycopene are among the various bioactive food components reported to
influence androgen concentrations. Environmental agents with estrogenic agonist or
antagonist activity may also alter gene expression during development, which may lead
to functional deficits later in life that predispose one to cancer development. Thus
there is the need for studies focusing on uncovering the mechanisms responsible for
the protective and detrimental effects on breast cancer risk of exposure to bioactive
food components and other environmental agents in utero. These studies should attempt
to more comprehensively address the changes in all potentially relevant pregnancy
hormones and growth factors.
Although the effects of in utero exposure to dietary components have been inadequately
examined, considerable evidence exists for their ability to modify IGF-1 concentrations
and mammary cancer susceptibility postnatally. Postnatal caloric restriction decreases
IGF-1 and decreases mammary tumor growth and metastases. Furthermore, postnatal soy
phytochemicals combined with green tea synergistically inhibited mammary tumor growth
and depressed serum IGF-1 levels in mice. Future studies are warranted to determine
whether in utero exposure to dietary manipulations that modulate IGF-1 expression
will influence subsequent breast cancer risk.
Maternal nutritional status can also alter the epigenetic state of the fetal genome
and imprint gene expression levels with lifelong consequences. Loss of imprinting
is the silencing of active imprinted genes or the activation of silent imprinted genes,
and is one of the most common epigenetic changes associated with the development of
a wide variety of tumors. Several lines of evidence support the relationship between
maternal nutrition and epigenetic changes in their offspring. Epigenetic changes may
provide a molecular mechanism for the impact of maternal nutrition or environmental
chemical exposures on postnatal disease susceptibility and deserves future research.
Investigators may choose from the full range of preclinical approaches. The use of
genetically engineered animal models including transgenic or knockouts, such as those
available through the Mouse Models of Human Cancer Consortium (MMHCC, http://emice.nci.nih.gov/),
is encouraged. Studies that apply new high-throughput genomic, epigenomic, proteomic,
and metabolomic technologies to determine how dietary and/or environmental chemical
exposures in utero influence adult breast cancer susceptibility are encouraged.
This funding opportunity will use the NIH investigator-initiated research project
grants (R01) and exploratory/developmental (R21) award mechanisms. Illustrative examples
for the development of R01 or R21 applications include, but are not limited to, the
following: 1) utilization of transgenic and knockout mouse models of human mammary
cancer to identify molecular sites of action of bioactive food components in cancer
prevention; 2) examination of the role of moderate caloric restriction in utero on
hormone concentrations and mammary cancer prevention; 3) evaluation of synergistic
effects of exposure to bioactive food components in utero and subsequent mammary cancer
risk; 4) evaluation of imprinted genes after exposure to bioactive food components
in utero and subsequent mammary cancer risk; 5) examination of the role of in utero
exposures to environmental agents such at mycotoxins, heterocylic amines, bisphenol
A, phthalates, and other agents with endocrine-like agonist or antagonist activity
and subsequent mammary cancer risk; and 6) examination of the interaction of in utero
exposures to bioactive food components and exposures to environmental agents in the
etiology of breast cancer later in life.
No set-aside funds are available for this funding opportunity. Applicants may request
up to 5 years of support for R01 awards with costs appropriately tailored to the proposed
work. No limit is set on the costs requested by R01 applicants. An R21 applicant may
request a project period of up to 2 years with a combined budget for direct costs
of up to $275,000 for the 2-year period. Normally, no more than $200,000 may be requested
in any single year.
Because the nature and scope of the proposed research will vary from application to
application, it is anticipated that the size and duration of each award will also
vary. Although the financial plans of the involved institutes and centers provide
support for this program, awards pursuant to this funding opportunity are contingent
upon the availability of funds and the receipt of a sufficient number of meritorious
applications.
Applications must be prepared using the most current PHS 398 research grant application
instructions and forms. The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html
in an interactive format. For further assistance contact GrantsInfo at 301-435-0714
or by e-mailing
GrantsInfo@nih.gov. Applications must have a Dun & Bradstreet Data Universal Numbering
System (DUNS) number as the universal identifier when applying for federal grants
or cooperative agreements. This number can be obtained by calling 1-866-705-5711 or
through the website at http://www.dnb.com/us/.
Applications must be received by the dates listed at http://grants.nih.gov/grants/funding/submissionschedule.htm.
The complete version of this PA is available at http://grants.nih.gov/grants/guide/pa-files/PA-05-059.html.
Contact: Cindy D. Davis, Division of Cancer Prevention, National Cancer Institute,
6130 Executive Blvd, EPN Rm 3159, MSC 7328, Bethesda, MD 20892-7328 USA, 301-594-9692,
fax: 301-480-3925, e-mail:
davisci@mail.nih.gov; Mary Frances Picciano, Office of Dietary Supplements, 6100 Executive
Blvd, Rm 3B01, Bethesda, MD 20892-7517 USA, 301-435-3608, e-mail:
PiccianM@mail.nih.gov; Jerry Heindel, Cellular, Organs, and Systems Pathobiology Branch,
Division of Extramural Research and Training, NIEHS, PO Box 12233, Research Triangle
Park, NC, 27709 USA, 919-541-0781, fax: 919-541-5064, e-mail:
heindelj@niehs.nih.gov. Reference PA No. PA-05-059