4.0 Individual Susceptibility
GOAL: Define individual
susceptibility to environmental exposures. There is wide variation in
individual responses to environmental agents.
This variation is accounted for by:
- Differences in environmental response proteins, such as those
controlling metabolic capacity;
- Differences in DNA repair capacity;
- Co-existing diseases or infections;
- Differences in gender;
- Differences in nutritional status.
This large diversity in responsiveness among individuals
to environmental toxicants makes it difficult to determine actual risks,
particularly at the low doses to which most people are exposed.
Opportunities now exist for studies of genetic susceptibility for cancer
and other diseases in which an environmental component can be presumed.
Knowledge from such studies could, in the future, allow markers of genetic
susceptibility to be incorporated into epidemiologic studies. This, in
turn, would permit adjustment of interpretation of results to account for
genetic susceptibility, thus greatly enhancing the sensitivity and power
of these studies to detect environmental components of important diseases.
Other projects being considered are a nutrition initiative to determine
how nutritional status alters disease susceptibility, and development of
transgenic mice that carry important environmental response genes.
N E W O R
E X P A N D E D
O P P O R T U N I T I E S
4.1 ENVIRONMENTAL GENOME PROJECT
The maintenance of health and the development of disease
are determined by the complex interplay between genetic susceptibility,
environmental exposures and aging. The rapid advances in molecular genetic
technologies provide new opportunities to understand the genetic basis for
individual differences in susceptibility to environmental exposure. The
NIEHS is expanding its research program on genetic susceptibility to
environmentally-associated diseases through a new Environmental Genome
Project (EGP). This project will use technology developed by the Human
Genome Project to identify genetic variants (polymorphisms) of
environmental disease susceptibility genes in the U.S. population. By
identifying those genetic variants that affect individual response to
environmental agents, scientists can better predict health risks and
assist regulatory agencies in the development of environmental protection
While many genes that play a role in susceptibility to
environmental exposure have been identified, the polymorphisms of these
genes have not been systematically sought, identified, or reported. The
goal of the Environmental Genome Project is to identify polymorphisms that
confer altered sensitivity or resistance to specific environmental
factors. The Project's ultimate aim is to provide markers of genetic
susceptibility that, when, incorporated into epidemiologic studies,
greatly enhance the ability of researchers to identify the environmental
components of human disease.
The NIEHS Environmental Genome Project is a
multi-disciplinary, collaborative effort, involving several other NIH
institutes as well as the Department of Energy (DOE) and other federal
agencies. Examples of categories that include environmental response genes
are those that control or affect:
- Xenobiotic metabolism and detoxification;
- Hormone metabolism;
- Receptor-ligand interaction;
- DNA repair;
- Cell cycles;
- Cell death;
- Immune and inflammatory responses;
- Nutritional factors;
- Oxidative processes;
- Signal transduction systems.
The Project will make available a central database of the
polymorphisms to support both functional studies of alleles and
population-based studies of disease risk. Population-based epidemiological
studies are central to the identification of both the genetic alleles and
the environmental exposures that cause disease, and represent an integral
component of the Environmental Genome Project. The Project will include
additional susceptibility genes as they are discovered.
- Identify the genetic variants of environmental response genes that
are relevant to enhanced or reduced susceptibility (i.e., have a
functional significance) to toxins, beginning with single nucleotide
- Identify and characterize the functional significance of
polymorphisms in environmental response genes that are also implicated
in individual susceptibility to aging (a partnership with NIA).
- Define the mechanisms of genetic susceptibility to tobacco-induced
cancers (a partnership with NCI).
- Provide EGP-generated information to researchers as quickly as
possible by supporting a website, GeneSNPS, that integrates sequencing
information on genes of interest as it becomes available.
- Ensure the ethical integrity of the EGP by ongoing evaluation of the
ethics of the project and the information generated.
- Define the role of environmental response genes in the development
of prostate cancer (a partnership with NCI and NIDDK).
4.2 GENDER-RELATED DIFFERENCES IN
MEN AND WOMEN CAN DIFFER IN
THEIR RESPONSE TO ENVIRONMENTAL AGENTS.
Men and women are prone to unique gender-based health problems. For
example, women appear to be at higher risk for autoimmune diseases,
develop heart disease at a later stage of life than men, but do not have
as good a prognosis as men undergoing the same heart surgeries. We need to
define the basic genetic and physiologic differences between men and women
that account for variation in disease risk. Of particular concern is the
role of chemicals in the environment that possess estrogenic or
endocrine-disrupting activity and their possible contribution to an
increased incidence of various diseases in hormone target tissue. There is
some evidence supporting the hypothesis that those endocrine-active
compounds, especially those that bioaccumulate, are related to increases
in breast cancer, endometriosis, and uterine fibroids in women and, in
men, decreased sperm count and quality, and reproductive tract
There are several promising lines of investigation that may help
account for these gender differences. These include the difference in the
hormonal milieu of males and females, differences in interactions among
the neurological, endocrine, and immune systems, and differences in
metabolic pathways and capacities.
- Define how estrogenic compounds affect homeostatic conditions in
tissues such as bone, liver, circulatory, ovarian, uterine, and mammary
tissues. The recent development of mouse models with estrogen receptor
deficiencies [-ERKO and
-ERKO] could be used to help define important
estrogenic pathways and roles in both males and females.
- Define how environmental endocrine-disrupting compounds interfere
with biological processes in males and females and how health endpoints
differ by gender.
- Define differences in neurological, endocrine, and immune systems
between males and females, how these differences change with life stage
such as puberty or pregnancy, and how these differences alter
susceptibility to environmental triggers of diseases such as thyroid
autoimmune disease, systemic lupus erythematosus, and
- Define how men and women differ in their ability to metabolize and
detoxify common environmental agents.
- Investigate if early fetal exposures account for some of the
variation in disease risk seen between men and women.
- Continue the NTP protocol in which routine toxicologic testing is
done in both sexes of rodents so that gender differences in toxicant
responsiveness can be identified and the basic mechanisms for these
differences can be studied.
- Develop biomarkers of susceptibility that could be incorporated into
- Develop a list of gender-related workplace exposures that can be
used to guide future testing (a partnership with
4.3 ANIMAL MODELS OF DISEASE
The study of many important human diseases, including the
molecular basis of their pathology, has been hampered by lack of relevant
laboratory models that duplicate these diseases. Recently developed
techniques for introducing human genes into animals (transgenic models) or
that eliminate a gene (knockout models) offer powerful tools for assessing
how a genetic variant enhances disease susceptibility or how the lack of a
particular gene affects disease onset. The NIEHS is evaluating current
animal models for their relevance in understanding environmentally-induced
diseases and creating new models that can help define the role of
environmental agents in disease initiation and progression.
- Evaluate transgenic and knockout animals models to assess the
chemopreventive effects of nutrients and therapeutics in breast cancer
- Use estrogen-receptor knockout mice to evaluate the probable effects
of environmental endocrine disruptors, which may interact with these
receptors to cause reproductive tract cancers, infertility, uterine
fibroids and other diseases.
- Develop mouse models for the breast cancer susceptibility genes,
BRCA1 and BRCA2.
4.4 NUTRITION INITIATIVE
NUTRITION CAN HAVE AN
IMPORTANT BEARING IN DISEASE RISKS, INCLUDING A PERSON'S
SUSCEPTIBILITY TO ENVIRONMENTAL AGENTS.
Diet can play a strong role in individual susceptibility to
environmental agents. For example, calcium can compete with charged metals
such as lead for uptake in the body. Thus people with high-calcium diets
absorb less lead from their environment than do those on low-calcium
diets. Diet also affects cancer risk. People on low-protein diets have a
reduced risk of aflatoxin-induced liver cancer than do those on
higher-protein diets. Evidence also suggests that dietary phytoestrogens
might reduce risks of sex hormone-related diseases such as breast cancer,
prostate cancer, and osteoporosis. Maternal dietary deficiency in folate,
an important micronutrient, has been linked with increased risk of neural
tube defect in newborns.
In fact, it has been suggested that deficiencies of micronutrients such
as folate could cause genetic instability, which would have significant
implications in terms of risks from environmental exposures. For these
reasons, the NIEHS is studying nutritional components of disease risks and
is planning a Nutrition Initiative to enhance this work. The initiative
will improve understanding of the molecular basis of nutrition while
studying nutrients in the context of complex mixtures. It will also
address the risks and benefits of high supplementation levels,
particularly in the area of those antioxidants that may become
pro-oxidants at high levels. This Initiative will also be used to develop
communication and future collaborations between environmental health
scientists and nutritionists.
- Convene a national workshop to evaluate research needs in nutrition
and implement recommendations.
- Evaluate (1) the effect of both high and low levels of antioxidants
on oxidative stress and free radical formation; (2) the effect of
high-calorie or high-protein diet on cancer and other chronic diseases;
and (3) the effect of phytoestrogens on breast and prostate cancers as
well as risk of osteoporosis.
- Determine the best ways to study nutritional elements as complex
- Assess the health consequences of depletion of critical
micronutrients in the diet.
- Develop cost-effective ways to include diet parameters in existing
- Improve collaboration between nutritionists and environmental health