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 policies.

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.

Objectives:

• 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 polymorphisms (SNPs).
  
  
• 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 SUSCEPTIBILITY

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 abnormalities.

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.

Objectives:

• 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 scleroderma.
  
  
• 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 future studies.
  
  
• Develop a list of gender-related workplace exposures that can be used to guide future testing (a partnership with NIOSH).
  
  

4.3 ANIMAL MODELS OF DISEASE SUSCEPTIBILITY

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.

Objectives:

• Evaluate transgenic and knockout animals models to assess the chemopreventive effects of nutrients and therapeutics in breast cancer development.
  
  
• 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.

Objectives:

• 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 mixtures.
  
  
• Assess the health consequences of depletion of critical micronutrients in the diet.
  
  
• Develop cost-effective ways to include diet parameters in existing epidemiologic studies.
  
  
• Improve collaboration between nutritionists and environmental health researchers.